Science of Pain

SCIENCE OF PAIN

This page intentionally left blank

SCIENCE OF PAIN

Editors Dr Allan I. Basbaum

University of California, San Francisco, CA, USA

Dr M. Catherine Bushnell McGill University, Montreal, Quebec, Canada

AMSTERDAM BOSTON HEIDELBERG LONDON NEW YORK OXFORD PARIS SAN DIEGO SAN FRANCISCO SINGAPORE SYDNEY TOKYO

Academic Press is an imprint of Elsevier The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK 525 B Street, Suite 1900, San Diego, CA 92101-4495, USA First edition 2009 Copyright ª 2009 Elsevier Inc. All rights reserved The following article is a US Government work in the public domain and is not subject to copyright: PSYCHOPHYSICS OF PAIN No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the publisher Permissions may be sought directly from Elsevier’s Science & Technology Rights Department in Oxford, UK: phone (þ44) (0) 1865 843830; fax (þ44) (0) 1865 853333; email: [email protected]. Alternatively you can submit your request online by visiting the Elsevier web site at http://elsevier.com/locate/permissions, and selecting Obtaining permission to use Elsevier material Notice No responsibility is assumed by the publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein, Because of rapid advances in the medical sciences, in particular, independent verfication of diagnoses and drug dosages should be made British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Library of Congress Catalog Number: 2008930958 ISBN: 978-012-374625-2 For information on all Elsevier publications visit our website at books.elsevier.com Printed and bound in Slovenia 07 08 09 10 11 10 9 8 7 6 5 4 3 2 1

Working together to grow libraries in developing countries www.elsevier.com | www.bookaid.org | www.sabre.org

Contents Introduction

ix

1

The Adequate Stimulus R D Treede, Johannes Gutenberg-University, Mainz, Germany

1

2

Pain Theories F Cervero, McGill University, Montreal, QC, Canada

5

3

Anatomy of Nociceptors S Mense, Institut fu¨r Anatomie und Zellbiologie, Universita¨t Heidelberg, Heidelberg, Germany

11

4

Molecular Biology of the Nociceptor/Transduction M S Gold, University of Pittsburgh, Pittsburgh PA, USA M J Caterina, Johns Hopkins School of Medicine, Baltimore, MD, USA

43

5

Zoster-Associated Pain and Nociceptors H Maija, Helsinki University Hospital, Helsinki, Finland

75

6

Ectopic Generators M Devor, Hebrew University of Jerusalem, Jerusalem, Israel

83

7

Sodium Channels John N Wood, University College London, London, UK

89

8

Physiology of Nociceptors M Ringkamp and R A Meyer, Johns Hopkins University, Baltimore, MD, USA

97

9

Itch E Carstens, University of California, Davis, CA, USA

115

10

Thermal Sensation (Cold and Heat) through Thermosensitive TRP Channel Activation Makoto Tominaga, National Institutes of Natural Sciences, Okazaki, Japan

127

11

The Development of Nociceptive Systems G J Hathway and M F Fitzgerald, University College London, London, UK

133

12

Appropriate/Inappropriate Developed ‘‘Pain’’ Paths Jens Schouenborg, Lund University, Lund, Sweden

147

13

Pain Control: A Child-Centered Approach Patricia A McGrath, The University of Toronto, Toronto, ON, Canada

155

14

Assaying Pain-Related Genes: Preclinical and Clinical Correlates V E Scott, R Davis-Taber, and P Honore, Global Pharmaceutical Research and Development, Abbott Park, IL, USA

165

15

Evolutionary Aspects of Pain E T Walters, University of Texas at Houston, Medical School, Houston, TX, USA

175

v

vi Contents

16

Redheads and Pain J S Mogil, McGill University, Montreal, QC, Canada

185

17

Autonomic Nervous System and Pain Wilfrid Ja¨nig, Physiologisches Institut, Christian-Albrechts-Universita¨t zu Kiel, Germany

193

18

Sympathetic Blocks for Pain A Sharma, Columbia University, New York, NY, USA J N Campbell and S N Raja, Johns Hopkins University, Baltimore, MD, USA

227

19

Sprouting in Dorsal Root Ganglia E M McLachlan, Prince of Wales Medical Research Institute, Randwick, NSW, Australia

237

20

Vagal Afferent Neurons and Pain W Ja¨nig, Christian-Albrechts-Universita¨t zu Kiel, Kiel, Germany

245

21

Sex, Gender, and Pain R B Fillingim, University of Florida College of Dentistry, Community Dentistry and Behavioral Science Gainesville, FL, USA

253

22

Neurotrophins and Pain Lorne M Mendell, State University of New York, Stony Brook, NY, USA

259

23

Morphological and Neurochemical Organization of the Spinal Dorsal Horn A Ribeiro-da-Silva, McGill University, Montreal, QC, Canada Y De Koninck, Centre de recherche Universite´ Laval Robert-Giffard, Que´bec, QC, Canada

279

24

Spinal Cord Physiology of Nociception A R Light, University of Utah, Salt Lake City, UT, USA S Lee, Korea Institute of Science and Technology, Seoul, Korea

311

25

What is a Wide-Dynamic-Range Cell? D Le Bars, INSERM U-713, Paris, France S W Cadden, University of Dundee, Dundee, UK

331

26

Spinal Cord Mechanisms of Hyperalgesia and Allodynia T J Coderre, McGill University, Montreal, QC, Canada

339

27

Glycine Receptors H U Zeilhofer, University of Zurich, Zurich, Switzerland

381

28

Pain Following Spinal Cord Injury R P Yezierski, Comprehensive Center for Pain Research and The McKnight Brain Institute, University of Florida, Gainesville, FL, USA

387

29

Long-Term Potentiation in Pain Pathways J Sandku¨hler, Medical University of Vienna, Vienna, Austria

401

30

Immune System, Pain and Analgesia H L Rittner, H Machelska, and C Stein, Charite´ – Universita¨tsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany

407

31

Mechanisms of Glial Activation after Nerve Injury L R Watkins, E D Milligan, and S F Maier, University of Colorado at Boulder, Boulder, CO, USA

429

32

Trigeminal Mechanisms of Nociception: Peripheral and Brainstem Organization D A Bereiter, University of Minnesota, Minneapolis, MN, USA K M Hargreaves, University of Texas Health Science Center, San Antonio, TX, USA J W Hu, University of Toronto, Toronto, ON, Canada

435

33

Migraine – A Disorder Involving Trigeminal Brainstem Mechanisms P J Goadsby, University of California, San Francisco, CA, USA

461

34

Tooth Pain M R Byers, University of Washington, Seattle WA, USA

469

Contents vii

35

Ascending Pathways: Anatomy and Physiology D Lima, Universidade do Porto, Porto, Portugal

477

36

Dorsal Columns and Visceral Pain W D Willis Jr. and K N Westlund, University of Texas Medical Branch, Galveston, TX, USA

527

37

Visceral Pain G F Gebhart and K Bielefeldt, University of Pittsburgh, Pittsburgh, PA, USA

543

38

Irritable Bowel Syndrome S Bradesi and E A Mayer, University of California, Los Angeles, CA, USA I Schwetz, Medical University, Graz, Austria

571

39

Pain in Childbirth U Wesselmann, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

579

40

Urothelium as a Pain Organ L A Birder, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

585

41

The Brainstem and Nociceptive Modulation M M Heinricher, Oregon Health & Science University, Portland, OR, USA S L Ingram, Washington State University, Vancouver, WA, USA

593

42

Emotional and Behavioral Significance of the Pain Signal and the Role of the Midbrain Periaqueductal Gray (PAG) K Keay and R Bandler, University of Sydney, Sydney, NSW, Australia

627

43

The Thalamus and Nociceptive Processing J O Dostrovsky, University of Toronto, Toronto, ON, Canada A D Craig, Barrow Neurological Institute, Phoenix, AZ, USA

635

44

Psychophysics of Sensations Evoked by Stimulation of the Human Central Nervous System S Ohara, C A Bagley, H C Lawson, and F A Lenz, Johns Hopkins Hospital, Baltimore, MD, USA

655

45

Nociceptive Processing in the Cerebral Cortex R D Treede, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany A V Apkarian, Northwestern University, Chicago, IL, USA

669

46

Phantom Limb Pain H Flor, Central Institute of Mental Health, Mannheim, Germany

699

47

Human Insular Recording and Stimulation F Mauguie`re, Lyon I University and INSERM U879, Bron, France M Frot, INSERM U879, Bron France J Isnard, Lyon I University and INSERM U879, Bron, France

707

48

The Rostral Agranular Insular Cortex L Jasmin, Neurosurgery and Gene Therapeutics Research Institute, Los Angeles, CA, USA P T Ohara, University of California, San Francisco, CA, USA

717

49

Descending Control Mechanisms K Ren and R Dubner, University of Maryland, Baltimore, MD, USA

723

50

Diffuse Noxious Inhibitory Controls (DNIC) D Le Bars, INSERM U-713, Paris, France J C Willer, INSERM U-731, Paris, France

763

51

Fibromyalgia R Staud, University of Florida, Gainesville, FL, USA

775

52

Pain Perception – Nociception during Sleep G J Lavigne, Universite´ de Montre´al, Montreal, QC, Canada K Okura, Tokushima Graduate School, Tokushima, Japan M T Smith, John Hopkins Medical School, Baltimore, MD, USA

783

viii Contents

53

Pharmacological Modulation of Pain A Dray, AstraZeneca Research and Development, Montreal, PQ, Canada

795

54

Forebrain Opiates J-K Zubieta, University of Michigan, Ann Arbor, MI, USA

821

55

Neuropathic Pain: Basic Mechanisms (Animal) M H Ossipov and F Porreca, University of Arizona, Tucson, AZ, USA

833

56

Animal Models and Neuropathic Pain I Decosterd and T Berta, University of Lausanne, Lausanne, Switzerland

857

57

Neuropathic Pain: Clinical R Baron, Christian-Albrechts-Universita¨t Kiel, Kiel, Germany

865

58

Neurogenic Inflammation in Complex Regional Pain Syndrome (CRPS) F Birklein, University of Mainz, Mainz, Germany M Schmelz, University of Heidelberg, Mannheim, Germany

901

59

Complex Regional Pain Syndromes R Baron, Christian-Albrechts-Universita¨t Kiel, Kiel, Germany

909

60

Poststroke Pain T S Jensen and N B Finnerup, Aarhus University Hospital, Aarhus, Denmark

919

61

Psychophysics of Pain R H Gracely, University of Michigan Health System, VAMC, Ann Arbor, MI, USA E Eliav, UMDNJ-New Jersey Dental School, Newark, NJ, USA

927

62

Consciousness and Pain M Devor, Hebrew University of Jerusalem, Jerusalem, Israel

961

63

Assessing Pain in Animals S W G Derbyshire, University of Birmingham, Birmingham, UK

969

64

Psychological Modulation of Pain D D Price, A Hirsh, and M E Robinson, University of Florida, Gainesville, FL, USA

975

65

The Placebo Effect F Benedetti, University of Turin Medical School, Turin, Italy

1003

66

Hypnotic Analgesia P Rainville, Universite´ de Montre´al, Montreal, QC, Canada I Marc, Universite´ Laval, Quebec City, QC, Canada

1009

Index

1017

Introduction ‘‘There is no coming to consciousness without pain.’’ Carl Gustav Jung

It has been argued that pain, unlike audition, vision, somatosensation, and olfaction, is not a primary sense, but instead is more of an emotional experience. Most researchers of pain, however, consider pain to be a complex perception evoked by noxious stimuli. Pain is probably far more complicated than the other perceptual modalities described in this series. For example, in the setting of tissue or nerve injury, where pain is persistent, the stimulus that evokes pain can change. In fact, under these conditions innocuous stimuli can readily evoke the perception of pain. But even these unusual characteristics do not capture the features that make pain among the most complex of perceptions. The International Association for the Study of Pain defines pain as ‘‘An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.’’ In other words, although there is a very discrete anatomical and physiological basis for the detection and transmission of messages that are interpreted as painful, what makes the experience of pain so special is that there is always a profound emotional quality to the experience. Pain in general, and pain research in particular, is especially exciting as it brings together elements of so many disciplines. This volume is comprehensive. It includes a wealth of information on the molecular biology, anatomy, physiology, and biochemical bases of ‘pain’, both in the normal and injury setting. But this volume also addresses the critical cognitive component of the pain experience, including some of the most provocative cerebral imaging studies that for the first time are providing insights into the gestalt of brain activity that occurs when pain is experienced. There are chapters on the pharmacological basis of the placebo, on the utility of hypnosis for the treatment of pain, and even an essay on consciousness and pain. This is not a ‘how to treat’ clinical textbook. Nevertheless, the editors are advocates of the new mantra in the field, namely that chronic pain is not a symptom of disease, but rather is a disease entity itself, a disease of nervous system function. Therefore, in addition to covering the fundamentals of acute ‘pain’ processing, from the nociceptor to cortical activation, we also cover, in depth, the changes that occur in the setting of injury, including molecular, structural, and biochemical alterations in the properties of nociceptors and central nervous system pathways. Some of the particularly intractable clinical pain conditions are discussed. These chapters not only provide insights into pathophysiology but also clues to pain management. Of course, a variety of compendia have recently appeared, and many also provide comprehensive reviews of the field. With this in mind, the editors have made a concerted effort to produce a final product that is different. Too often the excitement that epitomizes the field of pain research is buried within, or indeed omitted from, the typical edited book. Some textbooks include the proverbial ‘box’ that highlights an interesting topic, but these are generally very limited. We wanted to bring these topics to the forefront. Our approach is to include, in association with each major chapter, at least one or two cameos that illustrate fascinating and provocative areas of basic and clinical neuroscience that intersect the study of pain. A few years ago we knew almost nothing about the cortical mechanisms that underlie the pain experience. Today some scientists, albeit the minority, believe that cortical imaging can provide an objective measure of the pain experience. A few years ago, the tetrodotoxin-resistant subtype of voltage-gated sodium channel, NaV1.8, ix

x Introduction

was considered the Holy Grail for the next breakthrough in pain management. How fast things change. The discovery that a loss of function mutation of NaV1.7 underlies a condition of congenital insensitivity to pain and that a gain of function mutation underlies the excruciatingly painful condition of erythromelalgia has dramatically altered the focus, not only of the science community but also of the pharmaceutical industry. The pace of discovery in pain research is indeed remarkable. We hope that this volume conveys the excitement inherent in this discovery process and, most importantly, that it stimulates the next generation of basic and clinical scientists to unravel the mystery of the pain experience. Allan I. Basbaum and M. Catherine Bushnell

1 The Adequate Stimulus R D Treede, Johannes Gutenberg-University, Mainz, Germany ª 2009 Elsevier Inc. All rights reserved.

1.1 1.2 References

Noxious Stimulus Nociceptive Stimulus

1 3 3

Glossary nociception The processes of encoding and processing of noxious stimuli by the nervous system. nociceptive stimulus An actually or potentially tissue damaging event that is encoded by primary nociceptive afferents. Although actual or potential tissue damage is the common denominator of those stimuli that may cause pain, there are some types of tissue damage that are not detected by any afferents, and thus do not cause pain. Therefore, not all noxious stimuli are adequate stimuli of nociceptive afferents. The adequate stimuli of nociceptors are termed nociceptive stimuli, which is a subset of noxious stimuli.

nociceptor A primary afferent nerve fiber that is capable of encoding noxious stimuli. All non-nociceptive afferents (e.g., tactile receptors, warm receptors) do respond to noxious stimuli (mechanical or thermal, respectively), because these stimuli are way above their respective thresholds. But only nociceptors are capable of encoding the relevant properties of those stimuli (e.g., sharpness, heat intensity in the painful range). noxious stimulus An actual or potential tissue damaging event. This was found to be the common denominator of those stimuli that may cause pain. But there are some types of tissue damage that are not detected by any afferents, and thus do not cause pain. See nociceptive stimulus.

The term adequate stimulus (Kandel, E. R. et al., 2000) is used in sensory physiology to describe the class of environmental phenomena that requires the least amount of energy in order to elicit a percept mediated by a particular sensory system, for example, a visual percept can be elicited by a punch to the eye, but light from a television screen needs much less energy for this purpose. The implication from such observations in subjective sensory physiology is that the receptive organs of each sensory system are specialized to detect a corresponding class of environmental phenomena (i.e., photoreceptors in the eye are specialized to detect photons). It was difficult to transfer this concept to the perception of pain and to the nociceptive system. Many different stimuli may cause pain (e.g., pin prick, burn injury, freeze injury, and inflammation), none of which needs particularly low amounts of energy. Sherrington is credited with identifying the common denominator of those stimuli as being tissue damage (in Greek: vo

Noxe) or environmental phenomena that threaten to cause such damage. Hence, the adequate stimulus to elicit pain is traditionally called a noxious stimulus. It may be defined as follows.

1.1 Noxious Stimulus A noxious stimulus is an actual or potential tissue damaging event. Noxious stimuli may belong to thermal, mechanical, or chemical modalities of energy supply. Therefore, the sensory organs of the nociceptive system, free nerve endings of thinly myelinated A fibers, and unmyelinated C fibers in the skin and most other tissues, have a characteristic property: most of them are polymodal, that is, they respond to more than one modality of stimulus energy. Some nociceptive nerve endings, particularly those of A fibers, are specialized to be most sensitive to one particular stimulus modality (e.g., either heat or pin prick). The differential 1

2 The Adequate Stimulus

sensitivity spectra of nociceptive afferents suggest that pain quality may be encoded by a similar population code in the nociceptive system as taste quality in the gustatory system (Treede, R. D. et al., 1998). Polymodality is not the result of a primitive nonspecific responsivity to tissue damage. Instead, it is mediated by specialized signal transduction pathways, some of which have been elucidated at the molecular level ( Julius, D. and Basbaum, A. I., 2001). One member of the gene family of transient receptor potential channels (TRPV1), for example, is specifically activated by moderate heat stimuli, low tissue pH, and a class of irritant substances called vanilloids. For most inflammatory mediators, specific receptor molecules are present in the membranes of nociceptive nerve endings. The topic of this volume of the Handbook of the Senses is pain. The taxonomy of the International Association for the Study of Pain (IASP) defines pain as, ‘‘An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage’’ (Merskey, H. et al., 1979). This definition implicitly refers to the adequate stimulus as identified by Sherrington, in its extended form including potential tissue damage rather than calling for outright tissue damage. There are two good reasons for this extension. First, a system that only responds after tissue damage has occurred, cannot subserve a warning function for the organism. The sensory system that mediates pain sensation (the nociceptive system), however, provides even primitive organisms with an array of protective reflexes that can flexibly respond to threatening environmental challenges. Such a system needs to be sensitive enough to signal impending tissue damage before it occurs. Second, although primary nociceptive afferents, the sensory organs of the nociceptive system, encode different intensities of manifest tissue damage as graded action potential discharge rates (Raja, S. N. et al., 1999), the nociceptor activation thresholds were found to be clearly lower than the intensity needed to damage the skin. In humans as well as many animal species, heating the skin to above 40  C, cooling to below 30  C, or punctate pressure around 1–5 bars activates nociceptors, but none of these stimuli damages the skin. In fact, for most people these stimuli are not even painful. The relatively low peripheral nociceptor activation thresholds allow the nociceptive system to subserve its warning function in a highly flexible and plastic way. The peripheral input can be shut down by descending inhibition, if there is an a priori reason to ignore the warning signal. The system can also enhance its response to the warning signal by enhancing the

efficacy of its central synapses. This process is called central sensitization and may be considered to be one of the phylogenetically oldest mechanisms of learning and memory (Woolf, C. J. and Walters, E. T., 1991). Primary nociceptive afferents may also enhance their responsiveness to their adequate stimuli, a process called peripheral sensitization (Raja, S. N. et al., 1999). Both peripheral and central sensitization contribute to the warning function of the nociceptive system. As a warning system, the nociceptive system has gaps in its sensitivity: there are some types of tissue damage that are not detected by any afferents, and thus do not cause pain or any protective behavior. This is a well-known phenomenon in internal organs such as the liver or the brain, where a malignant tumor may cause extensive damage without being noticed by the patient. There is an even more common phenomenon of tissue damage that goes unnoticed by the nociceptive system: damage by ultraviolet radiation (Figure 1). The pain of sunburn always comes too late, after the skin has

Figure 1 The concept of the adequate stimulus to activate the nociceptive system and to elicit pain can be illustrated by this scene. Ultraviolet radiation causes tissue damage, but this noxious stimulus is not detected by the nociceptive nerve endings. Only the inflammatory response of the skin leads to adequate activation of nociceptive nerve endings via chemical mediators, which serve as nociceptive stimuli.

The Adequate Stimulus 3

already been damaged. This pain does not signal the initial damage but the body’s response by an inflammatory reaction. The ensuing peripheral and central sensitization of the nociceptive system lead to pronounced hyperalgesia of the injured skin to heat and mechanical stimuli, which then serves to protect the skin from further damage. These observations have led to the introduction of a new term, nociceptive stimulus (Cervero, F. and Merskey, H., 1996).

by the visual system and auditory stimuli are encoded by the auditory system. However, a full appreciation of our senses goes beyond these aspects of sensory physiology (Bieri, P., 1995; Metzinger, T., 2000): seeing comprises more than vision, hearing comprises more than audition, and pain comprises more than nociception. This is reflected in the definition of pain as given above that does not relate to any objective observable measure, but refers to the subjective experience of the person in pain.

1.2 Nociceptive Stimulus A nociceptive stimulus is an actual or potential tissue damaging event that is encoded by primary nociceptive afferents. In summary, the adequate stimulus to activate the receptive organs of the nociceptive system consists of either actual or potential tissue damage (noxious stimulus). However, not all noxious stimuli are detected by the nociceptive system. Therefore, the adequate stimulus for this system in the strict sense is that subset of noxious stimuli that can be encoded by the nociceptive system (nociceptive stimuli). It is not unusual for a sensory system to encode only a part of the range of environmental phenomena that its receptive organs are specialized for: visual stimuli consist of a restricted range of wavelengths of electromagnetic waves, and auditory stimuli consist of a restricted frequency range of pressure waves in the air. Likewise, nociceptive stimuli consist of a restricted range of actually or potentially tissue-damaging events. Linguistically, the term nociceptive stimulus may appear to be a little odd, as it also implies reception rather than just stimulation, but for exactly that reason it fits well into the broader system of terms in sensory physiology. According to the concept of the adequate stimulus, nociceptive stimuli are encoded by the nociceptive system, just as visual stimuli are encoded

References Bieri, P. 1995. Pain a Case Study for the Mind–Body Problem. In: Pain and the Brain: From Nociception to Cognition (eds. B. Bromm and J. E. Desmedt), pp. 99–110. Raven Press. Cervero, F. and Merskey, H. 1996. What is a noxious stimulus? Pain Forum 5, 157–161. Julius, D. and Basbaum, A. I. 2001. Molecular mechanisms of nociception. Nature 413, 203–210. Kandel, E. R, Schwartz, J. H, and Jessell, T. M 2000. Principles of Neural Science. 4th edn., p. 414. McGraw-Hill. Merskey, H., Albe-Fessard, D., Bonica, J. J., Carmon, A., Dubner, R., Kerr, F. W. L., Lindblom, U., Mumford, J. M., Nathan, P. W., Noordenbos, W., Pagni, C. A., Renaer, M. J., Sternbach, R. A., and Sunderland, S. 1979. Pain terms: a list with definitions and notes on usage. Recommended by the IASP subcommittee on taxonomy. Pain 6, 249–252. Metzinger, T. 2000. The Subjectivity of Subjective Experience: A Representationalist Analysis of the First-Person Perspective. In: Neural Correlates of Consciousness: Empirical and Conceptual Questions (ed. T. Metzinger), pp. 285–306. MIT Press. Raja, S. N., Meyer, R. A., Ringkamp, M., and Campbell, J. N. 1999. Peripheral Neural Mechanisms of Nociception. In: Textbook of Pain (eds. P. D. Wall and R. Melzack), 4th edn, pp. 11–57. Churchill Livingstone. Treede, R. D., Meyer, R. A., and Campbell, J. N. 1998. Myelinated mechanically insensitive afferents from monkey hairy skin: heat response properties. J. Neurophysiol. 80, 1082–1093. Woolf, C. J. and Walters, E. T. 1991. Common patterns of plasticity contributing to nociceptive sensitization in mammals and aplysia. Trends Neurosci. 14, 74–78.

This page intentionally left blank

2 Pain Theories F Cervero, McGill University, Montreal, QC, Canada ª 2009 Elsevier Inc. All rights reserved.

References

From the beginning of scientific enquiry there have been two opposing views on the biological meaning of pain. One view proposes that pain is a sense similar to vision or hearing, a component of the sensory repertoire of most animals that warns us of impending damage, gives accurate information to the brain about injuries, and helps us to heal. The inclusion of pain in The Senses: A Comprehensive Reference, alongside vision, hearing, or olfaction shows that this view is persuasive. But there has always been an alternative interpretation of pain that denies it being a sense like vision or hearing and attaches to both pain and its opposite pleasure fundamental roles in shaping the emotions and behaviors of the individual. Pain is seen as a trigger of emotional states, a behavioral drive, and a highly effective learning tool. Aristotle, who was the originator of this view, made it very clear: there are only five senses – vision, hearing, touch, taste, and smell. Pain and pleasure are not senses but passions of the soul. Whether or not pain is a sense like the others is not just an academic exercise. The experimental paradigms used to study the nervous system can be fundamentally different depending on the theoretical approach to the object of the study. If pain is regarded as a sense, like vision or hearing, then we will look for sensors that are activated selectively by painful stimuli and for sensory pathways in the brain and spinal cord that carry pain information much in the same way as we identify photoreceptors in the retina and a visual pathway to the cortex. This approach has generated an interpretation of pain mechanisms known as the specificity theory, which maintains that there are elements of the peripheral and central nervous system (CNS) specifically and exclusively dedicated to the processing of pain-related information. However, if pain is not a sense like vision or hearing, then we do not need to look for a specific neural machinery for its processing but for patterns of activation, spatial or temporal, in neurons that do not

9

necessarily have time-locked responses to painful stimuli. If pain is a passion of the soul then we need distributed networks and interactive parallel processing and not a pain pathway. This view has been articulated throughout the last 100 years as the pattern theory of pain, denying the existence of dedicated sensory elements for pain processing and attributing the perception of pain to interactions between patterns of impulses in nonspecific neuronal networks. The influential gate theory of pain (Melzack, R. and Wall, P. D., 1965) is the best contemporary example of such an interpretation. The specificity theory of pain was a natural development of the Doctrine of Specific Nerve Energies put forward by the German physiologist Johannes Mu¨ller in the nineteenth century. The basic proposal of Mu¨ller’s doctrine is that each sensory modality is the result of the activation of a specific neural system in the brain. If we are able to perceive touch it is because we have a subset of cells in our peripheral and CNS that respond to touch; if an animal can perceive infrared light or an electromagnetic field then it must have a subset of neurons capable of sensing and processing these stimuli. As he put it: ‘‘Sensation is not the conduction of a quality or state of external bodies to consciousness, but the conduction of a quality or state of our nerves to consciousness, excited by an external cause’’ (Mu¨ller, J., 1835–1840). At the end of the nineteenth century, von Frey M. (1895) extended Mu¨ller’s doctrine to pain sensation, thus reinforcing a strict sensory interpretation of pain. He proposed that the fine nerve endings of unmyelinated afferents were the pain receptors in the periphery and that there was a specific pain pathway taking their signals to the brain. This influential proposal is responsible for the well-known model of pain mechanisms often found in textbooks whereby a pain receptor in the periphery is activated by a noxious stimulus and sends impulses to the spinal cord and from there to the thalamus and cortex via a crossed spinothalamic 5

6 Pain Theories

animal models of inflammatory and pathological pain (see Cervero, F., 2005 for a recent discussion on the gate theory). The considerable amount of new information about pain mechanisms gathered in the last 40 years has relegated the specificity versus pattern argument to a secondary role. It is now well established that there are specialized sensors in the skin, muscles, and viscera of most animals that are activated exclusively by stimuli that cause injury and whose excitation leads to the sensation of pain (Belmonte, C. and Cervero, F., 1996). It is also known that pain cannot be evoked, under normal circumstances, by changing the patterns of activation of tactile sensory receptors (Ochoa, J. and Torebjork, E., 1983; 1989). There are also substantial data showing that there are neurons in the spinal cord and brain driven mainly or exclusively by nociceptive stimuli (Hunt, S. P. and Mantyh, P. W., 2001). However, there is also significant experimental evidence in favor of plasticity in the nociceptive sensory channel and of the existence of dynamic processes that can alter profoundly the functional properties of peripheral nociceptors and of nociceptive central neurons (Treede, R. D. et al., 1992; Hunt, S. P. and Mantyh, P. W., 2001; Julius, D. and Basbaum, A. I., 2001). It has also been demonstrated that following a peripheral injury or inflammation, the activation of tactile afferents from uninjured skin can evoke pain sensations (see Cervero,

pathway. In other words, a relatively simple and straight forward pain pathway (Figure 1(a)). In contrast, the pattern theory of pain represents a development of the Aristotelian concept of pain as a passion of the soul and was articulated in modern form by Goldscheider A. (1898) at the turn of the nineteenth century. The basic proposal is that pain is the result of intense stimulation of peripheral receptors, regardless of modality and tissue origin. For the pattern theory the neural substrate of pain perception consists of sequences of impulses in peripheral and central neurons that lead to pain sensations when certain spatial and temporal patterns of activity are produced. The emphasis of this interpretation is on patterns of neural activity evoked in the brain by a painful stimulus. In the 1960s, the gate theory of pain proposed a specific neural mechanism located at the first afferent relay in the spinal cord to illustrate how patterns of impulses in sensory receptors could lead to the modulation of pain sensation (Figure 1(b)). The gate theory emphasized the dynamic and plastic components of pain sensations and drew attention to pain modulation as opposed to an interpretation of pain exclusively as an alarm system. It also focused the attention of many researches on the clinical aspects of pain, away from physiological pain, which contributed a surge of studies on the effects of neuropathic lesions and on the development of

(a)

(b)

Central control Gate control system

L

– + +

Input

T

SG

Action system

–

S

– +

Figure 1 (a) Descartes’ drawing of a pathway-oriented pain mechanism. The fire activates pain nerves in the foot of the child and these signals are transmitted to the brain where they are reflected into motor nerves that draw the foot away from the fire. (b) Schematic diagram of the gate theory of pain mechanisms. The diagram shows the presynaptic interaction model between large (L) and small (S) afferent fibers and the key role of substantia gelatinosa (SG) neurons controlling the activity of transmission (T) cells. (a) From Descartes, R. 1664. L’homme. Chez Jacques Le Gras. (b) Reprinted with permission from AAAS from Melzack, R. and Wall, P.D. 1965. Pain mechanisms: a new theory. Science 150, 971–979.

Pain Theories 7

100 Hyperalgesia Pain sensation

F. and Laird, J. M. A., 1996). Clearly, a point has been reached where neither a strict specificity nor a pattern interpretation can account for all that it is known about pain mechanisms. We now realize that there are many different forms of pain (acute, traumatic, inflammatory, and neuropathic) and that pain is a dynamic process that cannot be explained with a single theory or a unique mechanism. One of the most striking expressions of the dynamic nature of pain sensation is its lack of adaptation. A continuous and uniform visual or auditory stimulus leads to sensory adaptation; we simply stop feeling this stimulus after a few seconds or minutes. However, the sensation of pain not only does not adapt to a continuous noxious stimulus but gets progressively worse so that, after a few minutes of persistent stimulation with a relatively mild painful stimulus, the sensation becomes unbearable. This change in pain sensitivity generates a state of pain amplification or hyperalgesia that is normally triggered and maintained by a persistent noxious stimulus but that can, under pathological circumstances, appear without an obvious cause so that the normal relationship between injury and pain is lost. Hyperalgesia and allodynia are the main symptoms of many chronic pain states and is the property of pain sensation that makes it particularly unpleasant and often unbearable. In psychophysical terms a hyperalgesic state is represented by a leftward shift that occurs, following a peripheral injury, in the curve that relates stimulus intensity to pain sensation (Cervero, F. and Laird, J. M. A., 1996) (Figure 2). This shift causes the lower portion of the pain curve to fall in the innocuous stimulus intensity range (allodynia or pain produced by an innocuous stimulus) whereas the top portion shows an increased pain sensation to noxious stimuli (hyperalgesia proper or increased pain sensitivity to a noxious stimulus). Allodynia and hyperalgesia provide protective mechanisms to the organism, preventing the individual from stimulating an injured area and in so doing helping the healing process. There are two forms of hyperalgesia: primary and secondary. Primary hyperalgesia is an increased pain sensitivity that occurs at the site of injury and it is the consequence of nociceptor sensitization, that is, the increased firing of peripheral nociceptors at the site of injury whose excitability has been increased by a number of locally released sensitizing agents. These sensitized nociceptors send enhanced afferent discharges to the CNS thus evoking increased pain from the primary hyperalgesic area and contributing

75 Injury

50

Normal pain

Allodynia 25 0 Innocuous

Noxious Stimulus intensity

Figure 2 Diagram illustrating the changes in pain sensation induced by injury. The normal relationship between stimulus intensity and the magnitude of pain sensation is represented by the curve at the right-hand side of the figure. Pain sensation is only evoked by stimulus intensities in the noxious range (the vertical dotted line indicates the pain threshold). Injury provokes a leftward shift in the curve relating stimulus intensity to pain sensation. Under these conditions, innocuous stimuli evoke pain (allodynia). Reproduced From Cervero, F. and Laird, J. M. A. 1996. Mechanisms of touch-evoked pain (allodynia): a new model. Pain 68, 13–23, used with permission.

to the alterations in central processing that are, in turn, responsible for secondary hyperalgesia (Treede, R. D. et al., 1992). Secondary hyperalgesia is defined as an increased sensitivity to pain occurring in areas adjacent or even remote to the site of injury. For instance, following an injury to the hand an area of hyperalgesia may develop covering the entire arm or an inflammation of the gastrointestinal tract or the bladder may produce an area of hyperalgesia in the abdominal or pelvic regions. Secondary hyperalgesia is the result of an alteration in the processing by the CNS of impulses from low-threshold mechanoreceptors, such that, these impulses are able to activate nociceptive neurons and evoke pain. This central alteration is initially triggered and later maintained by the enhanced afferent discharges from the primary hyperalgesic area (Treede, R. D. et al., 1992). Different forms of pain are mediated by different mechanisms which participate in various ways in the generation of pain and hyperalgesia (Cervero, F. and Laird, J. M. A., 1991; Klein, T. et al., 2005). Generally speaking we can identify three different forms of pain taking into account the relationship between noxious stimulus and pain sensation: nociceptive, inflammatory, and neuropathic (also called phase 1, 2, and 3 pains by Cervero, F. and Laird, J. M. A., 1991) (Figure 3). Nociceptive pain refers to the processing

8 Pain Theories

CNS

Pain

Phase 1 Brief

Brief injury Phase 2

Inflammation

+

Persisting

Phase 3 Nerve or CNS damage

+

Abnormal

Figure 3 Diagram showing the three models of pain processing for the three main types of pain (nociceptive, inflammatory, and neuropathic or phases 1, 2, and 3). See text for further explanation. Reproduced from Cervero, F. and Laird, J. M. A. 1991 One pain or many pains? A new look at pain mechanisms. News Physiol. Sci. 6, 268–273, used with permission.

of brief noxious stimuli; inflammatory pain is the consequence of prolonged noxious stimulation leading to tissue damage; and neuropathic pain is the consequence of neurological damage, including peripheral neuropathies and central pain states. Nociceptive pain is a protective sensation needed for the survival and well-being of the individual. The mechanisms subserving the processing of brief noxious stimuli can be viewed as a fairly simple pathway that carries impulses in peripheral nociceptors centrally toward the thalamus and cortex and leads to brief pain perception. In contrast, injury and tissue damage evoke an inflammatory reaction as part of the healing process and generate a pain state different from nociceptive pain as the response properties of the various components of the nociceptive system change. These changes include nociceptor sensitization and recruitment of populations of previously unresponsive receptors. In turn, CNS neurons show an amplification of their excitability expressed as increases in receptive field size and greater spontaneous and evoked firing. All of these changes indicate that the CNS has moved to a new, more excitable state as a result of the noxious input generated by tissue injury and inflammation. Under these conditions, an immediate correlation between

discharges in peripheral nociceptors and pain perception is lost. Neuropathic pain syndromes are the consequence of damage to peripheral nerves or to the CNS itself and produce pain sensations well outside the range of the sensations produced by the normal nociceptive system, even after serious peripheral injury or inflammation. These include spontaneous pain, greatly reduced pain thresholds, and mechanical allodynia. Neuropathic pain states are characterized by an almost complete lack of correlation between peripheral noxious stimuli and pain sensation and are produced by neurological lesions that cause abnormal impulse activity generated in nerve sprouts, neuromas, or in dorsal root ganglion cells, ephaptic coupling between adjacent nerve fibers and abnormal responses of peripheral nociceptors and CNS neurons. Nociceptive and inflammatory pains are symptoms of peripheral injury, whereas neuropathic pain is a symptom of neurological disease. Whereas the specificity theory can explain fairly well the simpler forms of pain, such as a pin prick or the acute pain of a minor burn, complex pain experiences, including hyperalgesic states require substantial peripheral and central plasticity such that low-intensity stimuli evoke pain (i.e., secondary

Pain Theories 9

CNS Nociceptor sensitization

Aδ/C N

Aβ

Synaptic strengthening by incoming afferent volleys

LT Secondary hyperalgesia

Aδ/C Activation of nociceptive neurons by LT afferents

N

Figure 4 Diagram representing the basic mechanisms of primary and secondary hyperalgesia and the three key processes implicated in their generation. Primary hyperalgesia is produced by the stimulation of nociceptors connected to A- and C-afferent fibers which activate nociceptive CNS pathways (N). Secondary hyperalgesia is produced by stimulation of tactile receptors connected to A-afferents which normally activate low-threshold (LT) pathways but that as a consequence of the amplification of the nociceptive input from the injured area can now access nociceptive neurons (N). See text for further explanation.

hyperalgesia or touch-evoked allodynia). It is very likely that both specific and nonspecific nociceptive systems participate in the generation and maintenance of different pain states. We can currently identify three key processes in the neurobiological approach to the mechanisms of pain and hyperalgesia: (1) the process of nociceptor activation and sensitization, responsible for the initial signaling of injury and the peripheral changes in the nociceptive system induced by a noxious stimulus; (2) the process of central amplification of nociceptive signals, known as central sensitization, generated by synaptic strengthening of connections between CNS neurons and responsible for the enhanced excitability that accompanies persistent pain states; and (3) the process whereby activity in low-threshold sensory receptors from undamaged peripheral areas can access the nociceptive system and evoke pain sensations and hyperalgesic states (e.g., touch-evoked pain, tactile allodynia) (Figure 4). The analysis of these three processes supersedes interpretations of pain based on a specificity or pattern approach as all three contain elements that require the existence of groups of neurons dedicated to the processing of nociceptive signals as well as the expression of functional changes induced by afferent activity. Several of these changes can lead to major alterations of pain sensitivity through quite separate mechanisms. For instance, touch-evoked pain can be

the result of sensitization of peripheral nociceptors leading to decreases in their activation threshold or be mediated by a purely central mechanism whereby low-threshold mechanoreceptors access nociceptive neurons. The emphasis has moved from theoretical interpretations based on a specific pain channel or on patterns of impulses to the in depth analysis of the functional processes that may cause the different pain and hyperalgesic states. Neither the specificity nor the pattern theories have been able to provide workable models for all forms of pain sensation. They still offer a useful theoretical framework for some of our observations but the weight of work has shifted to studying those processes that will help the development of effective pain relief therapies.

References Belmonte, C. and Cervero, F. 1996. Neurobiology of Nociceptors. Oxford University Press. Cervero, F. 2005. The Gate Theory Then and Now. In: The Paths of Pain (eds. H. Mershey, J. De Loeser, and R. Dubner), pp. 33–48. IASP Press. Cervero, F. and Laird, J. M. A. 1991. One pain or many pains? A new look at pain mechanisms. News Physiol. Sci. 6, 268–273. Cervero, F. and Laird, J. M. A. 1996. Mechanisms of touchevoked pain (allodynia): a new model. Pain 68, 13–23. Descartes, R. 1664. L’homme. Chez Jacques Le Gras. Goldschaider, A. 1898. U¨ber den Schmerz: Gesammelte Abhandlungen. Ambros.

10 Pain Theories Hunt, S. P. and Mantyh, P. W. 2001. The molecular dynamics of pain control. Nature Rev. Neurosci. 2, 83–91. Julius, D. and Basbaum, A. I. 2001. Molecular mechanisms of nociception. Nature 413, 203–210. Klein, T., Magerl, W., Rolke, R., and Treede, R. D. 2005. Human surrogate models of neuropathic pain. Pain 115, 227–233. Melzack, R. and Wall, P. D. 1965. Pain mechanisms: a new theory. Science 150, 971–979. Mu¨ller, J. 1835–1840. Handbuch der Physiologie des Menschen fu¨r Vorlesungen. J. Ho¨lscher.

Ochoa, J. and Torebjork, E. 1983. Sensations evoked by intraneural microstimulation of single mechanoreceptor units innervating the human hand. J. Physiol. 342, 633–654. Ochoa, J. and Torebjork, E. 1989. Sensations evoked by intraneural microstimulation of C nociceptor fibres in human skin nerves. J. Physiol. 415, 583–599. Treede, R. D., Meyer, R. A., Raja, S. N., and Campbell, J. N. 1992. Peripheral and central mechanisms of cutaneous hyperalgesia. Prog. Neurobiol. 38, 397–421. von Frey, M. 1895. Beitrage zur sinnesphysiologie der haut. Ber. Sachs. Ges. Wiss. 47, 166–184.

3 Anatomy of Nociceptors S Mense, Institut fu¨r Anatomie und Zellbiologie, Universita¨t Heidelberg, Heidelberg, Germany ª 2009 Elsevier Inc. All rights reserved.

3.1 3.2 3.2.1 3.2.2 3.3 3.3.1 3.3.1.1 3.3.1.2 3.3.2 3.3.2.1 3.3.2.2 3.3.3 3.3.3.1 3.3.3.2 3.3.3.3 3.3.3.4 3.3.3.5 3.3.4 3.3.4.1 3.3.4.2 3.4 3.4.1 3.4.2 3.4.3 3.5 3.5.1 3.5.2 3.5.3 3.6 References

Introduction General Morphological Features of Nociceptors Light Microscopic Structure Ultrastructure Nociceptors in Various Tissues Skin Light microscopy Electron microscopy Cornea Light microscopy Electron microscopy Deep Somatic Tissues Muscle pain compared to cutaneous pain Nociceptors in muscle and tendon Nociceptors in joints and ligaments Tooth pulp Dura mater encephali Visceral Organs Visceral pain Testis Neuropeptide Content of Nociceptors General Remarks Neuropeptides in Afferent Units of Different Tissues Neuropeptides in Nociceptors and Other Types of Free Nerve Ending Efferent Function of Nociceptors Release of Neuropeptides from the Nociceptive Ending The Axon Reflex Neurogenic Inflammation Receptor Molecules in the Membrane of Nociceptors

12 14 14 15 17 17 18 19 20 20 21 22 22 22 25 27 32 33 33 34 34 34 35 36 37 37 37 37 38 38

Glossary anterograde transport Intra-axonal transport in the distal direction (away from the soma) of substances synthesized in (or injected into) spinal or cranial ganglion cells. The transport is brought about by molecules (kinesin for anterograde, and dynein for retrograde, transport) that bind substances and vesicles and move along the microtubules in the axoplasm. axon reflex Release of neuropeptides from a branch of a nociceptor when the branch is invaded

antidromically (against the normal direction of propagation) by action potentials. The released neuropeptides influence the microcirculation in the vicinity of the ending. deep somatic tissues All subcutaneous tissues that are not viscera, namely tendon, fascia, muscles, ligaments, and joints. epitendineum (peritendineum externum) Dense connective tissue with blood vessels, lymphatic vessels, and nerve fibers surrounding a tendon.

11

12 Anatomy of Nociceptors

group I–IV fibers Nomenclature for afferent fibers that originate in deep somatic tissues. Group IV fibers correspond to C-fibers from the skin, and group III to A-fibers. Group I fibers comprise the primary endings from muscle spindles (Ia-fibers) and Ib-fibers from Golgi tendon organs. Group II fibers and cutaneous A-fibers are largely identical. The denominations using roman numerals are based on the diameter of the nerve fibers, those using arabic letters on the conduction velocity. noceffector This term was coined by Kruger L. (1988) for nociceptors in the tooth; it emphasizes the efferent function of the receptor. Efferent function means that the receptor is involved in the maintenance of the tissue under normal and pathological circumstances by releasing substances stored in the ending. One aspect of such a noceffector role in the skin would be regulation of Langerhans cell type expression and proliferation of keratinocytes. Under pathophysiological circumstances, the effector role of a nociceptor is reflected in the axon reflex (see above) and neurogenic inflammation. paciniform corpuscle A rapidly adapting mechanoreceptor with a morphology similar to that of a Pacinian corpuscle. It consists of a layered capsule that surrounds a central receptive core. The capsule is derived from the perineurium; the central core contains the receptive portion of the axon with Schwann cells around it. Compared to the Pacinian corpuscle, the paciniform corpuscle is smaller and has fewer laminae in its capsule. In

3.1 Introduction Originally, pain was assumed to be an emotion like pleasure and fear. In the nineteenth century, this concept was replaced by the view that pain is due to activation of a set of specialized nerve endings. Von Frey M. (1894) was the first to link pain to fine nerve terminals in the skin. The functional term nociceptor is derived from the Latin word noxius for damaging or harmful. It denotes a sensory ending that detects actual or potential tissue damage. When activated, it may cause pain in humans and painrelated reflexes in animals. Another definition of a

skeletal muscle, it is often supplied by a group III fiber. primary afferent unit The first sensory neuron in the body periphery. It includes the receptive ending, the afferent fiber, the soma in the spinal or cranial ganglion, and the central process in the dorsal root and the central nervous system (CNS). receptor matrix An arrangement of cell organelles (mitochondria, vesicles, and axonal reticulum, i.e., a network of fluid-filled vacuoles) embedded in a granulated axonal cytoplasm. Ruffini corpuscle A flat, encapsulated mechanoreceptor supplied by several myelinated nerve fibers. The fibers form a dense arborization within a capsule of connective tissue. sensory terminal tree The preterminal axon and its branches. The term is part of the concept that both group III and IV endings do not have just one sensory site, but possess several branches with many receptive loci that together enhance the sensitivity of the free nerve ending as a sense organ. varicosity An expansion of the preterminal axon of a slowly conducting sensory fiber (A- or C-fiber). The varicosity contains mitochondria, vesicles, and other cell organelles. It is discussed as a receptive site. The varicosities of a free nerve ending are connected by thin stretches of axon; this arrangement causes the beaded appearance of a free nerve ending and the preterminal axon under the light microscope.

nociceptor is an ending that by its discharge behavior is capable of distinguishing between an innocuous and a noxious stimulus. An important point for the understanding of the function of nociceptors is that their stimulation threshold is just below tissue-damaging intensity. The function of nociceptors is not to signal existing tissue damage, but to inform the central nervous system (CNS) when stimuli approach tissue-threatening intensities. Nociceptive endings are present in almost all tissues and organs of the organism. However, the fact that lesions of the brain and parenchyma of the lung, liver, and cartilage are not painful suggests that in

Anatomy of Nociceptors

3000

(b)

(μm2)

(a) 6000 Cross-sectional area (μm2)

these tissues nociceptors are not present. Conversely, by stimulation of cornea, dura mater, and tooth pulp, pain is the predominant or only sensation that can be elicited. These observations led to the assumption that these tissues are equipped exclusively with nociceptors. The available clinical and experimental evidence indicates that small-diameter afferent fibers have to be activated in order to elicit pain. These fibers conduct action potentials at a relatively slow velocity (below 30 m s1 in the cat); histologically they comprise either thin myelinated (A- or group III) fibers or nonmyelinated (C- or group IV) fibers. However, there are also nociceptors supplied by faster-conducting thick myelinated A/-fibers: in the rat, approximately 20% of all A/-fibers are nociceptive (for review, see Djouhri, L. and Lawson, S. N., 2004). The nomenclature with roman numerals (group I–IV fibers) was developed by Lloyd D. P. C. (1943) for muscle afferent fibers. It is now being used for afferent fibers from muscle, joint, tendons, and fascia (the socalled deep somatic tissues). Generally, there is a negative relationship between mechanical threshold and conduction velocity (CV) of sensory afferents: the higher the CV, the lower the mechanical threshold (Burgess, R. P. and Perl, E. R., 1967). In the dorsal root ganglion (DRG), the correlation between soma diameter and axonal CV is weaker than generally thought. In Figure 1 (Hoheisel, U. and Mense, S., 1987), this correlation is shown for intracellularly stained DRG cells of the cat. For group III units (those having CVs between 2.5 and 30 ms1), there was no significant correlation between soma size and CV, and for group IV units (conducting at % C-fibers Descending branch of Vtr: % C-fibers > A-fibers Direct sensory fiber projection to autonomic relay nuclei (e.g., NTS)

Cody F. W. et al. (1972), Linden R. W. (1978)

Lennartsson B. (1979), Bruenech J. R. and Ruskell G. L. (2001) Noden D. M. (1991), Artinger K. B. et al. (1998), Baker C. V. et al. (2002) Young R. F. and King R. B. (1973), Holland G. R. and Robinson P. P. (1992) Tashiro T. et al. (1984)

Cutaneous vasodilatation, hypotension and bradycardia to TG stimuli

Jacquin M. F. et al. (1983), Marfurt C. F. and Rajchert D. M. (1991), Panneton W. M. et al. (1994) Kumada M. et al. (1977), Drummond P. D. (1992), Ramien M. et al. (2004)

Vn TG; Goedert, M. et al., 1984); and sensitivity to cadmium-induced neurotoxicity (TG > DRG; Arvidson, B., 1983). Thus, developmental biology indicates some similarities with notable differences in the responsiveness to certain neurotrophic factors. Table 2 summarizes results from studies comparing adult TG and DRG systems under basal (naive) conditions. These studies reveal many similarities among markers associated with nociception such as the percentage of TRPV1-positive neurons (Ambalavanar, R. et al., 2005) and expression of P2X

439

receptor subtypes (Collo, G. et al., 1996; Cook, S. P. et al., 1997; Xiang, Z. et al., 1998). However, substantial differences also are observed that include: the percentage of neurons stained for substance P and somatostatin (TG > DRG; Kai-Kai, M. A., 1989), trkA receptor (DRG > TG; Mosconi, T. et al., 2001), galectin-1 (DRG >> TG; Akazawa, C. et al., 2004), m- and -opioid receptors (DRG > TG; Buzas, B. and Cox, B. M., 1997), CCK (DRG > TG; Ghilardi, J. R. et al., 1992), cytokeratin (TG >> DRG; Okabe, H. et al., 1997), and neuropeptide Y (NPY)-binding sites (TG > DRG; Mantyh, P. W. et al., 1994). In addition, TG and DRG systems display a differential sensitivity to ganglion cell labeling by selected anatomical tracers in which the TG system has a greater uptake of Fluoro-Gold than DRG but not of Fast Blue (Yoshimura, N. et al., 1994). Differences in cellular properties between the TG and DRG systems under naive conditions may contribute to differential responses to tissue injury. For example, sprouting of sympathetic nerve terminals into the DRG (McLachlan, E. M. et al., 1993), but not the TG after nerve injury (Bongenhielm, U. et al., 1999; Benoliel, R. et al., 2001) is consistent with findings that trkA-positive neurons are more numerous in the DRG than TG (Mosconi, T. et al., 2001). Comparison of nerve injury-induced changes for a majority of neuropeptides associated nociception such as substance P, TRPV1, P2X3, and NPY appear similar for TG and DRG systems (Zhang, X. et al., 1996; Okuse, K. et al., 1997; Eriksson, J. et al., 1998; Elcock, C. et al., 2001; Tsuzuki, K. et al., 2001; Stenholm, E. et al., 2002; Tsuzuki, K. et al., 2003). However, species differences have been reported such as a decrease in galanin in TG of ferret (Elcock, C. et al., 2001) compared to an increase in rat (Zhang, X. et al., 1996) after Vn injury, similar to the increase in galanin in rat DRG after spinal nerve injury (Villar, M. J. et al., 1989). Nerve injury causes higher spontaneous discharge rates and greater rhythmic firing patterns in DRGs than TGs (Tal, M. and Devor, M., 1992), effects often associated with sodium channel activity (see Wood, J. N. et al., 2004). However, the basis for this difference is not certain since changes in the expression of the tetrodotoxin (TTX)-resistant sodium channel, NaV1.8, appear comparable for DRG and TG systems (Dib-Hajj, S., et al., 1996; Bongenhielm, U. et al., 2000). Susceptibility to infection also may differ between TG and DRG systems, since injection of herpes simplex virus (HSV) to the left ear pinna in

440 Trigeminal Mechanisms of Nociception: Peripheral and Brainstem Organization Table 2

Comparison of trigeminal (TG) and dorsal root ganglion (DRG) systems under naive conditions

Factor

Details

References

Substance P Somatostatin P2X1, P2X2, P2X3, P2X4, P2X5, P2X6 mRNA P2X3-isolectin B4 co-expression TRPV1 trkA

TG  DRG TG  DRG TG  DRG; no P2X2, P2X3 in Vme

Kai-Kai M. A. (1989) Kai-Kai M. A. (1989) Collo G. et al. (1996), Cook S. P. et al. (1997) Xiang Z. et al. (1998) Ambalavanar R. et al. (2005) Guo A. et al. (1999) Mosconi T. et al. (2001)

Arginine vasopressin

5-HT1d Oxytocin NADPH-diaphorase CCK mRNA in monkey CCK(B) receptor PYY binding sites (NPY receptor) Galectin-1 mRNA Oncostatin M (OSM-) glycogen phosphorylase Cytokeratin (AE1 and CAM5.2) Glucocorticoid receptor (GR)

MOR mRNA DOR mRNA TGF- mitogenic effect in vitro Parvalbumin

Osteocalcin parvalbumin

Osteocalcin and TRPV1 coexpression Calretinin

S100 calcium-binding protein

DRG >> TG TG  DRG DRG > TG;  40% DRG versus 10–15% of TG neurons innervating pulp or cornea DRG > TG About 40% AVP is in capsaicin-sensitive neurons in both ganglia TG  DRG TG > DRG DRG: T5–L1 >> C1-T4 ¼ L2–S ¼ TG DRG ¼ 20%; TG ¼ 10% of neurons Rat, rabbit: TG  DRG Monkey: DRG > TG (nondetectable) TG  DRG DRG >> TG (nondetectable) DRG > TG (OSMr- coexpressed in TRPV1-positive neurons) DRG > TG TG >> DRG TG: GR expressed in substance P, CGRP, but not galanin-positive neurons DRG: GR expressed in substance P, CGRP, and galanin-positive neurons DRG: lumbar > thoracic  cervical > TG DRG: lumbar  thoracic  cervical > TG DRG: Yes TG: No TG smaller size than DRG, but both populations have high expression of carbonic anhydrase and low expression of CGRP TG: 25% of neurons (31% express parvalbumin) Vme: 63% of neurons (>90% express parvalbumin) DRG: 16% of neurons (>90% express parvalbumin) TG ¼ 14% DRG ¼ none TG: neurons mostly < 800 mm2 and 34% positive for tachykinin DRG: neurons mostly > 800 mm2 and 7% positive for tachykinin TG: 59% (> 90% coexpress parvalbumin and calbindin D-28k) DRG: 44% (> 90% coexpress parvalbumin, none with calbindin D-28k)

Kai-Kai M. A. and Che Y. M. (1995)

Potrebic S. et al. (2003) Kai-Kai M. A. (1989) Aimi Y. et al. (1991) Verge V. M. et al. (1993) Ghilardi J. R. et al. (1992) Mantyh P. W. et al. (1994) Akazawa C. et al. (2004) Tamura S. et al. (2003) Pfeiffer B. et al. (1995) Okabe H. et al. (1997) DeLeon M. et al. (1994)

Buzas B. and Cox B. M. (1997) Buzas B. and Cox B. M. (1997) Chalazonitis A. et al. (1992) Ichikawa H. et al. (1994)

Ichikawa H. et al. (1999)

Ichikawa H. and Sugimoto T. (2002) Ichikawa H. et al. (1993)

Ichikawa H. et al. (1997)

(Continued )

Trigeminal Mechanisms of Nociception: Peripheral and Brainstem Organization Table 2

441

(Continued)

Factor

Details

References

tr7kC at day E12.5 of development

DRG: Yes TG: No TG > DRG for responsiveness DRG > TG for loss of substance P- and somatostatin-positive neurons TG  DRG uptake of Fast Blue TG > DRG uptake of Fluoro-Gold

Elkabes S. et al. (1994)

NT-3 overexpression Neonatal anti-NGF antisera at E16.5 Uptake of fluorescent dyes

Albers K. M. et al. (1996) Goedert M. et al. (1984) Yoshimura N. et al. (1994)

5-HT1d, serotonin receptor subtype; CCK, cholecystokinin; CGRP, calcitonin gene-related peptide; DOR, -opioid receptor; DRG, dorsal root ganglion; MOR, m-opioid receptor, messenger RNA; NADPH, nicotinamide adenine dinucleotide phosphate hydrogen; ; NGF, nerve growth factor; NPY, neuropeptide Y; P2X, ATP receptor; PYY, polypeptide Y; TG, trigeminal ganglion; TGF, tumor growth factor; trkA, tyrosine kinase A receptor subtype; TRPV1, vanilloid receptor.

mice produces 100% HSV infection in both the ipsilateral TG and cervical DRG. Interestingly, 70% of the TGs contralateral to injection, while only 10% of contralateral DRGs were infected (Thackray, A. M. and Field, H. J., 1996). Interhemispheric neural communication likely contributes to the progression of joint-related pain in trigeminal (see Bereiter, D. A. et al., 2005b) as well as spinal systems (Levine, J. D. et al., 1985; Shenker, N. et al., 2003). The responsiveness to viral vectors in the Vn system has prompted recent efforts to deliver targeted transgene-derived products for control of trigeminal neuropathic pain (Meunier, A. et al., 2005). Collectively, these studies reveal significant differences in peripheral Vn and spinal systems under naı¨ve and injured conditions, differences that could not be predicted on the basis of results from spinal sensory systems alone.

32.3 Central Aspects of Trigeminal Organization Noxious sensory information is relayed from Vn afferents to second-order neurons in the TSNC and the upper cervical spinal cord. The TSNC is the initial site of synaptic integration for sensory input from the head and oral cavity and shares this feature with the spinal dorsal horn and dorsal column nuclei that receive sensory input from the rest of the body (Figure 1). However, unlike the spinal cord, the TSNC is comprised of several cell groups with distinct cytological and organizational features (see Darian-Smith, I., 1973; Kruger, L. and Young, R. F., 1981) yet each cell group receives direct primary afferent projections from specific craniofacial tissues. The TSNC consists of: the principal nucleus (Vp), supratrigeminal region (Vsup) lying

dorsal to Vp, an elongated spinal nucleus (Vsp) extending from the pons to the upper cervical spinal cord, and the interstitial islands or the paratrigeminal region (Pa5) embedded within the spinal trigeminal tract, dorsal and lateral to the caudal Vsp (Figure 2; see Kruger, L. and Young, R. F., 1981; Renehan, W. E. and Jacquin, M. F., 1993). The Vsp is further subdivided, from rostral to caudal, into subnucleus oralis (Vo), subnucleus interpolaris (Vi), and a laminated trigeminal subnucleus caudalis (Vc) as described originally by Olszewski J. (1950). Although nociceptive neurons in the caudal laminated portion of the TSNC, Vc, display properties similar to those at spinal levels (Price, D. D. et al., 1976; Dubner, R. and Bennett, G. J., 1983) consistent with a prominent role in nociceptive processing (see also Bereiter, D. A. et al., 2000; Sessle, B. J., 2000), the contribution of rostral portions of the TSNC to orofacial pain is less certain.

Vp Vo Vi Vc Vme

Vmo

Rostral

NTS

Caudal Figure 2 Trigeminal brainstem sensory complex.

442 Trigeminal Mechanisms of Nociception: Peripheral and Brainstem Organization

32.3.1

Somatotopy

that rostral portions of TSNC play a more prominent role in dental and intraoral pain than caudal portions (Young, R. F. and Perryman, K. M., 1984; see Sessle, B. J., 2000); however, the importance of multiple representation of extraoral tissues for other forms of craniofacial pain is not well understood. One reason for this uncertainty may be due to the fact that many craniofacial tissues are represented in a discontinuous manner along the rostrocaudal extent of the TSNC as summarized in Table 3. Although a small percentage of Vn afferents projects to both rostral and caudal portions of the TSNC (Silverman, J. D. and Kruger, L., 1985; Li, Y. Q. et al., 1992), most fibers either ascend in a short sensory root to terminate in Vp or descend to give off branches to Vo, Vi, Vc, and the upper cervical dorsal horn. Several aspects of the afferent input pattern to TSNC are notable. First, the superficial laminas in Vc receive substantial input from all specialized tissues well associated with craniofacial pain conditions (e.g., cornea, dura, teeth, temporomandibular joint (TMJ)), while afferents from structures with no known relationship to pain perception (vibrissas) do not project to this region. Second, dental pulp afferents are the

Somatotopy is a key feature of the trigeminal system and is seen within the TG as well as the TSNC distinct from the spinal cord. Craniofacial tissues are represented at multiple levels of the TSNC, while sensory afferents from other body loci terminate at several contiguous spinal segments of the spinal dorsal horn. Also, at caudal levels of the TSNC craniofacial tissues are represented in a series of semicircular bands that converge at the rostral midline of the face, often referred to as an onionskin arrangement and by a medial-lateral representation in which the head is inverted (Jacquin, M. F. et al., 1986; Shigenaga, Y. et al., 1986a). Although somatotopy along the mediolateral axis is preserved at all levels of the TSNC, the onion-skin arrangement is most apparent in Vc. The implications of this organization for facial pain have been debated since an early report by Sjoqvist O. (1938) that trigeminal tractotomy at the level of rostral Vc reduced the pain of trigeminal neuralgia, while preserving the sense of temperature and touch on the face. It is understood

Table 3 Summary of the relative density of trigeminal primary afferent terminals within different portions of the sensory trigeminal sensory nuclear complex. Vp

Vo

Vc

dm

vl

dm

vl

Vi

dPa5

Vi/Vc

I–II

III–IV

V

References

Cornea



þ



þ

þ



þþþ

þþ





Nasal mucosa Dura



þ

þ

þ

þþ



þþþ

þþþ

þ

þ









þ



þþþ

þþþ

þ



Teeth

þþ

þ

þþþ

þ

þ

þþþ



þþ



þ

Masseter muscle

þ



þ



þþ

þþ



þþ



þ

TMJ

þ



þ



þþ

þþ



þþþ



þ

Vibrissae



þþþ



þ

þþþ







þþ



Panneton W. M. and Burton H. (1981), Marfurt C. F. and del Toro D. R. (1987), Marfurt C. F. and Echtenkamp S. F. (1988) Anton F. and Peppel P. (1991); Panneton W. M. (1991) Arbab M. A. et al. (1988), Liu Y. et al. (2004) Marfurt C. F. and Turner D. F. (1984), Shigenaga Y. et al. (1986c); Takemura M. et al. (1993) Nishimori T. et al. (1986), Shigenaga Y. et al. (1988), Arvidsson J. and Raappana P. (1989) Jacquin M. F. et al. (1983); Shigenaga Y. et al. (1986a), (1986b), Capra N. F. (1987), Takemura M. et al. (1987) Jacquin M. F. et al. (1986), Nomura S. et al. (1986), Arvidsson J. (1982)

, very few or none; þ,þþ,þþþ, weak, moderate and dense terminal distribution; dPa5, dorsal paratrigeminal region; TMJ, temporomandibular joint; Vc, subnucleus caudalis; Vi, subnucleus interpolaris; Vo, subnucleus oralis; Vp, principal sensory nucleus.

Trigeminal Mechanisms of Nociception: Peripheral and Brainstem Organization

only group of putative nociceptive fibers with a substantial projection to rostral portions of the TSNC, namely, to the dorsomedial portions of Vp and Vo, thus supporting the role for these regions in intraoral pain (Marfurt, C. F. and Turner, D. F., 1984; Shigenaga, Y. et al., 1986c). Also, compared to other orofacial tissues associated with pain sensation, the termination pattern of dental afferents is particularly widespread along the rostrocaudal extent of the TSNC. Third, input from structures supplied by the ophthalmic branch of the Vn (e.g., cornea, nasal dura) project only sparsely to rostral portions of the TSNC suggesting that these regions play a lesser role than Vc in mediating pain due to uveitis, dry eye, sinusitis, or headache. Fourth, discontinuous representation is not unique to tissues supplied by the ophthalmic division (e.g., cornea, dura, nasal cavity) since the auriculotemporal nerve, a major source of innervation for the TMJ region also displays an uneven terminal distribution in the TSNC (Shigenaga, Y. et al., 1986a; 1986b). In rodents vibrissae afferents project to most levels of the TSNC (Arvidsson, J., 1982; Nomura, S. et al., 1986); however, the architectonic representation of the vibrissae fields, the so-called barrelettes, are well delineated in Vp, Vi, and Vc, but not Vo (Ma, P. M., 1991), supporting the notion that different levels of the TSNC mediate different aspects of sensory processing of innocuous as well as noxious inputs. 32.3.2

Intersubnuclear Connections

Rostral and caudal portions of the TSNC are connected by a rich longitudinal fiber network coursing within spinal trigeminal tract and through the deep bundles that extend from Vp to the upper cervical spinal cord (Gobel, S. and Purvis, M. B., 1972; Kruger, L. et al., 1977; Ikeda, M. et al., 1984; Jacquin, M. F. et al., 1990). Although propriospinal-like connections of the TSNC share anatomical similarities with those at lower spinal levels, intersubnuclear connections in the TSNC link spatially distinct brainstem regions with common somatotopic representation of facial fields. The implications of this organization for facial pain remain to be determined; however, results from numerous animal studies support the clinical findings of Sjoqvist O. (1938) and indicate that ascending connections from caudal Vc generally facilitate the activity of neurons in more rostral portions within the TSNC. Lesion or chemical blockade of caudal Vc reduced the excitability of rostral trigeminal neurons responsive to noxious stimulation of tooth pulp

443

(Greenwood, L. F. and Sessle, B. J., 1976; Chiang, C. Y. et al., 2002), dura (Davis, K. D. and Dostrovsky, J. O., 1988), and cornea (Hirata, H. et al., 2003). By contrast, innocuous sensory input from facial skin (Greenwood, L. F. and Sessle, B. J., 1976) and vibrissae (Hallas, B. H. and Jacquin, M. F., 1990) often was enhanced. Fewer studies have assessed the influence of rostral TSNC regions on caudal Vc neural activity, though in a recent study, muscimol blockade of the Vi/Vc transition region facilitated cornea-responsive neurons in laminas I–II of caudal Vc (Hirata, H. et al., 2003). These results suggest that ascending as well as descending connections within the TSNC contribute to the integration of sensory inputs relevant for craniofacial pain. 32.3.3 Relationship to the Autonomic Nervous System The trigeminal system is closely linked to brain regions that control autonomic outflow, especially parasympathetic outflow and vagus nerve activity. This linkage likely contributes to craniofacial pain conditions such as primary headache (Edvinsson, L. and Uddman, R., 2005) and dry eye (Hocevar, A. et al., 2003), sudden bradycardia and asystole during maxillofacial surgery (Schaller, B., 2004), and the so-called diving reflex in infant humans (Goksor, E. et al., 2002) and aquatic mammals (Butler, P. J. and Jones, D. R., 1997). Even facial skin differs from other cutaneous regions in that it is well supplied by parasympathetic fibers (Ramien, M. et al., 2004). Under experimental conditions noxious stimulation of craniofacial tissues in humans evokes long-lasting vasodilatation in orofacial regions (Drummond, P. D., 1992; Izumi, H., 1999) that differs from responses evoked by stimulation of other body regions consistent with the existence of specialized trigeminal vasodilator reflex mechanisms (Kemppainen, P. et al., 2001). Two aspects of the relationship between autonomic nerves and the trigeminal system are distinct from spinal cord and deserve special mention. Unlike at spinal levels where nearly all sensory nerves relay initially in the dorsal horn or dorsal column nuclei, many Vn afferents, especially those from the mandibular branch, project directly to brainstem nuclei that control autonomic outflow such as the nucleus tractus solitarius (NTS), parabrachial complex, and ventrolateral medulla (Kerr, F. W. L., 1961; Jacquin, M. F. et al., 1983; Marfurt, C. F. and Rajchert, D. M., 1991; Panneton, W. M., 1991; Panneton, W. M. et al., 1994). Also, unlike lower portions of the spinal cord, there is an extensive convergence of Vn, facial, glossopharyngeal, and vagal afferents to common laminae of

444 Trigeminal Mechanisms of Nociception: Peripheral and Brainstem Organization

the lower TSNC and upper cervical dorsal horn (Denny-Brown, D. and Yanagisawa, N., 1973; Beckstead, R. M. and Norgren, R., 1979; Contreras, R. J. et al., 1982; Altschuler, S. M. et al., 1989; McNeill, D. L. et al., 1991). The dorsal paratrigeminal region (dPa5) also receives inputs from multiple cranial nerves and upper cervical rootlets, has widespread connections to central autonomic pathways and other regions of the TSNC, and may be a key site of somatic–autonomic integration for cutaneous and visceral sensory input and control of homeostasis (Panneton, W. M. and Burton, H., 1985; Saxon, D. W. and Hopkins, D. A., 1998; Caous, C. A. et al., 2001). Considerable evidence suggests that the Vc/upper cervical cord (Vc/C2) junction region differs from lower spinal cord. In addition to receiving convergent input from multiple cranial nerves and upper cervical rootlets (Pfaller, K. and Arvidsson, J., 1988; Neuhuber, W. L. and Zenker, W., 1989), second-order Vc/C2 neurons have widespread ascending connections to the hypothalamus (Burstein, R. et al., 1990) and periaqueductal gray (PAG; Keay, K. A. et al., 1997), brainstem regions well associated with control of autonomic outflow, and endogenous pain modulation circuits. The Vc/C2 junction also sends long-range descending projections to the lower spinal cord and is a critical region for visceral sensory, particularly vagus nerve, modulation of somatic input to lower spinal segments (Chandler, M. J. et al., 2002). Although vagus nerve stimulation generally is associated with antinociception in humans (Kirchner, A. et al., 2000) and animals (Randich, A. and Gebhart, G. F., 1992; Khasar, S. G. et al., 1998), the relationship between vagus nerve activity and facial pain may be more complex. For example, increased vagal afferent activity has been suggested as one source of facial pain referred from the lung in cancer patients (see Sarlani, E. et al., 2003), whereas in animal studies increased vagal activity inhibits painlike behavior and c-fos expression after formalin injection into facial skin (Bohotin, C. et al., 2003) and tooth pulp-evoked activity of Vc/C2 dorsal horn neurons (Tanimoto, T. et al., 2002). The effects of vagus nerve stimulation have been tested mainly on neurons in the caudal portions of the TSNC; however, vagal stimulation also inhibits tooth pulp-evoked digastric reflexes (Bossut, D. F. et al., 1992) suggesting that modulation of neurons in rostral portions of the TSNC is possible. Given the extensive convergence and efferent projections of second-order neurons at the dPa5 and Vc/C2 regions, it is tempting to speculate that trigeminal–vagal interactions play a significant role in modulating pain above as well as below the neck.

32.3.4

Neurochemical Markers

The role of central neurons in mediating the various aspects of pain (e.g., sensation, autonomic control, motor reflexes) can be predicted, in part, on the basis of key factors such as the nature of the sensory input, encoding properties, response to analgesic agents, efferent projections (Price, D. D. and Dubner, R., 1977; Price, D. D. et al., 2003), and, more recently, the distribution of a growing list of neurochemical markers associated with nociceptive processing (Woolf, C. J. and Salter, M. W., 2000; Julius, D. and Basbaum, A. I., 2001; Lewin, G. R. et al., 2004). The data provided in Tables 4 (neurochemical markers) and 5 (efferent projections) are consistent with the notion that different portions of the TSNC contribute to different aspects of craniofacial pain. However, these data derive from results in naı¨ve animals and do not specifically indicate which regions respond with phenotypic or long-term structural changes during chronic pain (see Basbaum, A. I., 1999; Hunt, S. P. and Mantyh, P. W., 2001; Scholz, J. and Woolf, C. J., 2002), changes that likely occur unequally in different portions of the TSNC. Table 4 summarizes the pattern of distribution of selected neurochemical markers with known association to nociceptive processing and/or its modulation. The most striking aspect of these data is the dense and almost universal distribution of all markers within the superficial laminae of Vc, while only weak labeling is seen in laminae not associated with nociceptive processing (laminae III–IV). In rostral portions of the TSNC the density of different markers is more varied than in Vc. For example, the dorsomedial portions of Vp and Vo, regions that have a high density of afferent terminals from tooth pulp nerves, also display intense labeling for calcitonin gene-related peptide (CGRP) and trkA, whereas labeling for substance P and inositol 1,4,5 triphosphate (IP3) receptor are relatively weak and that for MOR1, the m-opioid receptor, is absent. Interestingly, selective agonists for the 5-HT1B receptor, a serotonergic receptor subtype that binds sumatriptan, an effective therapeutic agent for migraine, displays moderate density in the dorsomedial portions of Vp and Vo, yet neither region receives significant input from meningeal afferents. Although the laminar distribution of most neurochemical markers in Vc and the spinal dorsal horn are similar, significant differences have been reported for IB4 (Sugimoto, T. et al., 1997a) and TRPV1 (Bae, Y. C. et al., 2004), where spinal lamina IIi contains a greater expression of both markers than lamina IIo, while the reverse is seen in Vc. Also, the distribution of CGRP and substance P appears

Trigeminal Mechanisms of Nociception: Peripheral and Brainstem Organization

445

Table 4 Summary of the distribution of neurochemical markers associated with nociceptive processing in different portions of the trigeminal sensory nuclear complex Vp

Vo

Vc

dm

vl

dm

vl

Vi

dPa5

Vi/Vc

I–II

III–IV

V

References

IB4 TRPV1 SP

þ þ þ

  

þ þ þ

  

þ þ þ

þþ þþþ þþ

 þþ þþ

þþþ þþþ þþþ

  

  þ

NK1 CGRP

þ þþ

 

þ þþþ

 

þ þ

þ þþ

þ þþ

þþþ þþþ

þ 

þ þ

P2X2 trkA

þ þþþ

þ þ

þ þþ

þþ þ

þþ þþ

þ þþ

þþ þþ

þþ þþþ

þ þ

þ 

BDNF trkB EP3 ChAT nNOS

þ þþ  þ þ

 þþ   

þ þþ  þ þ

 þþ   

þ þþ  þ þ

þþ þþ   þþ

þþ þþ   þ

þþþ þþþ þþþ þþ þþþ

 þ   þ

 þ   

NR1 mGluR2 GABA

þþ þ þ

þ þ þ

þþ þ þþ

þ þ þ

þþ þ þ

þþþ þþ þ

þþ þ þþ

þþþ þþ þþþ

þ þ þþ

þ þ þ

GABAaR

þ

þ

þ

þ

þþ

þ

þþ

þþ

þ

þþ

GABAbR

þ

þ

þ

þ

þ

þþ

þþ

þþþ

þ

þ

NE/DA



þ

þ

þ

þ



þ

þ

þ

þ

AR/ 5-HT

þ þ

þ þ

þ þ

þ þ

þ þ

þ þ

þ þþ

þþ þþþ

þ þ

þ þ

5-HT1B/1D

þþ



þþ



þ

þþ

þ

þþþ

þ

þ

IP3R Calcineurin Osteocalcin

  

þ þ þ

  

þ þ þ

þ þ þ

  þþ

þ þ þ

þþ þþþ þþþ

 þ þ

  

Endo2 MOR1

 

 

þ 

 

þ 

þþ þþ

þ þ

þþþ þþþ

 

 

ER















þþþ

þ

Sugimoto T. et al. (1997a) Bae Y. C. et al. (2004) Boissonade F. M. et al. (1993), Sugimoto T. et al. (1997b) Nakaya Y. et al. (1994) Henry M. A. et al. (1996), Kruger L. et al. (1988), Sugimoto T. et al. (1997b) Kanjhan R. et al. (1999) Pioro E. P. and Cuello A. C. (1990), Sobreviela T. et al. (1994) Connor J. M. et al. (1997) Yan Q. et al. (1997) Nakamura K. et al. (2000) Tatehata T. et al. (1987) Dohrn C. S. et al. (1994), Rodrigo J. et al. (1994) Petralia R. S. et al. (1994) Ohishi H. et al. (1998) Ginestal E. and Matute C. (1993) Fritschy J. M. and Mohler H. (1995), Pirker S. et al. (2000) Margeta-Mitrovic M. et al. (1999) Kitahama K. et al. (2000), Levitt P. and Moore R. Y. (1979) Talley E. M. et al. (1996) Harding A. et al. (2004), Steinbusch H. W. M. (1981) Potrebic S. et al. (2003, Thor K. B. et al. (1992) Rodrigo J. et al. (1993) Strack S. et al. (1996) Ichikawa H. and Sugimoto T. (2002) Martin–Schild S. et al. (1999) Bereiter D. A. and Bereiter D. F. (2000), Ding Y. Q. et al. (1996) Bereiter D. A. et al. (2005a)

, very weak or no staining; þ,þþ,þþþ, weak, moderate and dense staining; 5-HT, serotonin; 5HT1/2, serotonin receptor subtypes; AR/, adrenergic receptor subtypes; BDNF, brain-derived neurotrophic factor; CGRP, calcitonin gene-related peptide; ChAT, choline acetyltransferase; dPa5, dorsal paratrigeminal region; Endo2, endomorphin 2; EP3, prostaglandin receptor; ER, estrogen receptor alpha subtype; GABA, gamma-aminobutyric acid; GABAaR, GABA receptor  subtype, b2/3 subunit; GABAbR, GABA receptor  subtype, R1a/b subunit; IB4, isolectin B4; IP3R, inositol triphosphate receptor; MOR1, m-opioid receptor; NE/DA, norepinephrine/ dopamine; NK1, neurokinin 1 receptor; nNOS, neuronal nitric oxide synthase; NR1, N-methyl-D-aspartic acid (NMDA) receptor subunit; P2X2, ATP receptor; SP, substance P; trkA, tyrosine kinase A receptor subtype; trkB, tyrosine kinase B receptor subtype; TRPV1, vanilloid receptor; Vc, subnucleus caudalis; Vi, subnucleus interpolaris; Vo, subnucleus oralis; Vp, principal sensory nucleus.

446 Trigeminal Mechanisms of Nociception: Peripheral and Brainstem Organization

more widely distributed across laminae I–III in Vc than in spinal dorsal horn where both neuropeptides are restricted to laminae I and IIo. The functional significance of these differences are not certain; however, the high degree of convergence of afferents from multiple sensory ganglion sources (e.g., trigeminal, nodose, cervical dorsal root) to the caudal Vc may underlie the

poor localization and spreading of pain for many craniofacial pain conditions. 32.3.5

Efferent Projections

Table 5 summarizes major efferent projection targets of trigeminal neurons in different portions of the

Table 5 Summary of efferent projections from different portions of the trigeminal sensory nuclear complex to thalamic, pontine and medullary targets associated with various aspects of nociception Vp

Vo

Vc

dm

vl

dm

vl

Vi

dPa5

Vi/Vc

I–II

III–IV

III–IV

References

Thalamus VPM

þþþ

þþþ

þ

þ

þþ

þ

þ

þþ

þ

þþ

PO



þ



þþ

þþ



þ

þþþ

þ

þ

SM









þ



þþþ

þþ





Shigenaga Y. et al. (1983), Bruce L. L. et al. (1987); Mantle-St. John L. A. and Tracey D. J. (1987) Dado R. J. and Giesler G. J. (1990), Guy N. et al. (2005) Craig A. D. and Burton H. (1981), Dado R. J. and Giesler G. J. (1990), Yoshida A. et al. (1991)

Pf

þ



þ



þ



þ





þþ

Krout K. E. et al. (2002)

Hypothalamus VMH





þ

þ

þ



þþ

þþþ

þ

þþ

LH

þ



þ



þ

þþ

þþ

þþ

þ

þþ

Malick A. and Burstein R. (1998) Malick A. and Burstein R. (1998), Ikeda T. et al. (2003)

Tectum APT SC

 

þ þþ

 

þ þþ

þþ þþ

 

þþ þþ

 þþ

 þ

 

PAG















þþ



þ

PBA

þ



þþ

þ

þ

þþþ

þþ

þþþ



þþ

NTS

þ



þ

þ

þ

þþþ

þ

þþ





ION







þ

þþ



þ

þ

þ



Yoshida A. et al. (1992) Bruce L. L. et al. (1987), Ndiaye A. et al. (2002) Beitz A. J. (1982), Mantyh P. W. (1982), Wiberg M et al. (1986), Keay K. A. et al. (1997) Panneton W. M. et al. (1994), Feil K. and Herbert H. (1995), Allen G. V. et al. (1996) Menetrey D. and Basbaum A. I. (1987), Zerari-Mailly F. et al. (2005) Huerta M. F. et al. (1985), Van Ham J. J. and Yeo C. H. (1992), Yatim N. et al. (1996)

, very weak or no staining; þ,þþ,þþþ, weak, moderate, and dense staining; APT, anterior pretectal nucleus; dPa5, dorsal paratrigeminal region; ION, inferior olivary nucleus; LH, lateral hypothalamic area; NTS, nucleus tractus solitarius; PAG, periaqueductal gray region; PBA, parabrachial region; Pf, medial and lateral parafascicular nuclei; PO, posterior thalamic nucleus; SC, superior colliculus; SM, nucleus submedius of thalamus; Vc, subnucleus caudalis; VMH, ventromedial hypothalamic area; Vi, subnucleus interpolaris; Vo, subnucleus oralis; Vp, principal sensory nucleus; VPM, ventroposteromedial nucleus of thalamus.

Trigeminal Mechanisms of Nociception: Peripheral and Brainstem Organization

TSNC independent of the functional class (i.e., nociceptive versus innocuous sensory encoding). These data derive largely from studies in rodents; however, the qualitative pattern of efferent projections from the TSNC is similar across species, although there are significant quantitative species differences for some targets. Efferent projections from secondorder neurons to the sensory thalamus have commanded considerable attention. The main sources of projections from the TSNC to the ventral posterior medial nucleus (VPM) arise from Vp and Vi, which in the case of rodents and most carnivores, is due to a heavy projection from vibrissae-driven rather than nociceptive neurons (Veinante, P. et al., 2000). Nociceptive neurons in Vc that project to VPM originate mainly in laminae I and V (Ikeda, M. et al., 2003) and moreover, the majority of projection neurons are found in rostral Vc rather than near the Vc/ C2 junction region (Guy, N. et al., 2005). Lamina I of Vc projects heavily to the posterior thalamus (PO); however, ventrolateral portions of Vo also provide a significant input to PO (Guy, N. et al., 2005). Both Vc and spinal dorsal horn lamina I cells project to similar though adjacent regions of PO (Gauriau, C. and Bernard, J. F., 2004). Projections to parafascicular thalamic nuclei from Vc are sparse compared to spinal dorsal horn (Craig, A. D., 2004; Gauriau, C. and Bernard, J. F., 2004). Trigeminal projections to thalamic nucleus submedius (SM) reveal a unique pattern that differs markedly from spinal cord and exhibits significant species differences. In the rat the majority of SM projections arise from the ventrolateral portion of the Vi/Vc transition region with only weak input from lamina I and V of caudal Vc, while spinal projections to SM originate mainly from laminae V–VII (Dado, R. J. and Giesler, G. J., 1990; Yoshida, A. et al., 1991). By contrast, in cat and monkey lamina I cells in Vc and spinal cord provide a significant direct input to SM with Vc displaying a somewhat more extensive projection (Craig A. D. and Burton, H., 1981). Trigeminal projections to autonomic control regions such as hypothalamus, parabrachial area, and NTS derive mainly from the dPa5, the Vi/Vc transition and lamina I of Vc, while more rostral regions of the TSNC provide relatively sparse input. This pattern is consistent with the dPa5 and lamina I of Vc receiving direct input from the vagus nerve. Spinal lamina I cells also project heavily to similar autonomic control regions of the brainstem (Cechetto, D. F. et al., 1985; Menetrey, D. and Basbaum, A. I., 1987; Westlund, K. N. and Craig, A. D., 1996). Although nociceptive neurons in Vc

447

(Sessle, B. J. et al., 1981; Chiang, C. Y. et al., 1994) and Vo (Chiang, C. Y. et al., 1989) are markedly inhibited by direct stimulation of PAG or rostral ventromedial medulla (RVM), the afferent pathways from second-order TSNC neurons to these endogenous pain control regions are not well defined. Compared to the significant input from upper cervical levels of spinal cord (Keay, K. A. et al., 1997) projections from TSNC to PAG are sparse (Beitz, A. J., 1982). These results add substantial support to the notion that laminae I–II of Vc are critical regions for processing nociceptive information relevant for multiple aspects of craniofacial pain. Behavioral evidence, though less extensively tested compared to spinal pain models, indicates that the Vc is necessary for opioid modulation of cutaneous facial pain (Oliveras, J. L. et al., 1986) and that levels of attention markedly influence Vc nociceptive neurons and behavioral responsiveness (Hayes, R. L. et al., 1981).

32.4 Functional Considerations Recent developments in methods that assess neural activity and encoding properties provide the strongest evidence regarding the functional role of different regions of the TSNC in craniofacial pain. Advances in neuroimaging can distinguish somatotopic and simultaneous activation of brainstem and cortical responses to trigeminal stimuli in conscious humans (DaSilva, A. F. et al., 2002), though resolution is not yet sufficient to discern the relative activation of different portions of the TSNC. Nociceptive neurons in the TSNC have been identified and their properties determined mainly on the basis of electrophysiological recording and, more recently, immediate early gene expression such as c-fos. Immunostaining for Fos, the protein product of c-fos, is a reliable method to identify populations of nociceptive central neurons at the single cell level (see Bullitt, E., 1990), an advantage not readily achieved by electrophysiology. Although there are examples of mismatches, properly designed c-fos studies generally complement electrophysiological results and have shed new light on long-standing controversies in trigeminal physiology. For example, a role for Vo in dental pain is suggested by: a dense terminal pattern in dorsomedial Vo from tooth pulp afferents (Marfurt, C. F. and Turner, D. F., 1984), a moderate-to-high density of CGRP staining (Sugimoto, T. et al., 1997b), and behavioral studies revealing preservation of dental pain after trigeminal

448 Trigeminal Mechanisms of Nociception: Peripheral and Brainstem Organization

tractotomy at the level of caudal Vi (Young, R. F. and Perryman, K. M., 1984). By contrast, few Vo neurons can be driven by natural stimulation of the tooth pulp compared to Vc (Hu, J. W. and Sessle, B. J., 1984) and few Fos-positive neurons are found in Vo after acute thermal stimulation of teeth (Chattipakorn, S. C. et al., 1999). Thus, despite the fact that many Vo cells can be classified as nociceptive on the basis of cutaneous RF properties (Dallel, R. et al., 1990), display wind-up to repeated cutaneous stimulation (Dallel, R. et al., 1999), and are inhibited by systemic morphine (Dallel, R. et al., 1996), the role of Vo in acute dental pain remains uncertain. It is possible that the Vo acts as a silent pain relay in the TSNC and becomes active only after persistent tissue damage since Fospositive cells first appear in Vo only several days after molar tooth pulp exposure (Byers, M. R. et al., 2000) and Vo neurons display sensitization provided input from Vc remains intact (Chiang, C. Y. et al., 2002; Hu, B. et al., 2002). Alternatively, rostral TSNC contributions to intraoral sensation and homeostasis may involve nonpulpal tissues (e.g., periodontal, muscosal receptors) and mediate select aspects of craniofacial pain (e.g., somatomotor reflexes).

32.4.1

Ocular Pain Processing

Ascribing a role for different portions of the TSNC in ocular pain appears more straightforward than for dental pain. Corneal afferents terminate mainly in ventrolateral portions of caudal Vi and Vc with few fibers projecting to more rostral regions (Panneton, W. M. and Burton, H., 1981; Marfurt, C. F. and del Toro, D. R., 1987; Marfurt, C. F. and Echtenkamp, S. F., 1988). Acute stimulation of the ocular surface in the rat evokes a high density of Fos-positive cells at the Vi/Vc transition and caudal Vc and none in rostral regions of TSNC (Lu, J. et al., 1993; Strassman, A. M. and Vos, B. P., 1993; Bereiter, D. A. et al., 1994; Meng, I. D. and Bereiter, D. A., 1996). Converging lines of evidence support the notion that the Vi/Vc transition and caudal Vc serve different aspects of ocular pain. All ocular cells in laminae I–II at the Vc/C2 junction are classified as nociceptive (wide-dynamic range (WDR), nociceptive specific (NS)), while many cells at the Vi/Vc transition have no cutaneous RF (Meng, I. D. et al., 1997; Hirata, H. et al., 1999). Many cells at the Vi/Vc transition are sensitive to the moisture status of the ocular surface, while few such neurons are found in caudal Vc, suggesting that this

region is critical for reflex lacrimation (Hirata, H. et al., 2004). Repeated ocular surface stimulation evokes a windup like response among caudal Vc units, while Vi/Vc cells rapidly become desensitized (Meng, I. D. et al., 1997). In a model for endotoxin-induced uveitis, at 7days after ocular inflammation convergent cutaneous RF areas become enlarged and responsiveness to ocular surface stimulation is enhanced among caudal Vc neurons, while Vi/Vc transition cells display no evidence of hyperalgesia (Bereiter, D. A. et al., 2005c). Systemic morphine inhibits all ocular cells at the caudal Vc, while nearly 30% of Vi/Vc cells are enhanced; an effect that can be produced by microinjection of m-opioid receptor agonists directly into the caudal Vc (Meng, I. D. et al., 1998; Hirata, H. et al., 2000). The modality of ocular units at the Vi/Vc and caudal Vc predicts, in part, the efferent projections to PO or salivatory nucleus in the brainstem (Hirata, H. et al., 2000). The Vi/Vc transition is unique among TSNC regions and is the main source of ascending projections to SM (Yoshida, A. et al., 1991; Ikeda, M. et al., 2003). These data suggest that the caudal Vc underlies the sensory-discriminative aspects of ocular pain and modulation of ocular cells in more rostral regions via intersubnuclear connections. By contrast, the Vi/Vc transition appears to play a significant role in mediating ocular-specific reflexes (e.g., lacrimation, eye blink). Projections to SM, coupled with the finding that many Vi/Vc neurons display enhanced responsiveness after morphine, suggests that this region may be part of the neural circuit that recruits endogenous pain controls in response to craniofacial tissue injury. Since a high percentage of ocular cells at each region also respond to meningeal stimulation (Strassman, A. M. et al., 1994; Burstein, R. et al., 1998; Schepelmann, K. et al., 1999), it is proposed that rostral and caudal portions of Vc mediate different aspects of headache as well as ocular pain.

32.5 Chronic Craniofacial Pain Chronic pain involving craniofacial tissues is a significant public health concern and a recognized research priority for the National Institutes of Health (NIH; e.g., PA 03-173: Neurobiology of Persistent Pain Mediated by the Trigeminal Nerve). The classification, diagnosis, and management of

Trigeminal Mechanisms of Nociception: Peripheral and Brainstem Organization

chronic craniofacial pain remain difficult since the mechanisms for many of these conditions are not well understood and animal models, though instructive, do not mimic the clinical state (Vos, B. P. et al., 1994; Roveroni, R. C. et al., 2001). Considerable progress has been in delineating the long-term changes in peripheral and central neural circuits that mediate pain sensation following tissue injury (Treede, R. D. et al., 1992; Woolf, C. J. and Salter, M. W., 2000; Hunt, S. P. and Mantyh, P. W., 2001; Julius, D. and Basbaum, A. I., 2001; Lewin, G. R. et al., 2004). Although similar cellular and molecular mechanisms may contribute to chronic pain due to Vn damage (Lavigne, G. et al., 2005), many chronic craniofacial pain conditions such as TMD, migraine, or chronic daily headache and trigeminal neuralgia present with no overt signs of tissue injury. Indeed, it has long been appreciated that the correlation between tissue injury and magnitude of pain sensation may be weak (Wall, P. D., 1979). This has lead to proposals of emotional or neuropsychological (Tenenbaum, H. C. et al., 2001; Korszun, A., 2002) and genetic factors as significant determinants of some forms of chronic craniofacial pain (TMD, Diatchenko, L. et al., 2005; migraine, Wessman, M. et al., 2004; trigeminal neuralgia, Duff, J. M., et al., 1999; dry eye in Sjogren’s syndrome, Takei, M. et al., 2005). Chronic craniofacial pain can be broadly classified according to the pattern and origin of pain episodes: chronic/recurrent (TMD, migraine headache, trigeminal neuralgia), chronic/persistent (burning mouth, dry eye syndromes), and chronic deafferentation pain (postherpetic neuralgia, posttraumatic neuralgia, phantom tooth). The mechanisms that underlie these diverse conditions involve markedly different tissues and are likely quite heterogeneous. However, three features of many chronic craniofacial pain conditions are notable and provide evidence of commonality. First, the prevalence of most chronic craniofacial pain conditions is higher in women than men (Dao, T. T. and LeResche, L., 2000; Macfarlane, T. V. et al., 2002a). This is especially apparent for the chronic/ recurrent conditions of TMD and migraine headache (LeResche, L., 1997; Rasmussen, B. K., 200l) and somewhat less so for trigeminal neuralgia (Kitt, C. A. et al., 2000; Manzoni, G. C. and Torelli, P., 2005). Women also are more likely to develop burning mouth (Bergdahl, M. and Bergdahl, J., 1999; Grushka, M. et al., 2003) and dry eye syndromes (Yazdani, C. et al., 2001) and report greater sensory disturbances after Vn damage (Sandstedt, P. and

449

Sorensen, S., 1995). Among TMD (Isselee, H. et al., 2002; LeResche, L. et al., 2003) and migraine patients (Rasmussen, B. K., 1993; MacGregor, E. A. and Hackshaw, A., 2004) pain severity and symptoms vary over the menstrual cycle suggesting a significant interaction with factors related to sex hormone status. Correspondingly, recent anatomical (Amandusson, A. et al., 1996; Pajot, J. et al., 2003; Bereiter, D. A. et al., 2005a; 2005b; Puri, V. et al., 2005) and electrophysiological evidence (Okamoto, K. et al., 2003; Flake, N. M. et al., 2005) from animal models support the notion that estrogen preferentially enhances the excitability of trigeminal neurons that contribute to craniofacial pain. Furthermore, within the TSNC, estrogen receptor-positive neurons are found almost exclusively within the superficial laminae of Vc and not in more rostral portions of the complex (Bereiter, D. A. et al., 2005a) suggesting that this region plays a key role in differential processing of orofacial sensory information under different sex hormone conditions. Second, spreading and referral of pain and sensitization evoked from outside the affected dermatomal region are common features of many chronic craniofacial pain conditions. Sensory disturbances occurring outside the affected region have been well documented in clinical studies of TMD (Maixner, W. et al., 1998; Sarlani, E. and Greenspan, J. D., 2003; 2005), migraine (Burstein, R. et al., 2000; Katsarava, Z., et al., 2002; Goadsby, P. J., 2005), trigeminal neuralgia (Dubner, R. et al., 1987; Nurmikko, T. J. and Eldridge, P. R., 2001; Devor, M. et al., 2002), and burning mouth syndrome (Svensson, P. et al., 1993; Ito, M. et al., 2002). Patients with postherpetic neuralgia involving trigeminal dermatomes had lower thermal warm and cool thresholds, while those with infection of spinal dermatomes had elevated thresholds (Pappagallo, M. et al., 2000) suggesting different underlying pathologies for neuropathic pain in trigeminal and spinal systems. Mechanical allodynia and increased temporal summation are consistent with the notion that central neural mechanisms maintain chronic craniofacial pain, while peripheral mechanisms are required mainly for initiation of the pain state. Third, many chronic craniofacial pain conditions are accompanied by significant disturbances of the autonomic and/or endocrine systems. Chronic TMD patients display altered secretion of stress hormones (Jones, D. A. et al., 1997; Korszun, A. et al., 2002) and elevated levels of neuropeptides and proinflammatory cytokines that could affect blood flow to joints (Kopp, S., 2001). The relationship between vascular reactivity and migraine has long been considered a

450 Trigeminal Mechanisms of Nociception: Peripheral and Brainstem Organization

critical variable (Janig, W., 2003; Goadsby, P. J., 2005), whereas stimulus-evoked oral mucosal blood flow is greater in patients with burning mouth syndrome (Heckmann, S. M. et al., 2001). Evidence from animal models indicate that contributions from vagus nerve activity (Khasar, S. G. et al., 2001) and adrenal medullary outflow (Green, P. G. et al., 2001) have marked sex-related effects on cutaneous pain behavior. Although treatments to reduce sympathetically maintained pain generally have a poor outcome for posttraumatic trigeminal neuralgic patients (Gregg, J. M., 1990), the influence of the autonomic nervous system on other forms chronic craniofacial pain has not been adequately explored. It may be significant that brainstem regions critically involved in control of autonomic outflow also are densely stained for estrogen receptor-positive neurons (Shughrue, P. J. et al., 1997; Simonian, S. X. et al., 1998; Merchenthaler, I. et al., 2004). Collectively, these features underscore the hypothesis that an interaction between sex hormone status and autonomic outflow occurs within the central nervous system to alter the expression of chronic craniofacial facial pain. We recognize that chronic craniofacial pain is a complex problem with varying etiologies and possible contributions from genetic, neuropsychological, and neurobiological factors. However, regardless of the origin and relative contribution of these factors on pain circuits within the brain, a greater understanding of the unique organizational features of the trigeminal system may provide new perspectives and strategies to manage chronic craniofacial pain that would not otherwise be apparent from studies conducted only at the spinal level.

References Aigner, M., Robert, Lukas J., Denk, M., Ziya-Ghazvini, F., Kaider, A., and Mayr, R. 2000. Somatotopic organization of primary afferent perikarya of the guinea-pig extraocular muscles in the trigeminal ganglion: a post-mortem DiItracing study. Exp. Eye Res. 70, 411–418. Aimi, Y., Fujimura, M., Vincent, S. R., and Kimura, H. 1991. Localization of NADPH-diaphorase-containing neurons in sensory ganglia of the rat. J. Comp. Neurol. 306, 382–392. Akazawa, C., Nakamura, Y., Sango, K., Horie, H., and Kohsaka, S. 2004. Distribution of the galectin-1 mRNA in the rat nervous system: its transient upregulation in rat facial motor neurons after facial nerve axotomy. Neuroscience 125, 171–178. Albers, K. M., Perrone, T. N., Goodness, T. P., Jones, M. E., Green, M. A., and Davis, B. M. 1996. Cutaneous overexpression of NT-3 increases sensory and sympathetic neuron number and enhances touch dome and hair follicle innervation. J. Cell Biol. 134, 487–497.

Allen, G. V., Barbrick, B., and Esser, M. J. 1996. Trigeminalparabrachial connections: possible pathway for nociceptioninduced cardiovascular reflex responses. Brain Res. 715, 125–135. Altschuler, S. M., Bao, X., Bieger, D., Hopkins, D. A., and Miselis, R. R. 1989. Viscerotopic representation of the upper alimentary tract in the rat: sensory ganglia and nuclei of the solitary and spinal trigeminal tracts. J. Comp. Neurol. 283, 248–268. Amandusson, A., Hermanson, O., and Blomqvist, A. 1996. Colocalization of oestrogen receptor immunoreactivity and preproenkephalin mRNA expression to neurons in the superficial laminae of the spinal and medullary dorsal horn of rats. Eur. J. Neurosci. 8, 2440–2445. Ambalavanar, R. and Morris, R. 1992. The distribution of binding by isolectin I-B4 from Griffonia simplicifolia in the trigeminal ganglion and brainstem trigeminal nuclei in the rat. Neuroscience 47, 421–429. Ambalavanar, R., Moritani, M., and Dessem, D. 2005. Trigeminal P2X(3) receptor expression differs from dorsal root ganglion and is modulated by deep tissue inflammation. Pain 117, 280–291. Anggard, A., Lundberg, J. M., and Lundblad, L. 1983. Nasal autonomic innervation with special reference to peptidergic nerves. Eur. J. Respir. Dis. Suppl. 128, 143–149. Anton, F. and Peppel, P. 1991. Central projections of trigeminal primary afferents innervating the nasal mucosa: a horseradish peroxidase study in the rat. Neuroscience 41, 617–628. Arbab, M. A., Delgado, T., Wiklund, L., and Svendgaard, N. A. 1988. Brain stem terminations of the trigeminal and upper spinal ganglia innervation of the cerebrovascular system: WGA-HRP transganglionic study. J. Cereb. Blood Flow Metab. 8, 54–63. Artinger, K. B., Fedtsova, N., Rhee, J. M., Bronner-Fraser, M., and Turner, E. 1998. Placodal origin of Brn-3-expressing cranial sensory neurons. J. Neurobiol. 36, 572–585. Arvidsson, J. 1982. Somatotopic organization of vibrissae afferents in the trigeminal sensory nuclei of the rat studied by transganglionic transport of HRP. J. Comp. Neurol. 211, 84–92. Arvidson, B. 1983. Influence of age on the development of cadmium-induced vascular lesions in rat sensory ganglia. Environ. Res. 32, 240–246. Arvidsson, J. and Raappana, P. 1989. An HRP study of the central projections from primary sensory neurons innervating the rat masseter muscle. Brain Res. 480, 111–118. Arvidsson, J., Pfaller, K., and Gmeiner, S. 1992. The ganglionic origins and central projections of primary sensory neurons innervating the upper and lower lips in the rat. Somatosensory Motor Res. 9, 199–209. Bae, Y. C., Oh, J. M., Hwang, S. J., Shigenaga, Y., and Valtschanoff, J. G. 2004. Expression of vanilloid receptor TRPV1 in the rat trigeminal sensory nuclei. J. Comp. Neurol. 478, 62–71. Baker, C. V., Stark, M. R., and Bronner-Fraser, M. 2002. Pax3-expressing trigeminal placode cells can localize to trunk neural crest sites but are committed to a cutaneous sensory neuron fate. Dev. Biol. 249, 219–236. Barker, D. J. and Welker, W. I. 1969. Receptive fields of firstorder somatic sensory neurons innervating rhinarium in coati and raccoon. Brain Res. 14, 367–386. Basbaum, A. I. 1999. Distinct neurochemical features of acute and persistent pain. Proc. Natl. Acad. Sci. U. S. A. 96, 7739–7743. Beckstead, R. M. and Norgren, R. 1979. An autoradiographic examination of the central distribution of the trigeminal, facial, glossopharyngeal, and vagal nerves in the monkey. J. Comp. Neurol. 184, 455–472.

Trigeminal Mechanisms of Nociception: Peripheral and Brainstem Organization Beitel, R. E. and Dubner, R. 1976. Response of unmyelinated (C) polymodal nociceptors to thermal stimuli applied to monkey’s face. J. Neurophysiol. 39, 1160–1175. Beitz, A. J. 1982. The organization of afferent projections to the midbrain periaqueductal gray of the rat. Neuroscience 7, 133–159. Belmonte, C., Garcia-Hirschfeld, J., and Gallar, J. 1997. Neurobiology of ocular pain. Prog. Retin. Eye Res. 16, 117–156. Benoliel, R., Eliav, E., and Tal, M. 2001. No sympathetic nerve sprouting in rat trigeminal ganglion following painful and nonpainful infraorbital nerve neuropathy. Neurosci. Lett. 297, 151–154. Bereiter, D. A. and Bereiter, D. F. 2000. Morphine and NMDA receptor antagonism reduce c-fos expression in spinal trigeminal nucleus produced by acute injury to the TMJ region. Pain 85, 65–77. Bereiter, D. A., Cioffi, J. L., and Bereiter, D. F. 2005a. Oestrogen receptor-immunoreactive neurons in the trigeminal sensory system of male and cycling female rats. Arch. Oral. Biol. 50, 971–979. Bereiter, D. A., Hathaway, C. B., and Benetti, A. P. 1994. Caudal portions of the spinal trigeminal complex are necessary for autonomic responses and display Fos-like immunoreactivity after corneal stimulation in the cat. Brain Res. 657, 73–82. Bereiter, D. A., Hirata, H., and Hu, J. W. 2000. Trigeminal subnucleus caudalis: beyond homologies with the spinal dorsal horn. Pain 88, 221–224. Bereiter, D. A., Okamoto, K., and Bereiter, D. F. 2005b. Effect of persistent monoarthritis of the temporomandibular joint region on acute mustard oil-induced excitation of trigeminal subnucleus caudalis neurons in male and female rats. Pain 117, 58–67. Bereiter, D. A., Okamoto, K., Tashiro, A., and Hirata, H. 2005c. Endotoxin-induced uveitis causes long-term changes in trigeminal subnucleus caudalis neurons. J. Neurophysiol. 94, 3815–3825. Bergdahl, M. and Bergdahl, J. 1999. Burning mouth syndrome: prevalence and associated factors. J. Oral Pathol. Med. 28, 350–354. Beuerman, R. W. and Tanelian, D. L. 1979. Corneal pain evoked by thermal stimulation. Pain 7, l–l4. Bleys, R. L., Groen, G. J., and Hommersom, R. F. 1996. Neural connections in and around the cavernous sinus in rat, with special reference to cerebrovascular innervation. J. Comp. Neurol. 369, 277–291. Bohotin, C., Scholsem, M., Multon, S., Martin, D., Bohotin, V., and Schoenen, J. 2003. Vagus nerve stimulation in awake rats reduces formalin-induced nociceptive behaviour and fos-immunoreactivity in trigeminal nucleus caudalis. Pain 101, 3–12. Boissonade, F. M., Sharkey, K. A., and Lucier, G. E. 1993. Trigeminal nuclear complex of the ferret: anatomical and immunohistochemical studies. J. Comp. Neurol. 329: 291–312. Bongenhielm, U., Boissonade, F. M., Westermark, A., Robinson, P. P., and Fried, K. 1999. Sympathetic nerve sprouting fails to occur in the trigeminal ganglion after peripheral nerve injury in the rat. Pain 82, 283–288. Bongenhielm, U., Nosrat, C. A., Nosrat, I., Eriksson, J., Fjell, J., and Fried, K. 2000. Expression of sodium channel SNS/PN3 and ankyrin(G) mRNAs in the trigeminal ganglion after inferior alveolar nerve injury in the rat. Exp. Neurol. 164, 384–395. Bongenhielm, U., Yates, J. M., Fried, K., and Robinson, P. P. 1998. Sympathectomy does not affect the early ectopic discharge from myelinated fibres in ferret inferior alveolar nerve neuromas. Neurosci. Lett. 245, 89–92.

451

Bossut, D. F., Whitsel, E. A., and Maixner, W. 1992. A parametric analysis of the effects of cardiopulmonary vagal electrostimulation on the digastric reflex in cats. Brain Res. 579, 253–260. Brannstrom, M. 1986. The hydrodynamic theory of dentinal pain: sensation in preparations, caries, and the dentinal crack syndrome. J. Endod. 12, 453–457. Bruce, L. L., McHaffie, J. G., and Stein, B. E. 1987. The organization of trigeminotectal and trigeminothalamic neurons in rodents: a double-labeling study with fluorescent dyes. J. Comp. Neurol. 262, 315–330. Bruenech, J. R. and Ruskell, G. L. 2001. Muscle spindles in extraocular muscles of human infants. Cells Tissues Organs 169, 388–394. Bryant, B. and Silver, W. L. 2000. Chemesthesis: the Common Chemical Sense. In: Neurobiology of Taste and Smell, 2nd edn (eds. T. E. Finger, W. L. Silver, and D. Restrepo), pp. 73–100. Wiley-Liss. Bullitt, E. 1990. Expression of c-fos-like protein as a marker for neuronal activity following noxious stimulation in the rat. J. Comp. Neurol. 296, 517–530. Burstein, R., Yamamura, H., Malick, A., and Strassman, A. M. 1998. Chemical stimulation of the intracranial dura induces enhanced responses to facial stimulation in brain stem trigeminal neurons. J. Neurophysiol. 79, 964–982. Burstein, R., Yarnitsky, D., Goor-Aryeh, I., Ransil, B. J., and Bajwa, Z. H. 2000. An association between migraine and cutaneous allodynia. Ann. Neurol. 47, 614–624. Butler, P. J. and Jones, D. R. 1997. Physiology of diving of birds and mammals. Physiol. Rev. 77, 837–899. Buzas, B. and Cox, B. M. 1997. Quantitative analysis of mu and delta opioid receptor gene expression in rat brain and peripheral ganglia using competitive polymerase chain reaction. Neuroscience 76, 479–489. Byers, M. R. 1984. Dental sensory receptors. Int. Rev. Neurobiol. 25, 39–94. Byers, M. R., Chudler, E. H., and Iadorola, M. J. 2000. Chronic tooth pulp inflammation causes transient and persistent expression of Fos in dynorphin-rich regions of rat brainstem. Brain Res. 861, 191–207. Caous, C. A., de Sousa Buck, H., and Lindsey, C. J. 2001. Neuronal connections of the paratrigeminal nucleus: a topographic analysis of neurons projecting to bulbar, pontine and thalamic nuclei related to cardiovascular, respiratory and sensory functions. Autonomic Neurosci. 94, 14–24. Capra, N. F. 1987. Localization and central projections of primary afferent neurons that innervate the temporomandibular joint in cats. Somatosensory Motor Res. 4, 201–213. Catania, K. C. 1999. A nose that looks like a hand and acts like an eye: the unusual mechanosensory system of the star-nosed mole. J. Comp. Physiol. A 185, 367–372. Catania, K. C. and Kaas, J. H. 1997. Somatosensory fovea in the star-nosed mole: behavioral use of the star in relation to innervation patterns and cortical representation. J. Comp. Neurol. 387, 215–233. Catania, K. C. and Remple, M. S. 2002. Somatosensory cortex dominated by the representation of teeth in the naked mole-rat brain. Proc. Natl. Acad. Sci. U. S. A. 99, 5692–5697. Cechetto, D. F., Standaert, D. S., and Saper, C. B. 1985. Spinal and trigeminal dorsal horn projections to the parabrachial nucleus in the rat. J. Comp. Neurol. 240, 153–162. Chalazonitis, A., Kessler, J. A., Twardzik, D. R., and Morrison, R. S. 1992. Transforming growth factor alpha, but not epidermal growth factor, promotes the survival of sensory neurons in vitro. J. Neurosci. 12, 583–594. Chandler, M. J., Zhang, J., Qin, C., and Foreman, R. D. 2002. Spinal inhibitory effects of cardiovascular inputs in monkeys:

452 Trigeminal Mechanisms of Nociception: Peripheral and Brainstem Organization neuronal processing in high cervical segments. J. Neurophysiol. 87, 1290–1302. Chattipakorn, S. C., Light, A. R., Willcockson, H. H., Nahri, M., and Maixner, W. 1999. The effect of fentanyl on c-fos expression in the trigeminal brainstem complex produced by pulpal heat stimulation in the ferret. Pain 82, 207–215. Cheng, S. B., Kuchiiwa, S., Kuchiiwa, T., and Nakagawa, S. 2000. Three novel pathways to the lacrimal glands of the cat: an investigation with cholera toxin B subunit as a retrograde tracer. Brain Res. 873, 160–164. Chiang, C. Y., Hu, B., Hu, J. W., Dostrovsky, J. O., and Sessle, B. J. 2002. Central sensitization of nociceptive neurons in trigeminal subnucleus orlais depends on the integrity of subnucleus caudalis. J. Neurophysiol. 88, 256–264. Chiang, C. Y., Hu, J. W., Dostrovsky, J. O., and Sessle, B. J. 1989. Changes in mechanoreceptive field properties of somatosensory brainstem neurons induced by stimulation of nucleus raphe magnus in cats. Brain Res. 485, 371–381. Chiang, C. Y., Hu, J. W., and Sessle, B. J. 1994. Parabrachial area and nucleus raphe magnus-induced modulation of nociceptive and nonnociceptive trigeminal subnucleus caudalis neurons activated by cutaneous or deep inputs. J. Neurophysiol. 71, 2430–2445. Cody, F. W., Lee, R. W., and Taylor, A. 1972. A functional analysis of the components of the mesencephalic nucleus of the fifth nerve in the cat. J. Physiol. 226, 249–261. Collo, G., North, R. A., Kawashima, E., Merlo-Pich, E., Neidhart, S., Surprenant, A., and Buell, G. 1996. Cloning of P2X5 and P2X6 receptors and the distribution and properties of an extended family of ATP-gated ion channels. J. Neurosci. 16, 2495–2507. Cometto-Muniz, J. E. and Cain, W. S. 1995. Relative sensitivity of the ocular trigeminal, nasal trigeminal and olfactory systems to airborne chemicals. Chem. Senses 20, 191–198. Connor, J. M., Lauterborn, J. C., Yan, Q., Gall, C. M., and Varon, S. 1997. Distribution of brain-derived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNS: evidence for anterograde axonal transport. J. Neurosci. 17, 2295–2313. Contreras, R. J., Beckstead, R. M., and Norgren, R. 1982. The central projections of the trigeminal, facial, glossopharyngeal and vagus nerves: an autoradiographic study in the rat. J. Autonomic Nerv. Syst. 6, 303–322. Cook, S. P., Vulchanova, L., Hargreaves, K. M., Elde, R., and McCleskey, E. W. 1997. Distinct ATP receptors on painsensing and stretch-sensing neurons. Nature 387, 505–508. Craig, A. D. 2004. Distribution of trigeminothalamic and spinothalamic lamina I terminations in the macaque monkey. J. Comp. Neurol. 477, 119–148. Craig, A. D. and Burton, H. 1981. Spinal and medullary lamina I projection to nucleus submedius in medial thalamus: a possible pain center. J. Neurophysiol. 45, 443–466. Dado, R. J. and Giesler, G. J. 1990. Afferent input to nucleus submedius in rats: retrograde labeling of neurons in the spinal cord and caudal medulla. J. Neurosci. 10, 2672–2686. Dallel, R., Duale, C., Luccarini, P., and Molat, J. L. 1999. Stimulus-function, wind-up and modulation by diffuse noxious inhibitory controls of responses of convergent neurons of the spinal trigeminal nucleus oralis. Eur. J. Neurosci. 11, 31–40. Dallel, R., Luccarini, P., Molat, J. L., and Woda, A. 1996. Effects of systemic morphine on the activity of convergent neurons of spinal trigeminal nucleus oralis in the rat. Eur. J. Pharmacol. 314, 19–25. Dallel, R., Raboisson, P., Woda, A., and Sessle, B. J. 1990. Properties of nociceptive and non-nociceptive neurons in trigeminal subnucleus oralis of the rat. Brain Res. 521, 95–106.

Dao, T. T. and LeResche, L. 2000. Gender differences in pain. J. Orofacial Pain 14, 169–184. DaSilva, A. F., Becerra, L., Makris, N., Strassman, A. M., Gonzalez, R. G., Geatrakis, N., and Borsook, D. 2002. Somatotopic activation in the human trigeminal pain pathway. J. Neurosci. 22, 8183–8192. Davis, K. D. and Dostrovsky, J. O. 1988. Effect of trigeminal subnucleus caudalis cold block on the cerebrovascularevoked responses of rostral trigeminal complex neurons. Neurosci. Lett. 94, 303–308. Davis, B. M., Albers, K. M., Seroogy, K. B., and Katz, D. M. 1994. Overexpression of nerve growth factor in transgenic mice induces novel sympathetic projections to primary sensory neurons. J. Comp. Neurol. 349, 464–474. DeLeon, M., Covenas, R., Chadi, G., Narvaez, J. A., Fuxe, K., and Cintra, A. 1994. Subpopulations of primary sensory neurons show coexistence of neuropeptides and glucocorticoid receptors in the rat spinal and trigeminal ganglia. Brain Res. 636, 338–342. Denny-Brown, D. and Yanagisawa, N. 1973. The function of the descending root of the fifth nerve. Brain 96, 783–814. Devor, M., Amir, R., and Rappaport, Z. H. 2002. Pathophysiology of trigeminal neuralgia: the ignition hypothesis. Clin. J. Pain 18, 4–13. Diatchenko, L., Slade, G. D., Nackley, A. G., Bhalang, K., Sigurdsson, A., Belfer, I., Goldman, D., Shabalina, S. A., Shagin, D., Max, M. B., Makarov, S. S., and Maixner, W. 2005. Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Human Mol. Genet. 14, 135–143. Dib-Hajj, S., Black, J. A., Felts, P., and Waxman, S. G. 1996. Down-regulation of transcripts for Na channel alpha-SNS in spinal sensory neurons following axotomy. Proc. Natl. Acad. Sci. U. S. A. 93, 14950–14954. Ding, Y. Q., Kaneko, T., Nomura, S., and Mizuno, N. 1996. Immunohistochemical localization of m-opioid receptors in the central nervous system of the rat. J. Comp. Neurol. 367, 375–402. Dohrn, C. S., Mullett, M. A., Price, R. H., and Beitz, A. J. 1994. Distribution of nitric oxide synthase-immunoreactive interneurons in the spinal trigeminal nucleus. J. Comp. Neurol. 346, 449–460. Drummond, P. D. 1992. The mechanism of facial sweating and cutaneous vascular responses to painful stimulation of the eye. Brain 115, 1417–1428. Dubner, R. and Bennett, G. J. 1983. Spinal and trigeminal mechanisms of nociception. Annu. Rev. Neurosci. 6, 38l–418. Dubner, R., Sharav, Y., Gracely, R. H., and Price, D. D. 1987. Idiopathic trigeminal neuralgia: sensory features and pain mechanisms. Pain 31, 23–33. Duff, J. M., Spinner, R. J., Lindor, N. M., Dodick, D. W., and Atkinson, J. L. 1999. Familial trigeminal neuralgia and contralateral hemifacial spasm. Neurology 53, 216–218. Edvinsson, L. and Uddman, R. 2005. Neurobiology in primary headaches. Brain Res. Brain Res. Rev 48, 438–456. Elcock, C., Boissonade, F. M., and Robinson, P. P. 2001. Changes in neuropeptide expression in the trigeminal ganglion following inferior alveolar nerve section in the ferret. Neuroscience 102, 655–667. Elkabes, S., Dreyfus, C. F., Schaar, D. G., and Black, I. B. 1994. Embryonic sensory development: local expression of neurotrophin-3 and target expression of nerve growth factor. J. Comp. Neurol. 341, 204–213. Eriksson, J., Bongenhielm, U., Kidd, E., Matthews, B., and Fried, K. 1998. Distribution of P2X3 receptors in the rat trigeminal ganglion after inferior alveolar nerve injury. Neurosci. Lett. 254, 37–40.

Trigeminal Mechanisms of Nociception: Peripheral and Brainstem Organization Esteve, P. and Bovolenta, P. 1999. cSix4, a member of the six gene family of transcription factors, is expressed during placode and somite development. Mech. Dev. 85, 161–165. Feil, K. and Herbert, H. 1995. Topographic organization of spinal and trigeminal somatosensory pathways to the rat parabrachial and Kolliker-Fuse nuclei. J. Comp. Neurol. 353, 506–528. Feindel, W., Penfield, W., and McNaughton, F. 1960. The tentorial nerves and Iocalization of intracranial pain in man. Neurology 10, 555–563. Flake, N. M., Bonebreak, D. B., and Gold, M. S. 2005. Estrogen and inflammation increase the excitability of rat temporomandibular joint afferent neurons. J. Neurophysiol. 93, 1585–1597. Fritschy, J. M. and Mohler, H. 1995. GABAA-receptor heterogeneity in the adult rat brain: differential regional and cellular distribution of seven major subunits. J. Comp. Neurol. 359, 154–194. Gauriau, C. and Bernard, J. F. 2004. A comparative reappraisal of projections from the superficial laminae of the dorsal horn in the rat: the forebrain. J. Comp. Neurol. 468, 24–56. Georgiades, P., Wood, J., and Brickell, P. M. 1998. Retinoid X receptor-gamma gene expression is developmentally regulated in the embryonic rodent peripheral nervous system. Anat. Embryol. (Berl.) 197, 477–484. Ghilardi, J. R., Allen, C. J., Vigna, S. R., McVey, D. C., and Mantyh, P. W. 1992. Trigeminal and dorsal root ganglion neurons express CCK receptor binding sites in the rat, rabbit, and monkey: possible site of opiate-CCK analgesic interactions. J. Neurosci. 12, 4854–4866. Ginestal, E. and Matute, C. 1993. Gamma-aminobutyric acidimmunoreactive neurons in the rat trigeminal nuclei. Histochemistry 99, 49–55. Goadsby, P. J. 2005. Trigeminal autonomic cephalgias: fancy term or constructive change to the IHS classification? J. Neurol. Neurosurg. Psychiatry 76, 301–305. Gobel, S. and Purvis, M. B. 1972. Anatomical studies of the organization of the spinal V nucleus: the deep bundles and the spinal V tract. Brain Res. 48, 27–44. Goedert, M., Otten, U., Hunt, S. P., Bond, A., Chapman, D., Schlumpf, M., and Lichtensteiger, W. 1984. Biochemical and anatomical effects of antibodies against nerve growth factor on developing rat sensory ganglia. Proc. Natl. Acad. Sci. U S. A. 81, 1580–1584. Goksor, E., Rosengren, L., and Wennergren, G. 2002. Bradycardic response during submersion in infant swimming. Acta Paediatr. 91, 307–312. Gonzalez-Martinez, T., Germana, G. P., Monjil, D. F., SilosSantiago, I., de Carlos, F., Germana, G., Cobo, J., and Vega, J. A. 2004. Absence of Meissner corpuscles in the digital pads of mice lacking functional TrkB. Brain Res. 1002, 120–128. Green, P. G., Dahlqvist, S. R., Isenberg, W. M., Mao, F. J., and Levine, J. D. 2001. Role of adrenal medulla in development of sexual dimorphism in inflammation. Eur. J. Neurosci. 14, 1436–1444. Greenwood, L. F. and Sessle, B. J. 1976. Inputs to trigeminal brain stem neurons from facial, oral, tooth pulp and pharyngolarygeal tissues: II. Role of trigeminal nucleus caudalis in modulating responses to innocuous and noxious stimuli. Brain Res. 117, 227–238. Gregg, J. M. 1990. Studies of traumatic neuralgia in the maxillofacial region: symptom complexes and response to microsurgery. J. Oral Maxillofac. Surg. 48, 135–140; discussion 141. Grushka, M., Epstein, J. B., and Gorsky, M. 2003. Burning mouth syndrome and other oral sensory disorders: a unifying hypthesis. Pain Res. Manag. 8, 133–135. Guo, A., Vulchanova, L., Wang, J., Li, X, and Elde, R. 1999. Immunocytochemical localization of the vanilloid receptor 1

453

(VR1): relationship to neuropeptides, the P2X3 purinoceptor and IB4 binding sites. Eur. J. Neurosci. 11, 946–958. Guy, N., Chalus, M., Dallel, R., and Voisin, D. L. 2005. Both oral and caudal parts of the spinal trigeminal nucleus project to the somatosensory thalamus in the rat. Eur. J. Neurosci. 21, 741–754. Hallas, B. H. and Jacquin, M. F. 1990. Structure–function relationships in rat brain stem subnucleus interpolaris. IX. inputs from subnucleus caudalis. J. Neurophysiol. 64, 28–45. Hansson, S. R., Mezey, E., and Hoffman, B. J. 1998. Ontogeny of vesicular monoamine transporter mRNAs VMAT1 and VMAT2. II. Expression in neural crest derivatives and their target sites in the rat. Brain Res. Dev. Brain Res. 110, 159–174. Harding, A., Paxinos, G., and Halliday, G. 2004. The serotonin and tachykinin systems. In: Paxinos, G. (ed.), The Rat Nervous System, pp.1205–256, Elsevier. Hayes, R. L., Price, D. D., Ruda, M. A., and Dubner, R. 1981. Neuronal activity in medullary dorsal horn of awake monkeys trained in a thermal discrimination task. II. Behavioral modulation of responses to thermal and mechanical stimuli. J. Neurophysiol. 46, 428–443. Heckmann, S. M., Heckmann, J. G., HiIz, M. J., Popp, M., Marthol, H., Neundorfer, B., Henry, M. A., Johnson, L. R., Nousek-Goebl, N., and Westrum, L. E. 1996. Light microscopic localization of calcitonin gene-related peptide in the normal feline trigeminal system and following retrogasserian rhizotomy. J. Comp. Neurol. 365, 526–540. Henry, M. A., Westrum, L. E., Bothwell, M., and Johnson, L. R. 1993. Nerve growth factor receptor (p75)-immunoreactivity in the normal adult feline trigeminal system and following retrogasserian rhizotomy. J. Comp. Neurol. 335, 425–436. Hicar, M. D., Robinson, M. L., and Wu, L. C. 2002. Embryonic expression and regulation of the large zinc finger protein KRC. Genesis 33, 8–20. Hildebrand, C., Fried, K., Tuisku, F., and Johansson, C. S. 1995. Teeth and tooth nerves. Prog. Neurobiol. 45, 165–222. Hirata, H., Hu, J. W., and Bereiter, D. A. 1999. Responses of medullary dorsal horn neurons to corneal stimulation by CO2 pulses in the rat. J. Neurophysiol. 82, 2092–2107. Hirata, H., Okamoto, K., and Bereiter, D. A. 2003. GABAA receptor activation modulates corneal unit activity in rostral and caudal portions of trigeminal subnucleus caudalis. J. Neurophysiol. 90, 2837–2849. Hirata, H., Okamoto, K., Tashiro, A., and Bereiter, D. A. 2004. A novel class of neurons at the trigeminal subnucleus interpolaris/caudalis transition region monitors ocular surface fluid status and modulates tear production. J. Neurosci. 24, 4224–4232. Hirata, H., Takeshita, S., Hu, J. W., and Bereiter, D. A. 2000. Cornea–responsive medullary dorsal horn neurons: modulation by local opioid agonists and projections to thalamus and brainstem. J. Neurophysiol. 84, 1050–1061. Hocevar, A., Tomsic, M., Praprotnik, S., Hojnik, M., Kveder, T., and Rozman, B. 2003. Parasympathetic nervous system dysfunction in primary Sjogren’s syndrome. Ann. Rheum. Dis. 62, 702–704. Hoffmann, K. D. and Matthews, M. A. 1990. Comparison of sympathetic neurons in orofacial and upper extremity nerves: implications for causalgia. J. Oral Maxillofac. Surg. 48, 720–726; discussion 727. Holland, G. R. and Robinson, P. P. 1992. Axon populations in cat lingual and chorda tympani nerves. J. Dent. Res. 71, 1468–1472. Hoyes, A. D. and Barber, P. 1976. Ultrastructure of the corneal nerves in the rat. Cell Tissue Res. 172, 133–144. Hu, B., Chiang, C. Y., Hu, J. W., Dostrovsky, J. O., and Sessle, B. J. 2002. P2X receptors in trigeminal subnucleus

454 Trigeminal Mechanisms of Nociception: Peripheral and Brainstem Organization caudalis modulate central sensitization in trigeminal subnucleus oralis. J. Neurophysiol. 88, 1614–1624. Hu, J. W. and Sessle, B. J. 1984. Comparison of responses of cutaneous nociceptive and nonnociceptive brain stem neurons in trigeminal subnucleus caudalis (medullary dorsal horn) and subnucleus oralis to natural and electrical stimulation of tooth pulp. J. Neurophysiol. 52, 39–53. Huerta, M. F., Hashikawa, T., Gayoso, M. J., and Harting, J. K. 1985. The trigemino-olivary projection in the cat: contributions of individual subnuclei. J. Comp. Neurol. 241, 180–190. Hu, J. W., Sun, K. Q., Vernon, H., and Sessle, B. J. 2005. Craniofacial inputs to upper cervical dorsal horn: implications for somatosensory information processing. Brain Res. 1044, 93–106. Hunt, S. P. and Mantyh, P. W. 2001. The molecular dynamics of pain control. Nat. Rev. Neurosci. 2, 83–91. Ichikawa, H. and Sugimoto, T. 2002. The difference of osteocalcin-immunoreactive neurons in the rat dorsal root and trigeminal ganglia: co-expression with nociceptive transducers and central projection. Brain Res. 958, 459–462. Ichikawa, H., Deguchi, T., Nakago, T., Jacobowitz, D. M., and Sugimoto, T. 1994. Parvalbumin, calretinin and carbonic anhydrase in the trigeminal and spinal primary neurons of the rat. Brain Res. 655, 241–245. Ichikawa, H., Itota, T., Torii, Y., Inoue, K., and Sugimoto, T. 1999. Osteocalcin-immunoreactive primary sensory neurons in the rat spinal and trigeminal nervous systems. Brain Res. 838, 205–209. Ichikawa, H., Jacobowitz, D. M., and Sugimoto, T. 1993. Calretinin-immunoreactive neurons in the trigeminal and dorsal root ganglia of the rat. Brain Res. 617, 96–102. Ichikawa, H., Jacobowitz, D. M., and Sugimoto, T. 1997. S100 protein-immunoreactive primary sensory neurons in the trigeminal and dorsal root ganglia of the rat. Brain Res. 748, 253–257. Ikeda, M., Tanami, T., and Matsushita, M. 1984. Ascending and descending internuclear connections of the trigeminal sensory nuclei in the cat. A study with the retrograde and anterograde horseradish peroxidase technique. Neuroscience 12, 1243–1260. Ikeda, T., Terayama, R., Jue, S., Sugiyo, S., Dubner, R., and Ren, K. 2003. Differential rostral projections of caudal brainstem neurons receiving trigeminal input after masseter inflammation. J. Comp. Neurol. 465, 220–233. Isselee, H., Laat, A. D., Mot, B. D., and Lysens, R. 2002. Pressure-pain threshold variation in temporomandibular disorder myalgia over the course of the menstrual cycle. J. Orofac. Pain 16, 105–117. Ito, M., Kurita, K., Ito, T., and Arao, M. 2002. Pain threshold and pain recovery after experimental stimulation in patients with burning mouth syndrome. Psychiatry Clin. Neurosci. 56, 161–168. Izumi, H. 1999. Nervous control of blood flow in the orofacial region. Pharmacol. Ther. 81, 141–161. Jacquin, M. F., Chiaia, N. L., Haring, J. H., and Rhoades, R. W. 1990. Intersubnuclear connections within the rat trigeminal brainstem complex. Somatosensory Motor Res. 7, 399–420. Jacquin, M. F., Renehan, W. E., Mooney, R. D., and Rhoades, R. W. 1986. Structure–function relationships in rat medullary and cervical dorsal horns. I. Trigeminal primary afferents. J. Neurophysiol. 55, 1153–1186. Jacquin, M. F., Semba, K., Egger, M. D., and Rhoades, R. W. 1983. Organization of HRP-labeled trigeminal mandibular primary afferent neurons in the rat. J. Comp. Neurol. 215, 397–420. Jain, N., Qi, H. X., Catania, K. C., and Kaas, J. H. 2001. Anatomic correlates of the face and oral cavity

representations in the somatosensory cortical area 3b of monkeys. J. Comp. Neurol. 429, 455–468. Janig, W. 2003. Relationship between pain and autonomic phenomena in headache and other pain conditions. Cephalalgia 23, 43–48. Jones, D. A., Rollman, G. B., and Brooke, R. I. 1997. The cortisol response to psychological stress in temporomandibular dysfunction. Pain 72, 171–182. Julius, D. and Basbaum, A. I. 2001. Molecular mechanisms of nociception. Nature 413, 203–210. Kai-Kai, M. A. 1989. Cytochemistry of the trigeminal and dorsal root ganglia and spinal cord of the rat. Comp. Biochem. Physiol. 93A, 183–193. Kai-Kai, M. A. and Che, Y. M. 1995. Distribution of argininevasopressin in the trigeminal, dorsal root ganglia and spinal cord of the rat: depletion by capsaicin. Comp. Biochem. Physiol. A Physiol. 110, 71–78. Kanjhan, R., Housley, G. D., Burton, L. D., Christie, D. L., Kippenberger, A., Thorne, P. R., Luo, L., and Ryan, A. F. 1999. Distribution of the P2X2 receptor subunit of the ATP-gated ion channels in the rat central nervous system. J. Comp. Neurol. 407, 11–32. Katsarava, Z., Lehnerdt, G., Duda, B., Ellrich, J., Diener, H. C., and Kaube, H. 2002. Sensitization of trigeminal nociception specific for migraine but not pain of sinusitis. Neurology 59, 1450–1453. Kawabata, A., Itoh, H., Kawao, N., Kuroda, R., Sekiguchi, F., Masuko, T., Iwata, K., and Ogawa, A. 2004. Activation of trigeminal nociceptive neurons by parotid PAR-2 activation in rats. Neuroreport 15, 1617–1621. Keay, K. A., Feil, K., Gordan, B. D., Herbert, H., and Bandler, R. 1997. Spinal afferents to functionally distinct periaqueductal gray columns in the rat: an anterograde and retrograde tracing study. J. Comp. Neurol. 385, 207–229. Kelleher, K. L., Matthaei, K. I., Leck, K. J., and Hendry, I. A. 1998. Developmental expression of messenger RNA levels of the alpha subunit of the GTP-binding protein, Gz, in the mouse nervous system. Brain Res. Dev Brain Res. 107, 247–253. Kemppainen, P., Forster, C., and Handwerker, H. O. 2001. The importance of stimulus site and intensity in differences of pain-induced vascular reflexes in human orofacial regions. Pain 91, 331–338. Kenshalo, D. R. 1960. Comparison of thermal sensitivity of the forehead, lip, conjunctiva and cornea. J. Appl. Physiol. 15, 987–991. Kerr, F. W. L. 1961. Structural relation of trigeminal spinal tract to upper cervical roots and solitary nucleus in cat. Exp. Neurol. 4, 134–146. Kerr, F. W. L. 1963. The divisional organization of afferent fibres of the trigeminal nerve. Brain 86, 721–732. Khasar, S. G., Isenberg, W. M., Miao, F. J., Gear, R. W., Green, P. G., and Levine, J. D. 2001. Gender and gonadal hormone effects on vagal modulation of tonic nociception. J. Pain 2, 91–100. Khasar, S. G., Miao, F. J., Janig, W., and Levine, J. D. 1998. Vagotomy-induced enhancement of mechanical hyperalgesia in the rat is sympathoadrenal-mediated. J. Neurosci. 15, 3043–3049. Kido, M. A., Kiyoshima, T., Ibuki, T., Shimizu, S., Kondo, T., Terada, Y., and Tanaka, T. 1995. A topographical and ultrastructural study of sensory trigeminal nerve endings in the rat temporomandibular joint as demonstrated by anterograde transport of wheat germ agglutininhorseradish peroxidase (WGA-HRP). J. Dental Res. 74, 1353–1359. Kim, S. J., Lee, J. W., Chun, H. S., Joh, T. H., and Son, J. H. 1997. Monitoring catecholamine differentiation in the

Trigeminal Mechanisms of Nociception: Peripheral and Brainstem Organization embryonic brain and peripheral neurons using E. coli lacZ as a reporter gene. Mol. Cells 7, 394–398. Kirchner, A., Birklein, F., Stefan, H., and Handwerker, H. O. 2000. Left vagus nerve stimulation suppresses experimentally induced pain. Neurology 55, 1167–1171. Kitahama, K., Nagatsu, I., Geffard, M., and Maeda, T. 2000. Distribution of dopamine-immunoreactive fibers in the rat brainstem. J. Chem. Neuroanat. 18, 1–9. Kitchener, P. D., Dziegielewska, K. M., Knott, G. W., Miller, J. M., Nawratil, P., Potter, A. E., and Saunders, N. R. Fetuin expression in the dorsal root ganglia and trigeminal ganglia of perinatal rats. Int. J. Dev. Neurosci. 15, 717–727. Kitt, C. A., Gruber, K., Davis, M., Woolf, C. J., and Levine, J. D. 2000. Trigeminal neuralgia: opportunities for research and treatment. Pain 85, 3–7. Klein, R., Smeyne, R. J., Wurst, W., Long, L. K., Auerbach, B. A., Joyner, A. L., and Barbacid, M. 1993. Targeted disruption of the trkB neurotrophin receptor gene results in nervous system lesions and neonatal death. Cell 75, 113–122. Kopp, S. 2001. Neuroendocrine, immune, and local responses related to temporomandibular disorders. J. Orofacial Pain 15, 9–28. Korszun, A. 2002. Facial pain, depression and stress-connections and directions. J. Oral Pathol. Med. 31, 615–619. Korszun, A., Young, E. A., Singer, K., Carlson, N. E., Brown, M. B., and Crofford, L. 2002. Basal circadian cortisol secretion in women with temporomandibular disorders. J. Dent. Res. 81, 279–283. Krout, K. E., Belzer, R. E., and Loewy, A. D. 2002. Brainstem projections to midline and intralaminar thalamic nuclei of the rat. J. Comp. Neurol. 448, 53–101. Kruger, L. and Young, R. F. 1981. Specialized features of the trigeminal nerve and its central connections. In: The Cranial Nerves (eds. M. Samii and P. J. Jannetta), pp. 274–301. Springer-Verlag. Kruger, L., Saporta, S., and Feldman, S. G. 1977. Axonal Transport Studies of the Sensory Trigeminal Complex. In: Pain in the Trigeminal Region (eds. D. J. Anderson and B. Matthews), pp. 191–201. Elsevier. Kruger, L., Sternini, C., Brecha, N. C., and Mantyh, P. W. 1988. Distribution of calcitonin-gene-related peptide immunoreactivity in relation to the rat central somatosensory projection. J. Comp. Neurol. 273, 149–162. Kumada, M., Dampney, R. A. L., and Reis, D. J. 1977. The trigeminal depressor response: a novel vasodepressor response originating from the trigeminal system. Brain Res. 119, 305–326. Lavigne, G., Woda, A., Truelove, E., Ship, J. A., Dao, T., and Goulet, J. P. 2005. Mechanisms associated with unusual orofacial pain. J. Orofac. Pain 19, 9–21. Lennartsson, B. 1979. Muscle spindles in the human anterior digastric muscle. Acta Odontol. Scand. 37, 329–333. LeResche, L. 1997. Epidemiology of temporomandibular disorders: implications for the investigation of etiological factors. Crit. Rev. Oral Biol. Med. 8, 291–305. LeResche, L., Mancl, L., Sherman, J. J., Gandara, B., and Dworkin, S. F. 2003. Changes in temporomandibular pain and other symptoms across the menstrual cycle. Pain 106, 253–261. Levine, J. D., Collier, D. H., Basbaum, A. I., Moskowitz, M. A., and Helms, C. A. 1985. Hypothesis: the nervous system may contribute to the pathophysiology of rheumatoid arthritis. J. Rheumatol. 12, 406–411. Levitt, P. and Moore, R. Y. 1979. Origin and organization of brainstem catecholamine innervation in the rat. J. Comp. Neurol. 186, 505–528. Levy, D. and Strassman, A. M. 2002. Distinct sensitizing effects of the cAMP-PKA second messenger cascade on rat dural mechanonociceptors. J. Physiol. 538, 483–493.

455

Lewin, G. R., Lu, Y., and Park, T. J. 2004. A plethora of painful molecules. Curr. Opin. Neurobiol. 14, 443–449. Li, Y. Q., Takada, M., Ohishi, H., Shinonaga, Y., and Mizuno, N. 1992. Trigeminal ganglion neurons which project by way of axon collaterals to both the caudal spinal trigeminal and the principal sensory trigeminal nuclei. Brain Res. 594, 155–159. Linden, R. W. 1978. Properties of intraoral mechanoreceptors represented in the mesencephalic nucleus of the fifth nerve in the cat. J. Physiol. 279, 395–408. Lipton, J. A., Ship, J. A., and Larach-Robinson, D. 1993. Estimated prevalence and distribution of reported orofacial pain in the United States. J. Am. Dent. Assoc. 124, 115–121. Liu, Y., Broman, J., and Edvinsson, L. 2004. Central projections of sensory innervation of the rat superior sagittal sinus. Neuroscience 129, 431–437. Lu, J., Hathaway, C. B., and Bereiter, D. A. 1993. Adrenalectomy enhances Fos-like immunoreactivity within the spinal trigeminal nucleus induced by noxious thermal stimulation of the cornea. Neuroscience 54, 809–818. Ma, P. M. 1991. The barrelettes – architectonic vibrissal representations in the brainstem trigeminal complex of the mouse. I. Normal structural organization. J. Comp. Neurol. 309, 161–199. Macfarlane, T. V., Blinkhorn, A. S., Davies, R. M., Kincey, J., and Worthington, H. V. 2002a. Association between female hormonal factors and oro-facial pain: study in the community. Pain 97, 5–10. Macfarlane, T. V., Blinkhorn, A. S., Davies, R. M., Kincey, J., and Worthington, H. V. 2002b. Oro-facial pain in the community: prevalence and associated impact. Comm. Dent. Oral Epidemiol. 30, 52–60. MacGregor, E. A. and Hackshaw, A. 2004. Prevalence of migraine on each day of the natural menstrual cycle. Neurology 63, 351–353. Maixner, W., Fillingim, R., Sigurdsson, A., Kincaid, S., and Silva, S. 1998. Sensitivity of patients with temporomandibular disorders to experimentally evoked pain: evidence for altered temporal summation of pain. Pain 76, 71–81. Maklad, A., Quinn, T., and Fritzsch, B. 2001. Intracranial distribution of the sympathetic system in mice: DiI tracing and immunocytochemical labeling. Anat. Rec. 263, 99–111. Malick, A. and Burstein, R. 1998. Cells of origin of the trigeminohypothalamic tract in the rat. J. Comp. Neurol. 400, 125–144. Manger, P. R., Woods, T. M., and Jones, E. G. 1995. Representation of the face and intraoral structures in area 3b of the squirrel monkey (Saimiri sciureus) somatosensory cortex, with special reference to the ipsilateral representation. J. Comp. Neurol. 362, 597–607. Mantle-St, John, L. A. and Tracey, D. J. 1987. Somatosensory nuclei in the brainstem of the rat: independent projections to the thalamus and cerebellum. J. Comp. Neurol. 255, 259–271. Mantyh, P. W. 1982. The ascending input to the midbrain periaqueductal gray of the primate. J. Comp. Neurol. 211, 50–64. Mantyh, P. W., Allen, C. J., Rogers, S., DeMaster, E., Ghilardi, J. R., Mosconi, T., Kruger, L., Mannon, P. J., Taylor, I. L., and Vigna, S. R. 1994. Some sensory neurons express neuropeptide Y receptors: potential paracrine inhibition of primary afferent nociceptors following peripheral nerve injury. J. Neurosci. 14, 3958–3968. Manzoni, G. C. and Torelli, P. 2005. Epidemiology of typical and atypical craniofacial neuralgias. Neurol. Sci. 26, S65–S67. Marfurt, C. F. 1981. The somatotopic organization of the cat trigeminal ganglion as determined by the horseradish peroxidase technique. Anat. Rec. 201, 105–118.

456 Trigeminal Mechanisms of Nociception: Peripheral and Brainstem Organization Marfurt, C. F. and del Toro, D. R. 1987. Corneal sensory pathway in the rat: a horseradish peroxidase tracing study. J. Comp. Neurol. 261, 450–459. Marfurt, C. F. and Echtenkamp, S. F. 1988. Central projections and trigeminal ganglion location of corneal afferent neurons in the monkey, Macaca fascicularis. J. Comp. Neurol. 272, 370–382. Marfurt, C. F. and Rajchert, D. M. 1991. Trigeminal primary afferent projections to ‘‘non-trigeminal’’ areas of the rat central nervous system. J. Comp. Neurol. 303, 489–511. Marfurt, C. F. and Turner, D. F. 1984. The central projections of tooth pulp afferent neurons in the rat as determined by the transganglionic transport of horseradish peroxidase. J. Comp. Neurol. 223, 535–547. Margeta-Mitrovic, M., Mitrovic, I., Riley, R. C., Jan, L. Y., and Basbaum, A. I. 1999. Immunohistochemical localization of GABAB receptors in the rat central nervous system. J. Comp. Neurol. 405, 299–321. Martin-Schild, S., Gerall, A. A., Kastin, A. J., and Zadina, J. E. 1999. Differential distribution of endomorphin 1- and endomorphin2-like immunoreactivies in the CNS of the rodent. J. Comp. Neurol. 405, 450–471. Matthews, B. 1989. Autonomic mechanisms in oral sensations. Proc. Finn. Dent. Soc. 85, 365–373. McLachlan, E. M., Janig, W., Devor, M., and Michaelis, M. 1993. Peripheral nerve injury triggers noradrenergic sprouting within dorsal root ganglia. Nature 363, 543–546. McNeill, D. L., Chandler, M. J., Fu, Q. G., and Foreman, R. D. 1991. Projection of nodose ganglion cells to the rat upper cervical spinal cord in the rat. Brain Res. Bull. 27, 151–155. Menetrey, D. and Basbaum, A. I. 1987. Spinal and trigeminal projections to the nucleus of the solitary tract: a possible substrate for somatovisceral and viscerovisceral reflex activation. J. Comp. Neurol. 255, 439–450. Meng, I. D. and Bereiter, D. A. 1996. Differential distribution of Fos-like immunoreactivity in the spinal trigeminal nucleus after noxious and innocuous thermal and chemical stimulation of rat cornea. Neuroscience 72, 243–254. Meng, I. D., Hu, J. W., and Bereiter, D. A. 1998. Differential effects of morphine on corneal-responsive neurons in rostral versus caudal regions of spinal trigeminal nucleus in the rat. J. Neurophysiol. 79, 2593–2602. Meng, I. D., Hu, J. W., Benetti, A. P., and Bereiter, D. A. 1997. Encoding of corneal input in two distinct regions of the spinal trigeminal nucleus in the rat: cutaneous receptive field properties, responses to thermal and chemical stimulation, modulation by diffuse noxious inhibitory controls, and projections to the parabrachial area. J. Neurophysiol. 77, 43–56. Merchenthaler, I., Lane, M. V., Numan, S., and Dellovade, T. L. 2004. Distribution of estrogen receptor a and b in the mouse central nervous system: in vivo autoradiographic and immunocytochemical analyses. J. Comp. Neurol. 473, 270–291. Meunier, A., Latremoliere, A., Mauborgne, A., Bourgoin, S., Kayser, V., Cesselin, F., Hamon, M., and Pohl, M. 2005. Attenuation of pain-related behavior in a rat model of trigeminal neuropathic pain by viral-driven enkephalin overproduction in trigeminal ganglion neurons. Mol. Ther. 11, 608–616. Meyer, R. A., Ringkamp, M., Campbell, J. N., and Raja, S. N. 2006. Peripheral Mechanisms of Cutaneous Nociception. In: Wall and Melzack’s Textbook of Pain (eds. S. B. McMahon and M. Koltzenburg), pp. 3–34. Elsevier. Moiseenkova, V., Bell, B., Motamedi, M., Wozniak, E., and Christensen, B. 2003. Wide-band spectral tuning of heat receptors in the pit organ of the copperhead snake (Crotalinae). Am. J. Physiol. Regul. Integr. Comp. Physiol. 284, R598–R606.

Molenaar, G. J. 1978. The sensory trigeminal system of a snake in the possession of infrared receptors. I. The sensory trigeminal nuclei. J. Comp. Neurol. 179, 123–135. Molliver, D. C. and Snider, W. D. 1997. Nerve growth factor receptor TrkA is down-regulated during postnatal development by a subset of dorsal root ganglion neurons. J. Comp. Neurol. 381, 428–438. Moore, C. I. 2004. Frequency-dependent processing in the vibrissa sensory system. J. Neurophysiol. 91, 2390–2399. Mosconi, T., Snider, W. D., and Jacquin, M. F. 2001. Neurotrophin receptor expression in retrogradely labeled trigeminal nociceptors – comparisons with spinal nociceptors. Somatosens. Mot. Res. 18, 312–321. Mukasa, T., Urase, K., Momoi, M. Y., Kimura, I., and Momoi, T. 1997. Specific expression of CPP32 in sensory neurons of mouse embryos and activation of CPP32 in the apoptosis induced by a withdrawal of NGF. Biochem. Biophys. Res. Commun. 231, 770–774. Muller, L. J., Marfurt, C. F., Kruse, F., and Tervo, T. M. 2003. Corneal nerves: structure, contents and function. Exp. Eye Res. 76, 521–542. Nakamura, K., Kaneko, T., Yamashita, Y., Hasegawa, H., Katoh, H., and Negishi, M. 2000. Immunohistochemical localization of prostaglandin EP3 receptor in the rat nervous system. J. Comp. Neurol. 421, 543–569. Nakaya, Y., Kaneko, T., Shigemoto, R., Nakanishi, S., and Mizuno, N. 1994. Immunohistochemical localization of substance P receptor in the central nervous system of the adult rat. J. Comp. Neurol. 347, 249–274. Nauta, H. J., Wehman, J. C., Koliatsos, V. E., Terrell, M. A., and Chung, K. 1999. Intraventricular infusion of nerve growth factor as the cause of sympathetic fiber sprouting in sensory ganglia. J. Neurosurg. 91, 447–453. Ndiaye, A., Pinganaud, G., Buisseret-Delmas, C., Buisseret, P., and Vanderwerf, F. 2002. Organization of trigeminocollicular connections and their relations to the sensory innervation of the eyelids in the rat. J. Comp. Neurol. 448, 373–387. Neuhuber, W. L. and Zenker, W. 1989. Central distribution of cervical primary afferents in the rat, with emphasis on proprioceptive projections to vestibular, perihypoglossal, and upper thoracic spinal nuclei. J. Comp. Neurol. 280, 231–253. Nishimori, T., Sera, M., Suemune, S., Yoshida, A., Tsuru, K., Tsuiki, Y., Akisaka, T., Okamoto, T., Dateoka, Y., and Shigenaga, Y. 1986. The distribution of muscle primary afferents from the masseter nerve to the trigeminal sensory nuclei. Brain Res. 372, 375–381. Noden, D. M. 1991. Vertebrate craniofacial development: the relation between ontogenetic process and morphological outcome. Brain Behav. Evol. 38, 190–225. Nomura, S., Itoh, K., Sugimoto, T., Yasui, Y., Kamiya, H., and Mizuno, N. 1986. Mystacial vibrissae representation within the trigeminal sensory nuclei of the cat. J. Comp. Neurol. 253, 121–133. Nurmikko, T. J. and Eldridge, P. R. 2001. Trigeminal neuralgia – pathophysiology, diagnosis and current treatment. Br. J. Anaesth. 87, 117–132. Ohishi, H., Neki, A., and Mizuno, N. 1998. Distribution of a metabotropic glutamate receptor, mGluR2, in the central nervous system of the rat and mouse: an immunohistochemical study with a monoclonal antibody. Neurosci. Res. 30, 65–82. Okabe, H., Okubo, T., Adachi, H., Ishikawa, T., and Ochi, Y. 1997. Immunohistochemical demonstration of cytokeratin in human embryonic neurons arising from placodes. Brain Dev. 19, 347–352. Okamoto, K., Hirata, H., Takeshita, S., and Bereiter, D. A. 2003. Response properties of TMJ neurons in superficial laminae

Trigeminal Mechanisms of Nociception: Peripheral and Brainstem Organization at the spinomedullary junction of female rats vary over the estrous cycle. J. Neurophysiol. 89, 1467–1477. Okuse, K., Chaplan, S. R., McMahon, S. B., Luo, Z. D., Calcutt, N. A., Scott, B. P., Akopian, A. N., and Wood, J. N. 1997. Regulation of expression of the sensory neuronspecific sodium channel SNS in inflammatory and neuropathic pain. Mol. Cell Neurosci. 10, 196–207. Oliveras, J. L., Maixner, W., Dubner, R., Bushnell, M. C., Jr., Kenshalo, D. R., Duncan, G. H., Thomas, D. A., and Bates, R. 1986. The medullary dorsal horn: a target for the expression of opiate effects on the perceived intensity of noxious heat. J. Neurosci. 6, 3086–3093. Olszewski, J. 1950. On the anatomical and functional organization of the trigeminal nucleus. J. Comp. Neurol. 92, 401–413. Pajot, J., Ressot, C., Ngom, I., and Woda, A. 2003. Gonadectomy induces site-specific differences in nociception in rats. Pain 104, 367–373. Panneton, W. M. 1991. Primary afferent projections from the upper respiratory tract in the muskrat. J. Comp. Neurol. 308, 51–65. Panneton, W. M. and Burton, H. 1981. Corneal and periocular representation within the trigeminal sensory complex in the cat studied with transganglionic transport of horseradish peroxidase. J. Comp. Neurol. 199, 327–344. Panneton, W. M. and Burton, H. 1985. Projections from the paratrigeminal nucleus and the medullary and spinal dorsal horns to the peribrachial area in the cat. Neuroscience 15, 779–797. Panneton, W. M., Johnson, S. N., and Christensen, N. D. 1994. Trigeminal projections to the peribrachial region in the muskrat. Neuroscience 58, 605–625. Pappagallo, M., Oaklander, A. L., Quatrano-Piacentini, A. L., Clark, M. R., and Raja, S. N. 2000. Heterogenous patterns of sensory dysfunction in postherpetic neuralgia suggest multiple pathophysiologic mechanisms. Anesthesiology 92, 691–698. Penfield, W. and Rasmussen, T. 1950. The Cerebral Cortex of Man: a Clinical Study of Localization of Function. Macmillan. Petersen, C. C. 2003. The barrel cortex – integrating molecular, cellular and systems physiology. Pflugers Arch. 447, 126–134. Petralia, R. S., Yokotani, N., and Wenthold, R. J. 1994. Light and electron microscope distribution of the NMDA receptor subunit NMDAR1 in the rat nervous system using a selective anti-peptide antibody. J. Neurosci. 14, 667–696. Pfaller, K. and Arvidsson, J. 1988. Central distribution of trigeminal and upper cervical primary afferents in the rat studied by anterograde transport of horseradish peroxidase conjugated to wheat germ agglutinin. J. Comp. Neurol. 268, 91–108. Pfeiffer, B., Buse, E., Meyermann, R., and Hamprecht, B. 1995. Immunocytochemical localization of glycogen phosphorylase in primary sensory ganglia of the peripheral nervous system of the rat. Histochem. Cell Biol. 103, 69–74. Pioro, E. P. and Cuello, A. C. 1990. Distribution of nerve growth factor receptor-like immunoreactivity in the adult rat central nervous system. Effect of colchicine and correlation with the cholinergic system – II. Brainstem, cerebellum and spinal cord. Neuroscience 34, 89–110. Pirker, S., Schwarzer, C., Wieselthaler, A., Sieghart, W., and Sperk, G. 2000. GABA(A) receptors: immunocytochemical distribution of 13 subunits in the adult rat brain. Neuroscience 101, 815–850. Potrebic, S., Ahn, A. H., Skinner, K., Fields, H. L., and Basbaum, A. I. 2003. Peptidergic nociceptors of both trigeminal and dorsal root ganglia express serotonin 1D receptors: implications for the selective antimigraine action of triptans. J. Neurosci. 23, 10988–10997.

457

Price, D. D. and Dubner, R. 1977. Neurones that subserve the sensori-discriminative aspects of pain. Pain 3, 307–338. Price, D. D., Dubner, R., and Hu, J. W. 1976. Trigeminothalamic neurons in nucleus caudalis responsive to tactile, thermal, and nociceptive stimulation of monkey’s face. J. Neurophysiol. 39, 936–953. Price, D. D., Greenspan, J. D., and Dubner, R. 2003. Neurons involved in the exteroceptive function of pain. Pain 106, 215–219. Proske, U., Gregory, J. E., and Iggo, A. 1998. Sensory receptors in monotremes. Phil. Trans. R. Soc. Lond. B Biol. Sci. 353, 1187–1198. Puri, V., Cui, L., Liverman, C. S., Roby, K. F., Klein, R. M., Welch, K. M., and Berman, N. E. 2005. Ovarian steroids regulate neuropeptides in the trigeminal ganglion. Neuropeptides 39, 409–417. Ramien, M., Roucco, I., Cuello, A. C., Louis, M. S., and Ribeiro-da-Silva, A. 2004. Parasympathetic nerve fibers invade the upper dermis following sensory denervation of the rat lower lip skin. J. Comp. Neurol. 469, 83–95. Randich, A. and Gebhart, G. F. 1992. Vagal afferent modulation of nociception. Brain Res. Rev. 17, 77–99. Remple, M. S., Henry, E. C., and Catania, K. C. 2003. Organization of somatosensory cortex in the laboratory rat (Rattus norvegicus): evidence for two lateral areas joined at the representation of the teeth. J. Comp. Neurol. 467, 105–118. Renehan, W. E. and Jacquin, M. F. 1993. Anatomy of Central Nervous System Pathways Related to Head Pain. In: The Headaches (eds. J. Olesen, P. Tfelt-Hansen, and K. Welch), pp. 59–68. Raven. Reuss, S. 1999. Trigeminal innervation of the mammalian pineal gland. Microsc. Res. Tech. 46, 305–309. Rodrigo, J., Springall, D. R., Uttenthal, O., Bentura, M. L., Abadia-Molina, F., Riveros-Moreno, V., Martinez-Murillo, R., Polak, J. M., and Moncada, S. 1994. Localization of nitric oxide synthase in the adult rat brain. Phil. Trans. R. Soc. Lond. B Biol. Sci. 345, 175–221. Rodrigo, J., Suburo, A. M., Bentura, M. L., Fernandez, T., Nakade, S., Mikoshiba, K., Martinez-Murillo, R., and Polak, J. M. 1993. Distribution of the inositol 1,4,5trisphosphate receptor, P400, in adult rat brain. J. Comp. Neurol. 337, 493–517. Roveroni, R. C., Prada, C. A., Cecilia, M., Veiga, F. A., and Tambeli, C. H. 2001. Development of a behavioral model of TMJ pain in rats: the TMJ formalin test. Pain 94, 185–191. Rozsa, A. J. and Beuerman, R. W. 1982. Density and organization of free nerve endings in the corneal epithelium of the rabbit. Pain 14, 105–120. Ruan, H. Z., Moules, E., and Burnstock, G. 2004. Changes in P2X3 purinoceptors in sensory ganglia of the mouse during embryonic and postnatal development. Histochem. Cell Biol. 122, 539–551. Sandstedt, P. and Sorensen, S. 1995. Neurosensory disturbances of the trigeminal nerve: a long-term followup of traumatic injuries. J. Oral Maxillofac. Surg. 53, 498–505. Sarlani, E. and Greenspan, J. D. 2003. Evidence for generalized hyperalgesia in temporomandibular disorders patients. Pain 102, 221–226. Sarlani, E. and Greenspan, J. D. 2005. Why look in the brain for answers to temporomandibular disorder pain? Cells Tissues Organs 180, 69–75. Sarlani, E., Schwartz, A. H., Greenspan, J. D., and Grace, E. G. 2003. Facial pain as first manifestation of lung cancer: a case of lung cancer-related cluster headache and a review of the literature. J. Orofac. Pain 17, 262–267.

458 Trigeminal Mechanisms of Nociception: Peripheral and Brainstem Organization Saxon, D. W. and Hopkins, D. A. 1998. Efferent and collateral organization of paratrigeminal nucleus projections: an anterograde and retrograde fluorescent tracer study in the rat. J. Comp. Neurol. 402, 93–110. Schaller, B. 2004. Trigeminocardiac reflex. A clinical phenomenon or a new physiological entity? J. Neurol. 251, 658–665. Schepelmann, K., Ebersberger, A., Pawlak, M., Oppmann, M., and Messlinger, K. 1999. Response properties of trigeminal brain stem neurons with input from dura mater encephali in the rat. Neuroscience 90, 543–554. Scholz, J. and Woolf, C. J. 2002. Can we conquer pain? Nat. Neurosci. 5, 1062–1067. Sessle, B. J. 2000. Acute and chronic craniofacial pain: brainstem mechanisms of nociceptive transmission and neuroplasticity, and their clinical correlates. Crit. Rev. Oral Biol. Med. 11, 57–91. Sessle, B. J., Hu, J. W., Dubner, R., and Lucier, G. E. 1981. Functional properties of neurons in cat trigeminal subnucleus caudalis (medullary dorsal horn). II. Modulation of responses to noxious and nonnoxious stimuli by periaqueductal gray, nucleus raphe magnus, cerebral cortex, and afferent influences, and effect of naloxone. J Neurophysiol. 45, 193–207. Shenker, N., Haigh, R., Roberts, E., Mapp, P., Harris, N., and Blake, D. 2003. A review of contralateral responses to a unilateral inflammatory lesion. Rheumatology 42, 1279–1286. Shigenaga, Y., Chen, I. C., Suemune, S., Nishimori, T., Nasution, I. D., Yoshida, A., Sato, H., Okamoto, T., Sera, M., and Hosoi, M. 1986a. Oral and facial representation within the medullary and upper cervical dorsal horns in the cat. J. Comp. Neurol. 243, 388–408. Shigenaga, Y., Nakatani, Z., Nishimori, T., Suemune, S., Kuroda, R., and Matano, S. 1983. The cells of origin of cat trigeminothalamic projections: especially in the caudal medulla. Brain Res. 277, 20l–222. Shigenaga, Y., Okamoto, T., Nishimori, T., Suemune, S., Nasution, I. D., Chen, I. C., Tsuru, K., Yoshida, A., Tabuchi, K., Hosoi, M., and Tsuru, H. 1986b. Oral and facial representation in the trigeminal principal and rostral spinal nuclei of the cat. J. Comp. Neurol. 244, 1–18. Shigenaga, Y., Sera, M., Nishimori, T., Suemune, S., Nishimura, M., Yoshida, A., and Tsuru, K. 1988. The central projection of masticatory afferent fibers to the trigeminal sensory nuclear complex and upper cervical spinal cord. J. Comp. Neurol. 268, 489–507. Shigenaga, Y., Suemune, S., Nishimura, M., Nishimori, T., Sato, H., Ishidori, H., Yoshida, A., Tsuru, K., Tsuiki, Y., Dakeoka, Y., Nasution, I. D., and Hosoi, M. 1986c. Topographic representation of lower and upper teeth within the trigeminal sensory nuclei of adult cat as demonstrated by the transganglionic transport of horseradish peroxidase. J. Comp. Neurol. 251, 299–3l6. Shughrue, P. J., Lane, M. V., and Merchenthaler, I. 1997. Comparative distribution of estrogen receptor-a and -b mRNA in the rat central nervous system. J. Comp. Neurol. 388, 507–525. Silverman, J. D. and Kruger, L. 1985. Projections of the rat trigeminal sensory nuclear complex demonstrated by multiple fluorescent dye retrograde transport. Brain Res. 361, 383–388. Simonian, S. X., Delaleu, B., Caraty, A., and Herbison, A. E. 1998. Estrogen receptor expression in brainstem noradrenergic neurons of the sheep. Neuroendocrinology 67, 392–402. Sjoqvist, O. 1938. Studies on pain conduction in the trigeminal nerve. A contribution to the surgical treatment of facial pain. Acta Psychiat. Neurol. Scand. 1, 1–139. Sobreviela, T., Clary, D. O., Reichardt, L. F., Brandabur, M. M., Kordower, J. H., and Mufson E. J. 1994. TrkA-

immunoreactive profiles in the central nervous system: colocalization with neurons containing p75 nerve growth factor receptor, choline acetyltransferase, and serotonin. J. Comp. Neurol. 350, 587–611. Son, J. H., Min, N., and Joh, T. H. 1996. Early ontogeny of catecholaminergic cell lineage in brain and peripheral neurons monitored by tyrosine hydroxylase-lacZ transgene. Brain Res. Mol. Brain Res. 36, 300–308. Steinbusch, H. W. M. 1981. Distribution of serotoninimmunoreactivity in the central nervous system of the rat-cell bodies and terminals. Neuroscience 6, 557–618. Stenholm, E., Bongenhielm, U., Ahlquist, M., and Fried, K. 2002. VRl- and VRL-l-like immunoreactivity in normal and injured trigeminal dental primary sensory neurons of the rat. Acta Odontol. Scand. 60, 72–79. Strack, S., Wadzinski, B. E., and Ebner, F. F. 1996. Localization of the calcium/calmodulin-dependent protein phosphatase, calcineurin, in the hindbrain and spinal cord of the rat. J. Comp. Neurol. 375, 66–76. Strassman, A. M. and Vos, B. P. 1993. Somatotopic and laminar organization of Fos-like immunoreactivity in the medullary and cervical dorsal horn induced by noxious facial stimulation in the rat. J. Comp. Neurol. 331, 495–516. Strassman, A. M., Potrebic, S., and Maciewicz, R. J. 1994. Anatomical properties of brainstem trigeminal neurons that respond to electrical stimulation of dural blood vessels. J. Comp. Neurol. 346, 349–365. Sugimoto, T., Fujiyoshi, Y., He, Y. F., Xiao, C., and Ichikawa, H. 1997a. Trigeminal primary projection to the rat brain stem sensory trigeminal nuclear complex and surrounding structures revealed by anterograde transport of cholera toxin B subunit-conjugated and Bandeiraea simplicifolia isolectin B4-conjugated horseradish peroxidase. Neurosci. Res. 28, 361–371. Sugimoto, T., Fujiyoshi, Y., Xiao, C., He, Y. F., and Ichikawa, H. 1997b. Central projection of calcitonin gene-related peptide (CGRP)- and substance P (SP)-immunoreactive trigeminal primary neurons in the rat. J. Comp. Neurol. 378, 425–442. Svensson, P., Bjerring, P., Arendt-Nielsen, L., and Kaaber, S. 1993. Sensory and pain thresholds to orofacial argon laser stimulation in patients with chronic burning mouth syndrome. Clin. J. Pain 9, 207–215. Takemura, M., Nagase, Y., Yoshida, A., Yasuda, K., Kitamura, S., Shigenaga, Y., and Matano, S. 1993. The central projections of the monkey tooth pulp afferent neurons. Somatosens. Mot. Res. 10, 217–227. Takemura, M., Sugimoto, T., and Sakai, A. 1987. Topographic organization of central terminal region of different sensory branches of the rat mandibular nerve. Exp. Neurol. 96, 540–557. Takei, M., Shiraiwa, H., Azuma, T., Hayashi, Y., Seki, N., and Sawada, S. 2005. The possible etiopathogenic genes of Sjogren’s syndrome. Autoimmun. Rev. 4, 479–484. Tal, M. and Devor, M. 1992. Ectopic discharge in injured nerves: comparison of trigeminal and somatic afferents. Brain Res. 579, 148–151. Talley, E. M., Rosen, D. I., Lee, A., Guyenet, P. G., and Lynch, K. R. 1996. Distribution of alpha 2A-adrenergic receptor-like immunoreactivity in the rat central nervous system. J. Comp. Neurol. 372, 111–134. Tamura, S., Morikawa, Y., Miyajima, A., and Senba, E. 2003. Expression of oncostatin M receptor beta in a specific subset of nociceptive sensory neurons. Eur. J. Neurosci. 17, 2287–2298. Tanimoto, T., Takeda, M., and Matsumoto, S. 2002. Suppressive effect of vagal afferents on cervical dorsal horn neurons responding to tooth pulp electrical stimulation in the rat. Exp. Brain Res. 145, 468–479.

Trigeminal Mechanisms of Nociception: Peripheral and Brainstem Organization Tashiro, T., Higo, S., and Matsuyama, T. 1984. Soma size comparison of the trigeminal ganglion cells giving rise to the ascending and descending tracts: a horseradish peroxidase study in the cat. Exp. Neurol. 84, 37–46. Tatehata, T., Shiosaka, S., Wanaka, A., Rao, Z. R., and Tohyama, M. 1987. Immunocytochemical localization of the choline acetyltransferase containing neuron system in the rat lower brain stem. J. Hirnforsch. 28, 707–716. Tenenbaum, H. C., Mock, D., Gordan, A. S., Goldberg, M. B., Grossi, M. L., Locker, D., and Davis, K. D. 2001. Sensory and affective components of orofacial pain: is it all in your brain? Crit. Rev. Oral Biol. Med. 12, 455–468. Thackray, A. M. and Field, H. J. 1996. Differential effects of famciclovir and valaciclovir on the pathogenesis of herpes simplex virus in a murine infection model including reactivation from latency. J. Infect. Dis. 173, 291–299. Thor, K. B., Blitz-Siebert, A., and Helke, C. J. 1992. Autoradiographic localization of 5HT1 binding sites in the medulla oblongata of the rat. Synapse 10, 185–205. Toda, K., Ishii, N., and Nakamura, Y. 1997. Characteristics of mucosal nociceptors in the rat oral cavity: an in vitro study. Neurosci. Lett. 228, 95–98. Treede, R. D., Meyer, R. A., Raja, S. N., and Campbell, J. N. 1992. Peripheral and central mechanisms of cutaneous hyperalgesia. Prog. Neurobiol. 38, 397–421. Trowbridge, H. O., Franks, M., Korostoff, E., and Emling, R. 1980. Sensory response to thermal stimulation in human teeth. J. Endod. 6, 405–412. Trulsson, M. and Johansson, R. S. 2002. Orofacial mechanoreceptors in humans: encoding characteristics and responses during natural orofacial behaviors. Behav. Brain Res. 135, 27–33. Tsuzuki, K., Fukuoka, T., Sakagami, M., and Noguchi, K. 2003. Increase of preprotachykinin mRNA in the uninjured mandibular neurons after rat infraorbital nerve transection. Neurosci. Lett. 345, 57–60. Tsuzuki, K., Kondo, E., Fukuoka, T., Yi, D., Tsujino, H., Sakagami, M., and Noguchi, K. 2001. Differential regulation of P2X(3) mRNA expression by peripheral nerve injury in intact and injured neurons in the rat sensory ganglia. Pain 91, 351–360. Van Bijsterveld, O. P., Kruize, A. A., and Bleys, R. L. 2003. Central nervous system mechanisms in Sjogren’s syndrome. Br. J. Ophthalmol. 87, 128–130. Van Ham, J. J. and Yeo, C. H. 1992. Somatosensory trigeminal projections to the inferior olive, cerebellum and other precerebellar nuclei in rabbits. Eur. J. Neurosci. 4, 302–317. Vass, Z., Shore, S. E., Nuttall, A. L., Jansco, G., Brechtelsbauer, P. B., and Miller, J. M. 1997. Trigeminal ganglion innervation of the cochlea – a retrograde transport study. Neuroscience 79, 605–615. Veinante, P., Jacquin, M. F., and Deschenesm, M. 2000. Thalamic projections from the whisker-sensitive regions of the spinal trigeminal complex in the rat. J. Comp. Neurol. 420, 233–243. Verge, V. M., Wiesenfeld-Hallin, Z., and Hokfelt, T. 1993. Cholecystokinin in mammalian primary sensory neurons and spinal cord: in situ hybridization studies in rat and monkey. Eur. J. Neurosci. 5, 240–250. Villar, M. J., Cortes, R., Theodorsson, E., Wiesenfeld-Hallin, Z., Schalling, M., Fahrenkrug, J., Emson, P. C., and Hokfelt, T. 1989. Neuropeptide expression in rat dorsal root ganglion cells and spinal cord after peripheral nerve injury with special reference to galanin. Neuroscience 33, 587–604. Vos, B. P., Strassman, A. M., and Maciewicz, R. J. 1994. Behavioral evidence of trigeminal neuropathic pain following chronic constriction injury to the rat’s infraorbital nerve. J. Neurosci. 14, 2708–2723.

459

Wall, P. D. 1979. On the relation of injury to pain. Pain 6, 253–264. Wanaka, A., Milbrandt, J., and Johnson, E. M., Jr. 1991. Expression of FGF receptor gene in rat development. Development 111, 455–468. Wang, H., Rivero-Melian, C., Robertson, B., and Grant, G. 1994. Transganglionic transport and binding of the isolectin B4 from Griffonia simplicifolia I in rat primary sensory neurons. Neuroscience 62, 539–551. Wasner, G., Backonja, M. M., and Baron, R. 1998. Traumatic neuralgias: complex regional pain syndromes (reflex sympathetic dystrophy and causalgia): clinical characteristics, pathophysiological mechanisms and therapy. Neurol. Clin. 16, 851–868. Welker, C. 1971. Microelectrode delineation of fine grain somatotopic organization of (SmI) cerebral neocortex in albino rat. Brain Res. 26, 259–275. Wessman, M., Kaunisto, M. A., Kallela, M., and Palotie, A. 2004. The molecular genetics of migraine. Ann. Med. 36, 462–473. Westlund, K. N. and Craig, A. D. 1996. Association of spinal lamina I projections with brainstem catecholamine neurons in the monkey. Exp. Brain Res. 110, 151–162. Whitehead, M. C., Ganchrow, J. R., Ganchrow, D., and Yao, B. 1999. Organization of geniculate and trigeminal ganglion cells innervating single fungiform taste papillae: a study with tetramethylrhodamine dextran amine labeling. Neuroscience 93, 931–941. Wiberg, M., Westman, J., and Blomqvist, A. 1986. The projection to the mesencephalon from the sensory trigeminal nuclei. An anatomical study in the cat. Brain Res. 399, 51–68. Wolf, E., Petersson, K., Petersson, A., and Nilner, M. 2001. Longlasting orofacial pain – a study of 109 consecutive patients referred to a pain group. Swed. Dent. J. 25, 129–136. Wood, J. N., Boorman, J. P., Okuse, K., and Baker, M. D. 2004. Voltage-gated sodium channels and pain pathways. J. Neurobiol. 61, 55–71. Woolf, C. J. and Salter, M. W. 2000. Neuronal plasticity: increasing the gain in pain. Science 288, 1765–1768. Xiang, Z., Bo, X., and Burnstock, G. 1998. Localization of ATPgated P2X receptor immunoreactivity in rat sensory and sympathetic ganglia. Neurosci. Lett. 256, 105–108. Yan, Q., Radeke, M. J., Matheson, C. R., Talvenheimo, J., Welcher, A. A., and Feinstein, S. C. 1997. Immunocytochemical localization of TrkB in the central nervous system of the adult rat. J. Comp. Neurol. 378, 135–157. Yatim, N., Billig, I., Compoint, C., Buisseret, P., and BuisseretDelmas, C. 1996. Trigeminocerebellar and trigemino-olivary projections in rats. Neurosci. Res. 25, 267–283. Yazdani, C., McLaughlin, T., Smeeding, J. E., and Walt, J. 2001. Prevalence of treated dry eye disease in a managed care population. Clin. Ther. 23, 1672–1682. Yoshida, A., Dostrovsky, J. O., Sessle, B. J., and Chiang, C. Y. 1991. Trigeminal projections to the nucleus submedius of the thalamus in the rat. J. Comp. Neurol. 307, 609–625. Yoshimura, N., White, G., Weight, F. F., and de Groat, W. C. 1994. Patch-clamp recordings from subpopulations of autonomic and afferent neurons identified by axonal tracing techniques. J. Auton. Nerv. Syst. 49, 85–92. Young, R. F. and King, R. B. 1973. Fiber spectrum of the trigeminal sensory root of the baboon determined by electron microscopy. J. Neurosurg. 38, 65–71. Young, R. F. and Perryman, K. M. 1984. Pathways for orofacial pain sensation in the trigeminal brain-stem nuclear complex of the Macaque monkey. J. Neurosurg. 61, 563–568. Zerari-Mailly, F., Buisseret-Delmas, P., and Nosjean, A. 2005. Trigemino-solitarii-facial pathway in rats. J. Comp. Neurol. 487, 176–189. Zhang, X., Ji, R. R., Arvidsson, J., Lundberg, J. M., Bartfai, T., Bedecs, K., and Hokfelt, T. 1996. Expression of peptides, nitric

460 Trigeminal Mechanisms of Nociception: Peripheral and Brainstem Organization oxide synthase and NPY receptor in trigeminal and nodose ganglia after nerve lesions. Exp. Brain Res. 111, 393–404.

Further Reading Arvidsson, J. and Rice, F. L. 1991. Central projections of primary sensory neurons innervating different parts of the vibrissae follicles and intervibrissal skin on the mystacial pad of the rat. J. Comp. Neurol. 309, 1–16. Crockett, D. P., Wang, L., Zhang, R. X., and Egger, M. D. 1999. Distribution of the low-affinity neurotrophin receptor (p75) in the developing trigeminal brainstem complex in the rat. Anat. Rec. 254, 549–565. Darian-Smith, I. 1973. The Trigeminal System. In: Handbook of Sensory Physiology, vol. 2 Somatosensory System (ed. A. Iggo), pp. 271–314. Springer. Hummel, T. 2001. Oral mucosal blood flow in patients with burning mouth syndrome. Pain 90, 281–286. Kawabata, A., Feil, K., Gordan, B. D., Herbert, H., and Bandler, R. 1997. Spinal afferents to functionally distinct periaqueductal gray columns in the rat: an anterograde and retrograde tracing study. J. Comp. Neurol. 385, 207–229. Lima, D., Mendes-Ribeiro, J. A., and Combra, A. 1991. The spino-latero-reticular system of the rat: Projections from the superficial dorsal horn and structural characterization of marginal neurons involved. Neuroscience 45, 137–152. Luo, P. and Dessem, D. 1995. Inputs from identified jaw-muscle spindle afferents to trigeminothalamic neurons in the rat: a double-labeling study using retrograde HRP and intracellular biotinamide. J. Comp. Neurol. 353, 50–66.

Panneton, W. M., Klein, B. G., and Jacquin, M. F. 1991. Trigeminal projections to contralateral dorsal horn originate in midline hairy skin. Somatosensory Motor Res. 8, 165–173. Pedersen, J., Reddy, H., Funch-Jensen, P., Arendt-Nielsen, L., Gregersen, H., and Drewes, A. M. 2004. Differences between male and female responses to painful thermal and mechanical stimulation of the human esophagus. Dig. Dis. Sci. 49, 1065–1074. Rasmussen, B. K. 1993. Migraine and tension-type headache in a general population: precipitating factors, female hormones, sleep pattern and relation to lifestyle. Pain 53, 65–72. Rasmussen, B. K. 2001. Epidemiology of headache. Cephalalgia 21, 774–777. Sessle, B. J. and Hu, J. W. 1981. Raphe-induced suppression of the jaw-opening reflex and single neurons in trigeminal subnucleus oralis, and influence of naloxone and subnucleus caudalis. Pain 10, 19–36. Shigenaga, Y., Nishimura, M., Suemune, S., Nishimori, T., Doe, K., and Tsuru, H. 1989. Somatotopic organization of tooth pulp primary afferent neurons in the cat. Brain Res. 477, 66–89. Wiberg, M., Westman, J., and Blomqvist, A. 1987. Somatosensory projection to the mesencephalon: an anatomical study in the monkey. J. Comp. Neurol. 264, 92–117. Willis, W. D., Jr., Zhang, X., Honda, C. N., and Giesler, G. J., Jr. 2001. Projections from the marginal zone and deep dorsal horn to the ventrobasal nuclei of the primate thalamus. Pain 92, 267–276. Yoshida, A., Dostrovsky, J. O., and Chiang, C. Y. 1992. The afferent and efferent connections of the nucleus submedius in the rat. J. Comp. Neurol. 324, 115–133.

33 Migraine – A Disorder Involving Trigeminal Brainstem Mechanisms P J Goadsby, University of California, San Francisco, CA, USA ª 2009 Elsevier Inc. All rights reserved.

33.1 33.2 33.3 33.3.1 33.3.2 33.4 33.5 33.5.1 33.6 33.6.1 33.6.2 33.6.3 33.7 33.7.1 33.7.2 33.7.3.1 33.7.3.2 33.8 33.8.1 33.8.2 33.8.3 33.9 References

Introduction Migraine – Explaining the Clinical Features Genetics of Migraine Genetic Epidemiology Familial Hemiplegic Migraine Migraine Aura Headache – Anatomy The Trigeminal Innervation of Pain-Producing Intracranial Structures Headache Physiology – Peripheral Connections Plasma Protein Extravasation Sensitization and Migraine Neuropeptide Studies Headache Physiology – Central Connections The Trigeminocervical Complex Higher-Order Processing Thalamus Activation of modulatory regions Central Modulation of Trigeminal Pain Brain Imaging in Humans Animal Experimental Studies of Sensory Modulation Electrophysiology of Migraine in Humans What is Migraine?

33.1 Introduction Headache in general, and in particular migraine (Goadsby, P. J. et al., 2002) and cluster headache (Goadsby, P. J., 2002), is better understood now than has been the case for the last four millennia (Lance, J. W. and Goadsby, P. J., 2005). Migraine is a common, disabling recurrent disorder of the central nervous system with a core manifestation involving activation, or the perception of activation, of trigeminal nociceptive afferents (Olesen, J. et al., 2005). Here how studies of the anatomy and physiology of the pain-producing innervation of the dura mater and large cranial vessels, the trigeminovascular system, has contributed to our current understanding of one of the most common maladies of humans will be explored.

461 461 462 462 462 462 463 463 463 463 463 464 464 464 466 466 466 466 466 467 467 467 468

33.2 Migraine – Explaining the Clinical Features Migraine is in essence a familial episodic disorder whose key marker is headache with certain associated features (Table 1). It is these features that give clues to its pathophysiology, and ultimately will provide insights leading to new treatments. The essential elements to be considered are: Genetics of migraine; Physiological basis for the aura; Anatomy of head pain, particularly that of the trigeminovascular system; Physiology and pharmacology of activation of the peripheral branches of ophthalmic branch of the trigeminal nerve;

461

462 Migraine – A Disorder Involving Trigeminal Brainstem Mechanisms Table 1 International Headache Society features of migraine (Headache Classification Committee of the International Headache Society, 2004) Repeated episodic headache (4–72 h) with the following features: Any two of: Any one of: unilateral nausea/vomiting throbbing photophobia and phonophobia worsened by movement moderate or severe

Physiology and pharmacology of the trigeminal nucleus, in particular its caudal most part, the trigeminocervical complex (TCC); Brainstem and diencephalic modulatory systems that influence trigeminal pain transmission and other sensory modality processing.

33.3 Genetics of Migraine One of the most important aspects of the pathophysiology of migraine is the inherited nature of the disorder. It is clear from clinical practice that many patients have first-degree relatives who also suffer from migraine (Lance, J. W. and Goadsby, P. J., 2005). Transmission of migraine from parents to children has been reported as early as the seventeenth century, and numerous published studies have reported a positive family history.

33.3.1

Genetic Epidemiology

Studies of twin pairs are the classical method to investigate the relative importance of genetic and environmental factors. A Danish study included 1013 monozygotic and 1667 dizygotic twin pairs of the same gender, obtained from a population-based twin register. The pairwise concordance rate was significantly higher among monozygotic than dizygotic twin pairs (P < 0.05). Several studies have attempted to analyze the possible mode of inheritance in migraine families and conflicting results have been obtained. Both twin studies and population-based epidemiological surveys strongly suggest that migraine without aura is a multifactorial disorder, caused by a combination of genetic and environmental factors.

33.3.2

Familial Hemiplegic Migraine

In approximately 50% of the reported families, familial hemiplegic migraine (FHM) has been assigned to chromosome 19p13. Few clinical differences have been found between chromosome 19linked and unlinked FHM families. Indeed, the clinical phenotype does not associate particularly with the known mutations. The most striking exception is cerebellar ataxia, which occurs in approximately 50% of the chromosome 19-linked, but in none of the unlinked families. Another less striking difference includes the fact that patients from chromosome 19linked families are more likely to have attacks that can be triggered by minor head trauma or are that associated by coma. The biological basis for the linkage to chromosome 19 is mutations (Ophoff, R. A. et al., 1996) involving the Cav2.1 (P/Q) type voltage-gated calcium channel CACNA1A gene. Now known as FHM-I, this mutation is responsible for about 50% of identified families. Mutations in the ATP1A2 gene have been identified to be responsible for about 20% of FHM families. Interestingly, the phenotype of some FHM-II involves epilepsy, while it has also been suggested that alternating hemiplegia of childhood can be due to ATP1A2 mutations. The latter cases are most unusual for migraine. Most recently mutations in the neuronal voltage-gated sodium channel SCN1A have been identified as the cause of FHM-III, thus continuing the ionopathic theme. Taken together, the known mutations suggest that migraine, or at least the neurological manifestations currently called the aura, are caused by an ionopathy. Linking the channel disturbance for the first time to the aura process has demonstrated that human mutations expressed in a knockin mouse produce a reduced threshold for cortical spreading depression (CSD), which has some profound implications for understanding that process.

33.4 Migraine Aura Migraine aura is defined as a focal neurological disturbance manifest as visual, sensory, or motor symptoms (Headache Classification Committee of the International Headache Society, 2004). It is seen in about 30% of patients, and it is clearly neurally driven. The case for the aura being the human equivalent of the CSD of Leao has been

Migraine – A Disorder Involving Trigeminal Brainstem Mechanisms

well made (Lauritzen, M., 1994). In humans, visual aura has been described as affecting the visual field, suggesting the visual cortex, and it starts at the center of the visual field and propagates to the periphery at a speed of 3 mm min1. This is very similar to spreading depression described in rabbits. Blood flow studies in patients have also shown that a focal hyperemia tends to precede the spreading oligemia, and again this is similar to what would be expected with spreading depression. After this passage of oligemia, the cerebrovascular response to hypercapnia in patients is blunted while autoregulation remains intact. Again this pattern is repeated with experimental spreading depression. Human observations have rendered the arguments reasonably sound that human aura has as its equivalent in animals in CSD. An area of controversy surrounds whether aura triggers the rest of the attack, and is indeed painful. Based on the available experimental and clinical data this author is not at all convinced that aura is painful per se, but this does not diminish its interest or the importance of understanding it. Indeed therapeutic developments may shed further light on these relationships, and studies are required to understand how in some patients aura is clearly not a sufficient trigger to pain.

33.5 Headache – Anatomy 33.5.1 The Trigeminal Innervation of PainProducing Intracranial Structures Surrounding the large cerebral vessels, pial vessels, large venous sinuses, and dura mater is a plexus of largely unmyelinated fibers that arise from the ophthalmic division of the trigeminal ganglion and in the posterior fossa from the upper cervical dorsal roots. Trigeminal fibers innervating cerebral vessels arise from neurons in the trigeminal ganglion that contain substance P and calcitonin gene-related peptide (CGRP), both of which can be released when the trigeminal ganglion is stimulated either in humans or cats (Goadsby, P. J. et al., 1988). Stimulation of the cranial vessels, such as the superior sagittal sinus (SSS), is certainly painful in humans (Wolff, H. G., 1948). Human dural nerves that innervate the cranial vessels largely consist of small diameter myelinated and unmyelinated fibers that almost certainly subserve a nociceptive function.

463

33.6 Headache Physiology – Peripheral Connections 33.6.1

Plasma Protein Extravasation

Moskowitz M. A. (1990) has provided a series of experiments to suggest that the pain of migraine may be a form of sterile neurogenic inflammation. Although this seems clinically implausible, the model system has been helpful in understanding some aspects of trigeminovascular physiology. Neurogenic plasma extravasation can be seen during electrical stimulation of the trigeminal ganglion in the rat. Plasma extravasation can be blocked by ergot alkaloids, indomethacin, acetylsalicylic acid, and the serotonin-5-HT1B/1D agonist, sumatriptan. The pharmacology of abortive antimigraine drugs has been reviewed in detail. In addition there are structural changes in the dura mater that are observed after trigeminal ganglion stimulation. These include mast cell degranulation and changes in postcapillary venules including platelet aggregation. While it is generally accepted that such changes, and particularly the initiation of a sterile inflammatory response, would cause pain, it is not clear whether this is sufficient of itself, or requires other stimulators, or promoters. Preclinical studies suggest that CSD may be a sufficient stimulus to activate trigeminal neurons, although this has been a controversial area. Although plasma extravasation in the retina, which is blocked by sumatriptan, can be seen after trigeminal ganglion stimulation in experimental animals, no changes are seen with retinal angiography during acute attacks of migraine or cluster headache. A limitation of this study was the probable sampling of both retina and choroids elements in rats, given that choroidal vessels have fenestrated capillaries. Clearly, however, blockade of neurogenic plasma protein extravasation is not completely predictive of antimigraine efficacy in humans as evidenced by the failure in clinical trials of substance P, neurokinin-1 antagonists, specific plasma protein extravasation (PPE) blockers, CP122,288 and 4991w93, an endothelin antagonist, and a neurosteroid. The implications of these data have been recently reviewed (Peroutka, S. J., 2005).

33.6.2

Sensitization and Migraine

While it is highly doubtful that there is a significant sterile inflammatory response in the dura mater during migraine, it is clear that some form of sensitization takes

464 Migraine – A Disorder Involving Trigeminal Brainstem Mechanisms

place during migraine, since allodynia is common. About two-thirds of patients complain of pain from non-noxious stimuli, allodynia (Selby, G. and Lance, J. W., 1960). A particularly interesting aspect is the demonstration of allodynia in the upper limbs ipsilateral and contralateral to the pain. This finding is consistent with at least third-order neuronal sensitization, such as sensitization of thalamic neurons, and firmly places the pathophysiology within the central nervous system. Sensitization in migraine may be peripheral with local release of inflammatory markers, which would certainly activate trigeminal nociceptors. More likely in migraine is a form of central sensitization, which may be classical central sensitization, or a form of disinhibitory sensitization with dysfunction of descending modulatory pathways (Knight, Y. E. et al., 2002). Just as dihydroergotamine (DHE) can block trigeminovascular nociceptive transmission, probably at least by a local effect in the TCC, DHE can block central sensitization associated with dural stimulation by an inflammatory soup, as can cyclo-oxygenase block both sensitization and trigeminocervical transmission. 33.6.3

Neuropeptide Studies

Electrical stimulation of the trigeminal ganglion in both humans and cats leads to increases in extracerebral blood flow and local release of both CGRP and SP (Goadsby, P. J. et al., 1988). In the cat trigeminal ganglion stimulation also increases cerebral blood flow by a pathway traversing the greater superficial petrosal branch of the facial nerve (Goadsby, P. J. and Duckworth, J. W., 1987) again releasing a powerful vasodilator peptide, vasoactive intestinal polypeptide (VIP; May, A. and Goadsby, P. J., 1999). Interestingly, the VIPergic innervation of the cerebral vessels is predominantly anterior rather than posterior, and this may contribute to this region’s vulnerability to spreading depression, explaining why the aura is so very often seen to commence posteriorly. Stimulation of the more specifically vascular painproducing superior sagittal sinus increases cerebral blood flow and jugular vein CGRP levels. Human evidence that CGRP is elevated in the headache phase of migraine (Goadsby, P. J. et al., 1990), supporting the view that the trigeminovascular system may be activated in a protective role in these conditions. Moreover, nitric oxide (NO)-donor-triggered migraine, which is in essence typical migraine, also results in increases in CGRP that are blocked by sumatriptan, just as in spontaneous migraine (Goadsby, P. J. and Edvinsson, L., 1993). It is of

interest in this regard that compounds that have not shown activity in migraine (Peroutka, S. J., 2005), notably the conformationally restricted analogue of sumatriptan, CP122,288, and the conformationally restricted analog of zolmitriptan, 4991w93, were both ineffective inhibitors of CGRP release after superior sagittal sinus in cats. The recent development of nonpeptide highly specific CGRP antagonists, and the announcement of proof-ofconcept for a CGRP antagonist in acute migraine (Olesen, J. et al., 2004), firmly establishes this as a novel and important new emerging principle for acute migraine. At the same time the lack of any effect of CGRP blockers on plasma protein extravasation, explains in some part why that model has proved inadequate at translation into human therapeutic approaches (Peroutka, S. J., 2005).

33.7 Headache Physiology – Central Connections 33.7.1

The Trigeminocervical Complex

Fos immunohistochemistry is a method for looking at activated cells by plotting the expression of Fos protein. After meningeal irritation with blood Fos expression is noted in the trigeminal nucleus caudalis, while after stimulation of the superior sagittal sinus Fos-like immunoreactivity is seen in the trigeminal nucleus caudalis and in the dorsal horn at the C1 and C2 levels in cats and monkey. These latter findings are in accord with similar data using 2-deoxyglucose measurements with superior sagittal sinus stimulation. Similarly, stimulation of a branch of C2, the greater occipital nerve, increases metabolic activity in the same regions, i.e., trigeminal nucleus caudalis and C1/2 dorsal horn, and fos expression can be elicited by injection of mustard oil into the occipital muscles. In experimental animals one can record directly from trigeminal neurons with both supratentorial trigeminal input and input from the greater occipital nerve, a branch of the C2 dorsal root (Bartsch, T. and Goadsby, P. J., 2002). Stimulation of the greater occipital nerve for 5 min results in substantial increases in responses to supratentorial dural stimulation, which can last for over 1 h. Conversely, stimulation of the middle meningeal artery dura mater with the C-fiber irritant mustard oil sensitizes responses to occipital muscle stimulation. Taken together these data suggest convergence of cervical and ophthalmic inputs at the level of the secondorder neuron. Moreover, stimulation of a lateralized

Migraine – A Disorder Involving Trigeminal Brainstem Mechanisms

structure, the middle meningeal artery, produces Fos expression bilaterally in both cat and monkey brains. This group of neurons from the superficial laminas of trigeminal nucleus caudalis and C1/2 dorsal horns should be regarded functionally as the TCC. These data demonstrate that trigeminovascular nociceptive information comes by way of the most caudal cells. This concept provides an anatomical explanation for the referral of pain to the back of the head in migraine. Moreover, experimental pharmacological evidence suggests that some abortive antimigraine drugs, such as, ergot derivatives, acetylsalicylic acid, sumatriptan, eletriptan, naratriptan, rizatriptan, and zolmitriptan can have actions at these

465

second-order neurons that reduce cell activity and suggest a further possible site for therapeutic intervention in migraine. This action can be dissected out to involve each of the 5-HT1B, 5-HT1D, and 5-HT1F receptor subtypes, and are consistent with the localization of these receptors on peptidergic nociceptors. Interestingly, triptans also influence the CGRP promoter, and regulate CGRP secretion from neurons in culture, as well as perhaps require cell surface expression for their effect. Furthermore, the demonstration that some part of this action is postsynaptic with either 5-HT1B or 5-HT1D receptors located nonpresynatically offers a prospect of highly anatomically localized treatment options (Figure 1).

Ventroposteromedial thalamus Posterior hypothalamus Periaqueductal gray matter (PAG)

Dural vasculature

PAG

Locus coeruleus (LC) LC Trigeminal ganglion

Cervical muscle and joints

Cervical dorsal root ganglion

Trigeminocervical complex

Midline

Figure 1 Illustration of the some elements of migraine biology. Patients inherit a dysfunction in brain control systems for pain and other afferent stimuli, which can be triggered and are in turn capable of activating the trigeminovascular system as the initiating event in a positive feedback of neurally driven vasodilatation. Nociceptive afferents from the cervical region terminate in the trigeminocervical complex (illustrated by Fos protein expression in the superficial laminas) and this accounts for the nontrigeminal distribution of pain in many patients. These afferents project to the thalamus, including ventroposteromedial thalamus, and are at least influenced by neurons in the posterior hypothalamic gray, the periaqueductal gray (PAG), and probably by neurons of the nucleus locus coeruleus in the pons. Functional brain imaging suggests that the brainstem, notably the pons as illustrated after Bahra, A., Matharu, M. S., Buchel, C., Frackowiak, R. S. J., and Goadsby, P. J. 2001. Brainstem activation specific to migraine headache. Lancet 357, 1016–1017, is a pivotal region in the migraine process.

466 Migraine – A Disorder Involving Trigeminal Brainstem Mechanisms Table 2

Neuroanatomical processing of vascular head pain Structure

Comments

Target innervation: Cranial vessels Dura mater

Ophthalmic branch of trigeminal nerve

First Second

Trigeminal ganglion Trigeminal nucleus (quintothalamic tract)

Third

Thalamus

Modulatory

Midbrain Hypothalamus Cortex

Final

33.7.2

Higher-Order Processing

Following transmission in the caudal brainstem and high cervical spinal cord information is relayed rostrally (Table 2).

33.7.3.1

Thalamus Processing of vascular nociceptive signals in the thalamus occurs in the ventroposteromedial (VPM) thalamus, medial nucleus of the posterior complex, and in the intralaminar thalamus. It has been shown by application of capsaicin to the superior sagittal sinus that trigeminal projections with a high degree of nociceptive input are processed in neurons particularly in the ventroposteromedial thalamus and in its ventral periphery. These neurons in the VPM can be modulated by activation of gamma-aminobutyric acid (GABA)A inhibitory receptors, and perhaps of more direct clinical relevance by propranolol though a 1-adrenoceptor mechanism (Shields, K. G. and Goadsby, P. J., 2005). Remarkably, triptans through 5-HT1B/1D mechanisms can also inhibit VPM neurons locally, as demonstrated by microiontophoretic application, suggesting a hitherto unconsidered locus of action for triptans in acute migraine. Human imaging studies have confirmed activation of thalamus contralateral to pain in acute migraine (Bahra, A. et al., 2001).

33.7.3.2

Activation of modulatory regions

Stimulation of nociceptive afferents by stimulation of the superior sagittal sinus in cats activates neurons in

Middle cranial fossa Trigeminal nucleus caudalis and C1/C2 dorsal horns Ventrobasal complex Medial nucleus of posterior group Intralaminar complex Periaqueductal gray matter ? Insulas Frontal cortex Anterior cingulate cortex Basal ganglia

the ventrolateral periaqueductal gray matter (PAG). PAG activation in turn feeds back to the TCC with an inhibitory influence. PAG is clearly included in the area of activation seen in positron emission tomography (PET) studies in migraineurs. This typical negative feedback system will be further considered below as a possible mechanism for the symptomatic manifestations of migraine. Another potentially modulatory region activated by stimulation of nociceptive trigeminovascular input is the posterior hypothalamic gray. This area is crucially involved in several primary headaches, notably cluster headache (Goadsby, P. J., 2002), Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), paroxysmal hemicrania and hemicrania continua. Moreover, the clinical features of the premonitory phase, and other features of the disorder, suggest dopamine neuron involvement. Orexinergic neurons in the posterior hypothalamus can be both pro- and antinociceptive, offering a further possible region whose dysfunction might involve the perception of head pain.

33.8 Central Modulation of Trigeminal Pain 33.8.1

Brain Imaging in Humans

Functional brain imaging with PET has demonstrated activation of the dorsal midbrain, including the PAG, and in the dorsal pons, near the locus coeruleus, in studies during migraine without aura.

Migraine – A Disorder Involving Trigeminal Brainstem Mechanisms

Dorsolateral pontine activation is seen with PET in spontaneous episodic and chronic migraine, and with nitrogylcerin-triggered attacks (Bahra, A. et al., 2001; Afridi, S. et al., 2005). These areas are active immediately after successful treatment of the headache but are not active interictally. The activation corresponds with the brain region that Raskin initially reported, and confirmed, to cause migrainelike headache when stimulated in patients with electrodes implanted for pain control. Similarly, excess iron in the PAG of patients with episodic and chronic migraine, and chronic migraine can develop after a bleed into a cavernoma in the region of the PAG, or with a lesion of the pons. What could dysfunction of these brain areas lead to? 33.8.2 Animal Experimental Studies of Sensory Modulation It has been shown in experimental animals that stimulation of nucleus locus coeruleus, the main central noradrenergic nucleus, reduces cerebral blood flow in a frequency-dependent manner (Goadsby, P. J. et al., 1982) through an 2-adrenoceptor-linked mechanism. This reduction is maximal in the occipital cortex. While a 25% overall reduction in cerebral blood flow is seen, extracerebral vasodilatation occurs in parallel (Goadsby, P. J. et al., 1982). In addition, the main serotonin-containing nucleus in the brainstem, the midbrain dorsal raphe nucleus, can increase cerebral blood flow when activated. Furthermore, stimulation of PAG will inhibit sagittal sinus-evoked trigeminal neuronal activity in cats, while blockade of P/Q-type voltage-gated Ca2þ channels in the PAG facilitates trigeminovascular nociceptive processing (Knight, Y. E. et al., 2002) with the local GABAergic system in the PAG still intact. 33.8.3 Electrophysiology of Migraine in Humans Studies of evoked potentials and event-related potentials provide some link between animal studies and human functional imaging. Authors have shown changes in neurophysiological measures of brain activation but there is much discussion as to how to interpret such changes (Schoenen, J. et al., 2003). Perhaps the most reliable theme is that the migrainous brain does not habituate to signals in a normal way. Similarly, contingent negative variation (CNV), an event related potential, is abnormal in migraineurs

467

compared to controls. Changes in CNV predict attacks and preventive therapies alter, normalize, such changes. Attempts to correlate clinical phenotypes with electrophysiological changes, may enhance further studies in this area.

33.9 What is Migraine? Migraine is an inherited, episodic disorder involving sensory sensitivity. Patients complain of pain in the head that is throbbing, but there is no reliable relationship between vessel diameter and the pain, or its treatment. They complain of discomfort from normal lights and the unpleasantness of routine sounds. Some mention otherwise pleasant odors are unpleasant. The anatomical connections of, for example, the pain pathways are clear, the ophthalmic division of the trigeminal nerve subserves sensation within the cranium and explains why the top of the head is headache, and the maxillary division is facial pain. The convergence of cervical and trigeminal afferents explains why neck stiffness or pain is so common in primary headache. The genetics of channelopathies is opening up a plausible way to think about the episodic nature of migraine. However, where is the lesion, what is actually the pathology? Migraine aura cannot be the trigger alone, there is no evidence at all after 4000 years that it occurs in more than 30% of migraine patients; aura can be experienced without pain at all, and is seen in the other primary headaches. Perhaps electrophysiological changes in the brain have been mislabeled as hyperexcitability whereas dyshabituation might be a simpler explanation. If migraine was basically an attentional problem with changes in cortical synchronization (Niebur, E. et al., 2002), hypersynchronization, all its manifestations could be accounted for in a single over-arching pathophysiological hypothesis of a disturbance of subcortical sensory modulation systems. While it seems likely that the trigeminovascular system, and its cranial autonomic reflex connections, the trigeminal-autonomic reflex (May, A. and Goadsby, P. J., 1999), act as a feed-forward system to facilitate the acute attack, the fundamental problem in migraine is in the brain. Unraveling its basis will deliver great benefits to patients and considerable understanding of some very fundamental neurobiological processes.

468 Migraine – A Disorder Involving Trigeminal Brainstem Mechanisms

Acknowledgment The work of the author has been supported by the Migrane Trust.

References Afridi, S., Matharu, M. S., Lee, L., Kaube, H., Friston, K. J., Frackowiak, R. S. J., and Goadsby, P. J. 2005. A PET study exploring the laterality of brainstem activation in migraine using glyceryl trinitrate. Brain 128, 932–939. Bahra, A., Matharu, M. S., Buchel, C., Frackowiak, R. S. J., and Goadsby, P. J. 2001. Brainstem activation specific to migraine headache. Lancet 357, 1016–1017. Bartsch, T. and Goadsby, P. J. 2002. Stimulation of the greater occipital nerve induces increased central excitability of dural afferent input. Brain 125, 1496–1509. Goadsby, P. J. 2002. Pathophysiology of cluster headache: a trigeminal autonomic cephalgia. Lancet Neurol. 1, 37–43. Goadsby, P. J. and Duckworth, J. W. 1987. Effect of stimulation of trigeminal ganglion on regional cerebral blood flow in cats. Am. J. Physiol. 253, R270–R274. Goadsby, P. J. and Edvinsson, L. 1993. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann. Neurol. 33, 48–56. Goadsby, P. J., Edvinsson, L., and Ekman, R. 1988. Release of vasoactive peptides in the extracerebral circulation of man and the cat during activation of the trigeminovascular system. Ann. Neurol. 23, 193–196. Goadsby, P. J., Edvinsson, L., and Ekman, R. 1990. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann. Neurol. 28, 183–187. Goadsby, P. J., Lambert, G. A., and Lance, J. W. 1982. Differential effects on the internal and external carotid circulation of the monkey evoked by locus coeruleus stimulation. Brain Res. 249, 247–254. Goadsby, P. J., Lipton, R. B., and Ferrari, M. D. 2002. Migraine – current understanding and treatment. New Engl. J. Med. 346, 257–270. Headache Classification Committee of the International Headache Society. 2004. The International Classification of Headache Disorders (2nd edn.). Cephalalgia 24, 1–160.

Knight, Y. E., Bartsch, T., Kaube, H., and Goadsby, P. J. 2002. P/Q-type calcium channel blockade in the PAG facilitates trigeminal nociception: a functional genetic link for migraine? J. Neurosci. 22, 1–6. Lance, J. W. and Goadsby, P. J. 2005. Mechanism and Management of Headache. Elsevier. Lauritzen, M. 1994. Pathophysiology of the migraine aura. The spreading depression theory. Brain 117, 199–210. May, A. and Goadsby, P. J. 1999. The trigeminovascular system in humans: pathophysiological implications for primary headache syndromes of the neural influences on the cerebral circulation. J. Cerebr. Blood Flow Metabol. 19, 115–127. Moskowitz, M. A. 1990. Basic mechanisms in vascular headache. Neurolog. Clin. 8, 801–815. Niebur, E., Hsiao, S. S., and Johnson, K. O. 2002. Synchrony: a neural mechanism for attentional selection? Curr. Opin. Neurobiol. 12, 190–194. Olesen, J., Diener, H. C., Husstedt, I. W., Goadsby, P. J., Hall, D., Meier, U., Pollentier, S., and Lesko, L. M. 2004. Calcitonin gene-related peptide (CGRP) receptor antagonist BIBN4096BS is effective in the treatment of migraine attacks. New Engl. J. Med. 350, 1104–1110. Olesen, J., Tfelt-Hansen, P., Ramadan, N., Goadsby, P. J., and Welch, K. M. A. 2005. The Headaches. Lippincott, Williams & Wilkins. Ophoff, R. A., Terwindt, G. M., Vergouwe, M. N., van Eijk, R., Oefner, P. J., Hoffman, S. M. G., Lamerdin, J. E,, Mohrenweiser, H. W., Bulman, D. E., Ferrari, M., Haan, J., Lindhout, D., van Ommen, G. J., Hofker, M. H., Ferrari, M. D., and Frants, R. R. 1996. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2þ channel gene CACNL1A4. Cell 87, 543–552. Peroutka, S. J. 2005. Neurogenic inflammation and migraine: implications for therapeutics. Mol. Intervent. 5, 306–313. Schoenen, J., Ambrosini, A., Sandor, P. S., and Maertens de Noordhout, A. 2003. Evoked potentials and transcranial magnetic stimulation in migraine: published data and viewpoint on their pathophysiologic significance. Clin. Neurophysiol. 114, 955–972. Selby, G. and Lance, J. W. 1960. Observations on 500 cases of migraine and allied vascular headache. J. Neurol. Neurosurg. Psychiatry 23, 23–32. Shields, K. G. and Goadsby, P. J. 2005. Propranolol modulates trigeminovascular responses in thalamic ventroposteromedial nucleus: a role in migraine? Brain 128, 86–97. Wolff, H. G. 1948. Headache and Other Head Pain. Oxford University Press.

34 Tooth Pain M R Byers, University of Washington, Seattle WA, USA ª 2009 Elsevier Inc. All rights reserved.

34.1 34.2 34.2.1 34.2.2 34.2.3 34.3 34.4 References

Introduction Dental Sensory Mechanisms Normal Teeth/Acute Pain Inflammatory Tooth Pain Dental Neuropathic Pain Tooth Pain: Diagnosis and Management Conclusions

470 470 470 472 472 473 474 474

Glossary ASIC receptors Acid-sensing ion channels that detect low pH, a typical condition of pulpitis. atypical odontalgia A condition in which tooth pain derives from neuropathic or referred mechanisms. Tooth extractions or root canals do not relieve the pain. BK receptors Activated by the inflammatory mediator, bradykinin. convergence Many sensory afferents from multiple tissues project to individual central trigeminal neurons. dentin Specialized, calcified, collagenous matrix that surrounds the pulp. hot tooth An inflamed tooth that resists regional anesthesia and remains sensitive when neighboring teeth are numb. hypersensitive dentin Sharp pain elicited from light touch to exposed dentin. ionotropic receptors Activated by specific ligands causing ion flux through receptor pores. mesencephalic trigeminal nucleus Location of cell bodies of primary sensory neurons that innervate stretch receptors in periodontal ligament, sutures, or mastication muscles. metabotropic receptors Interaction with ligand activates G-protein intracellular signaling. NK receptors Receptors for neurokinins such as substance P or neurokinin A. nucleus caudalis Caudal region of spinal trigeminal subnuclei, specialized for processing, relaying and modulating orofacial pain.

odontalgia Tooth pain. odontoblast Neural crest-derived cells that make dentin and regulate the pulp–dentin barrier. P2 receptors Purinergic nucleotide receptors that respond to adenosine triphosphate (ATP). periapex Region at base of root socket that surrounds the root apex, and includes periodontal ligament, neurovascular bundles and endings, and alveolar bone. prepain The first sensation (tingling, vibration, or touch) elicited by electrical stimulation of teeth. It changes to sharp tooth pain at stronger levels of stimulation. pulpitis Inflamed tooth pulp that can be healed locally (reversible), that can consume the pulp and spread into periapex (irreversible), or that can be undetected (silent) until it reaches the periapex. receptive field Patch of tissue that activates a primary afferent or central neuron. referred pain Pain that is felt at a different site from the neural activity that causes it. Ruffini mechanoreceptors Complex stretch mechanoreceptors located in periodontal ligament. Trk receptors Tyrosine kinase receptors that respond to neurotrophin factors. TRP receptors Transient receptor potential channels (vanilloid receptor family) that are activated by capsaicin, heat, or low pH.

469

470 Tooth Pain

34.1 Introduction Tooth pain is the most common type of orofacial pain (Lipton, J. et al., 1993; Hargreaves, K. M., 2002). Dental nerve fibers branch centrally to activate many neurons in the trigeminal brainstem complex or extratrigeminal relay sites, and those central neurons also receive extensive convergent input from other orofacial tissues, making location of tooth pain difficult. However, most of the time our teeth do not hurt, and most dental neural activity is unperceived. The sensory functions of tooth nerves are presented here, along with unusual features of central processing, mechanisms, perception, diagnosis, and treatment of tooth pain, which can be sharp or dull, focused or diffuse, episodic or relentless, referred or neuropathic (for reviews see: Na¨rhi, M. V. O. et al., 1996; Olgart, L., 1996; Byers, M. R. and Na¨rhi, M. V. O., 1999; Dionne, R. A. and Berthold, C. W., 2001; Byers, M. R. and Na¨rhi, M. V. O., 2002; Hargreaves, K. M.,

2002; Hu, J. W., 2004; Lavigne, G. et al., 2004; Truelove, E., 2004; Sessle, B. J., 2005; Henry, M. A. and Hargreaves, K. M., 2007).

34.2 Dental Sensory Mechanisms 34.2.1

Normal Teeth/Acute Pain

A-fibers respond especially well to acute stimuli that move fluid in dentin (Bra¨nnstro¨m, M and A˚stro¨m, A., 1972) and C-fibers respond to acute heat stimuli or pulp damage (Na¨rhi, M. V. O. et al., 1996; Na¨rhi, M. V. O., 2005). Different factors affect axonal conduction in trigeminal nerves, ganglion, central tracts, and synaptic termination regions in the brainstem (Figure 1). Dental afferents project to low threshold mechanoreceptive, nociceptive-specific, and widedynamic-range central neurons, all of which receive a major input from other tissues, often from more than one trigeminal division (Sessle, B. J. et al., 1986).

Figure 1 Interactions affecting dental neuronal function. ATP, adenosine triphosphate; LTM, low-threshold mechanoreceptor; NS, nociceptive specific; WDR, wide-dynamic neuron. Target Neurons: reprinted from Pain, 27, Sessele, B. J., Hu J. W., Amano, N., and Zhong, G., Convergence of cutaneous, tooth pulp, visceral, neck and muscle afferents onto nociceptive and nonnociceptive neurons in trigeminal subnucleus caudalis (medullary dorsal horn) and its implications for referred pain, 219–235, Copyright 1986, with permission from The International Association for the Study of Pain.

Tooth Pain

Most tooth pain perceptions are acute, and they derive from activation of neurons in nucleus caudalis, although rostral trigeminal nuclei are also involved, and there are other connection sites such as the paratrigeminal nucleus and reticular formation (Sessle, B. J., 2000; 2005). Human studies show three kinds of evoked sensation from dental nerves: prepain, sharp pain, and dull ache. The first two depend on activation of fast A- and A--fibers and the latter involves polymodal capsaicin-sensitive slow A- and C-fibers (Na¨rhi, M. V. O. et al., 1996; Ikeda, H. et al., 1997), some of which express neuropeptide receptors for autocrine modulation (Suzuki, H. et al., 2002). Each of our teeth is innervated by many hundreds of highly branched trigeminal neurons, and the density of sensory nerve endings in coronal pulp and inner dentin is enormous (Figure 2). However, most intradental neural activity involves unperceived neural efferent functions or reflexes, such as vasodilatation by neuropeptides from sensory fibers that is counterbalanced by sympathetic-mediated vasoconstriction (Figure 3; Olgart, L. 1996; Fristad, I. et al., 1997; Berggreen, E. and Heyeraas, K. J., 2000). Touch sensations during chewing come from Ruffini mechanoreceptors in the periodontal ligament outside the roots, while unconscious aspects of jaw reflexes involve intradental mechanoreceptive A-fibers and the periodontal endings of mesencephalic trigeminal neurons (Dong, W. K. et al., 1993). Dental neurons can express a variety of ionotropic receptors (e.g., TRP-V1, TRP-V2, P2X3, ASIC), metabotropic receptors (BK-1, BK-2, NK1-3, TrkA), ion channels, receptors for

neuropeptides, neurotrophins, and opioid peptides that sensitize, inhibit, or modulate sensory neurons (Hu, J. W., 2004), and even immune regulators (Wadachi, R. and Hargreaves, K. M., 2006). The regulation of the pulpal milieu and the quality of tooth pain vary in relation to those activating and modulating systems. Many dental nerve endings form close appositions with the odontoblasts (Figures 2(a) and 2(b)), while others end freely in pulp and dentin. Neuro-odontoblast interactions are not fully understood, and may involve odontoblast support for the free sensory endings, modulation of sensory activity, and/or specific sensory activity. The lack of synaptic contacts or gap 10

0

20

30

40

50

a

b

c Sympathetic block or cut

Control

Figure 3 Laser Doppler demonstration of sensory nervemediated increased blood flow in rat incisor pulp after -adrenergic block (b) or sympathectomy (c) compared to intact blood flow (a). All teeth received brief bipolar electrical stimulation of the intact tooth crown. Reproduced from Olgart, L. and Kerezoudis, N. P. 1994. Nerve–pulp interactions. Arch. Oral Biol. 39, 47S–54S, with permission.

(b)

(a)

471

OD

(c)

OD

N

D

RD

OD

OD Aδ

Aβ P

50 μm

0.5 μm

10 μm

Figure 2 (a) Sensory endings in pulp (P) and dentin (D) (thin arrows) are shown by autoradiography of axonally transported 3 H-protein in adult rat molars. They avoid reparative dentin (RD) but come close to surface of tooth (wide arrow). Reprinted from Byers, M.R. 1984. Dental sensory receptors. Int. Rev. Neurobiol. 25, 39–94. (b) Electron microscopic autoradiography showed that transported 3H-proteins (black coiled silver grain) are confined to sensory endings (N). Odontoblasts (OD) are connected by numerous gap junctions (arrowheads). A special apposition separates OD and N (white arrow). Reproduced from Byers, M. R. 1977. Fine structure of trigeminal receptors in rat molars. In: Pain in the Trigeminal Region (eds. D. J. Anderson and B. Matthews), pp. 13–24, with permission from Elsevier. (c) Mouse molar root nerves include A- fibers that exceed 6 mm in diameter and several sizes of A- axons.

472 Tooth Pain

junctions between odontoblasts and nerves suggests a supportive role. However, demonstrations of neurallike ion channels (Guo, L. and Davidson, R. M., 1998) and TREK-1, a mechanosensitive potassium channel, in odontoblasts (Magloire, H. et al., 2003) show that they are excitable and mechanosensitive. They also attract sensory nerves (Maurin, J. C. et al., 2004) and express neurotrophin factors and receptors in developing, adult, and injured teeth (Fried, K. et al., 2000; Woodnutt, D. A. et al., 2000). It is still not clear whether odontoblast excitability directly affects tooth pain or just allows those cells to monitor dentinogenic requirements. 34.2.2

Rt

0.1 mm

(b)

(c) Rt

Inflammatory Tooth Pain

When pulp or periapex are inflamed, there are local cellular changes, nerve sprouting, peripheral and central sensitization, and neurochemical plasticity that alter the quality of tooth pain perceptions (Hargreaves, K. M., 2002; Hu, J. W., 2004). Many of the events in inflamed teeth are typical of any inflammation, but there are unusual nerve-sprouting reactions near the pulpitis, and those either subside if healing occurs, or they persist for months or years when lesions escape into the periapical region (Figures 4(a) and 4(b); Byers, M. R. and Na¨rhi, M. V. O., 1999). Important changes occur in dental neuronal satellite cell glia (Figure 4(c)) when inflammation continues in teeth, such as expression of glial fibrillary acidic protein (Stephenson, J. L. and Byers, M. R., 1995). Specialized vascular reactions also occur (Olgart, L., 1996). Recording from individual fibers shows that there are expansions of receptive fields of the A-fiber afferents after 1–2 weeks of inflammation (Figure 5), that would further affect sensitization in the central neurons. 34.2.3

(a)

0.1 mm

50 μm

Figure 4 (a, b) Several weeks after tooth injury the lesion has destroyed the pulp and emerged from the root (Rt) into periapical tissue, where there is intense sprouting and immunoreactivity for calcitonin gene-related peptide (CGRP) nerve fibers compared to a normal molar (b). Arrows indicate sensory nerve in alveolar canal. (c) Satellite cells surrounding trigeminal cell bodies are shown by immunocytochemistry to express glial fibrillary acidic protein (black rings) after molar injury in adult rats. (a, b) Reproduced from Kimberly, C. L. and Byers, M. R. 1988. Inflammation of rat molar pulp and periodontium causes increased calcitonin gene-related peptide and axonal sprouting. Anat. Rec. 222, 289–300, with permission.

(a)

Controls

(b)

Inflamed 1 week

Dental Neuropathic Pain

Teeth are major players in referred orofacial pain, either as the source or the referral site, and that situation can lead to unnecessary multiple extractions. Teeth can also exhibit neuropathic symptoms such as hyperalgesia, allodynia, and spontaneous pain (Truelove, E., 2004; Lavigne, G. et al., 2004). A principal mechanism for atypical odontalgia or dental neuropathic pain is the extensive convergence of inputs onto brainstem neurons from a wide area, often involving multiple trigeminal divisions and a variety of tissues (Sessle, B. J., 2000; 2005), and glial actions also affect pain quality (Xie, Y. F. et al., 2006).

Figure 5 Receptive fields (black patches) for individual A-fibers were larger in dog teeth after 1 week of induced pulpitis compared to control teeth. Reproduced from Na¨rhi, M. V. O., Yamamoto, H., and Ngassapa, D. 1996. Function of Intradental Nociceptors in Normal and Inflamed Teeth. In: Dentin/Pulp Complex (eds. M. Shimono, T. Maeda, H. Suda, and K. Takahashi), pp. 136–140. Quintessence Publishing Co, Inc., with permission.

Tooth Pain

34.3 Tooth Pain: Diagnosis and Management Dentists routinely use evoked acute pain to diagnose tooth pathology, pulp vitality, and treatment (Bender, I. B., 2000). Dental procedures such as orthodontia or root canal treatment cause transient pain that usually decreases within a few days, as the local inflammation subsides, especially with nonsteroidal anti-inflammatory treatment (Dionne, R. A. and Berthold, C. W., Before the tourniquet procedure

473

2001). However, pain can persist weeks, months, or years, especially in individuals who have had longterm tooth pain or other chronic pain (Bender, I. B., 2000; Truelove, E., 2004). Tooth pain can expand to a wide area, making it difficult to locate the pathology. Competition from a second pain source can narrow the site to just one tooth, at least for a few minutes to aid diagnosis (Figure 6). This diffuse noxious inhibition implies substantial changes in central physiology for the widely dispersed tooth pains

At ischemic tolerance

5 min past ischemic tolerance point

50 Individual responses Mean response (n = 10)

* p < 0.05

40

Relative magnitude

Very intolerable

Intolerable 30

20

Very distressing (SEM)

Very annoying Distressing

10

Annoying Slightly annoying 0 Before tourniquet

5 min past IPT

At ischemic pain tolerance Figure 6 Prior to tourniquet-evoked arm pain, the area of dental pain was large. After maximal arm pain, the tooth pain area was reduced to an individual tooth. By 5 min later, the pain was still focused although the pain intensity (red lines) was returning to prestimulus levels. IPT, ischemic pain tolerance. Reprinted from Pain, 57, Sigurdsson, A. and Maxiner, W., Effects of experimental and clinical noxious counterirritants on pain perception, 265–275, Copyright 1994, with permission from The International Association for the Study of Pain.

474 Tooth Pain

(Sessle, B. J., 2005), though important changes in neural sodium channels occur in painful teeth (Renton, T. et al., 2005; Henry, M. A. and Hargreaves, K. M., 2007) offering possible pharmacologic therapeutic targets.

34.4 Conclusions Unusual features of tooth pain include: (1) difficulty locating the source of pain; (2) intense pain from stimulation of dentin; (3) hypersensitive dentin after loss of its protective enamel or periodontal covering, with concomitant pulpitis; (4) special neuro-pulpal interactions; (5) silent pulpal inflammation that only becomes painful when it invades periapical tissues; (6) the hot tooth problem, in which an inflamed painful tooth becomes difficult to anesthetize, even when the rest of the jaw is numb; and (7) referred pain. It is, perhaps, surprising that prolonged tooth pain is unusual, given the huge number of dental procedures every day that can cause tooth, nerve, or bone damage (i.e., dental implants that screw into the jaw, third molar extractions, delicate access for anesthetic injections to reach bone-encased nerves, root canals that remove pulp to eliminate infection). The keys to prevention of debilitating chronic tooth pain include avoiding nerve damage in the jaw, and removal of infected pulp (Bender, I. B., 2000; Hargreaves, K. M., 2002; Hu, J. W., 2004; Truelove, E., 2004; Sessle, B. J., 2005; Henry, M. A. and Hargreaves, K. M., 2007).

References Bender, I. B. 2000. Pulp pain diagnosis – a review. J. Endodon. 26, 175–179. Berggreen, E. and Heyeraas, K. J. 2000. Effect of the sensory neuropeptide antagonists h-CGRP (8-37) and SR 140.33 on pulpal and gingival blood flow in ferrets. Arch. Oral Biol. 45, 537–542. Bra¨nnstro¨m, M and A˚stro¨m, A. 1972. The hydrodynamics of dentine: its possible relationship to dentinal pain. Int. Dent. J. 22, 219–227. Byers, M. R. 1978. Fine Structure of Trigeminal Receptors in Rat Molars. In: Pain in the Trigeminal Region (eds. D. J. Anderson and B. Matthews), pp. 13–24, Elsevier. Byers, M. R. and Na¨rhi, M. V. O. 1999. Dental injury models: experimental tools for understanding neuro-inflammatory interactions and polymodal nociceptor functions. Crit. Rev. Oral Biol. Med. 10, 4–39. Byers, M. R. and Na¨rhi, M. V. O. 2002. Nerve Supply of the Pulpodentin Complex and Responses to Injury. In: Seltzer and Bender’s Dental Pulp (eds. K. M. Hargreaves and H. E. Goodis), pp. 151–179. Quintessence.

Dionne, R. A. and Berthold, C. W. 2001. Therapeutic uses of non-steroidal anti-inflammatory drugs in dentistry. Crit. Rev. Oral Biol. Med. 12, 315–330. Dong, W. K., Shiwaku, T., Kawakami, Y., and Chudler, E. H. 1993. Static and dynamic responses of periodontal ligament mechanoreceptors and intradental mechanoreceptors. J. Neurophysiol. 69, 1567–1582. Fried, K., Nosrat, C., Lillesaar, C., and Hildebrand, C. 2000. Molecular signaling and pulpal nerve development. Crit. Rev. Oral Biol. Med. 11, 318–332. Fristad, I., Kvinnsland, I. H., Johnsson, R., and Heyeraas, K. J. 1997. Effect of intermittent long-lasting electrical tooth stimulation on pulpal blood flow and immunocompetent cells: a hemodynamic and immunohistochemical study in young rat molars. Exp. Neurol. 146, 230–239. Guo, L. and Davidson, R. M. 1998. Potassium and chloride channels in freshly isolated odontoblasts. J. Dent. Res. 77, 341–350. Hargreaves, K. M. 2002. Pain Mechanisms of the Pulpodentin Complex. In: Seltzer and Bender’s Dental Pulp (eds. K. M. Hargreaves and H. E. Goodis), pp. 181–203. Quintessence. Henry, M. A. and Hargreaves, K. M. 2007. Peripheral mechanisms of odontogenic pain. Dent. Clin. North Am. 51, 19–44. Hu, J. W. 2004. Tooth Pulp. In: Clinical Oral Physiology (eds. T. S. Miles, B. Nauntofte, and P. Svensson), pp. 141–162. Quintessence. Ikeda, H., Tokita, Y., and Suda, H. 1997. Capsaicin-sensitive Adelta fibers in cat tooth pulp. J. Dent. Res. 76, 1341–1349. Kimberly, C. L. and Byers, M. R. 1988. Inflammation of rat molar pulp and periodontium causes increased calcitonin generelated peptide and axonal sprouting. Anat. Rec. 222, 289–300. Lavigne, G., Woda, A., Truelove, E., Ship, J. A., Dao, T., and Goulet, J. P. 2004. Mechanisms associated with unusual orofacial pain. J. Orofac. Pain 19, 9–21. Lipton, J., Ship, J., and Larach-Robinson, D. 1993. Estimated prevalence and distribution of reported orofacial pain in the United States. J. Am. Dent. Assoc. 124, 115–121. Magloire, H., Lesage, F., Couble, M. L., Lazdunski, M., and Bleicher, F. 2003. Expression and localization of TREK-1 Kþ channels in human odontoblasts. J. Dent. Res. 82, 542–545. Maurin, J. C., Couble, M. L., Didier-Bazes, M., Brisson, C., Magloire, H., and Bleicher, F. 2004. Expression and localization of reelin in human odontoblasts. Matrix Biol. 23, 277–285. Na¨rhi, M. V. O., Yamamoto, H., and Ngassapa, D. 1996. Function of Intradental Nociceptors in Normal and Inflamed Teeth. In: Dentin/Pulp Complex (eds. M. Shimono, T. Maeda, H. Suda, and K. Takahashi), pp. 136–140. Quintessence. Na¨rhi, M. V. O. 2006. Nociceptors in the Dental Pulp. In: Pain Encyclopedia (eds. R. F. Schmidt and W. D. Willis), Springer. Olgart, L. 1996. Neural control of pulpal blood flow. Crit. Rev. Oral Biol. Med. 7, 159–171. Olgart, L. and Kerezoudis, N. P. 1994. Nerve–pulp interactions. Arch. Oral Biol. 39, 47S–54S. Renton, T., Yiangou, Y., Plumpton, C., Tate, S., Bountra, C., and Anand, P. 2005. Sodium channel Nav1.8 immunoreactivity in painful human dental pulp. BMC Oral Health 5, 5. Sessle, B. J. 2000. Acute and chronic craniofacial pain: brainstem mechanisms of nociceptive transmission and neuroplasticity, and their clinical correlates. Crit. Rev. Oral Biol. Med. 11, 57–91. Sessle, B. J. 2005. Orofacial Pain. In: The Paths of Pain (eds. H. Merskey, J. D. Lowser, and R. Dubner), pp. 131–150. IASP Press.

Tooth Pain Sessle, B. J., Hu, J. W., Amano, N., and Zhong, G. 1986. Convergence of cutaneous, tooth pulp, visceral, neck and muscle afferents onto nociceptive and non-nociceptive neurons in trigeminal subnucleus caudalis (medullary dorsal horn) and its implications for referred pain. Pain 27, 219–235. Stephenson, J. L. and Byers, M. R. 1995. GFAP immunoreactivity in trigeminal ganglion satellite cells after tooth injury in rats. Exp. Neurol. 131, 11–22. Sigurdsson, A. and Maixner, W. 1994. Effects of experimental and clinical noxious counterirritants on pain perception. Pain 57, 265–275. Suzuki, H., Iwanaga, T., Yoshie, H., Li, J., Yamabe, K., Yanaihara, N., Langel, U., and Maeda, T. 2002. Expression of galanin receptor-1 (GALR1) in the rat trigeminal ganglia and molar teeth. Neurosci. Res. 42, 197–207.

475

Truelove, E. 2004. Management issues of neuropathic trigeminal pain from a dental perspective. J. Orofac. Pain 18, 374–380. Wadachi, R. and Hargreaves, K. M. 2006. Trigeminal nociceptors express TLR-4 and CD-14; a mechanism for pain due to infection. J. Dent. Res. 85, 49–53. Woodnutt, D. A., Wager-Miller, J., O’Neill, P. C., Bothwell, M., and Byers, M. R. 2000. Neurotrophin receptors and nerve growth factor are differentially expressed in adjacent nonneuronal cells of normal and injured tooth pulp. Cell Tissue Res. 299, 225–236. Xie, Y. F., Zhang, S., Chiang, C. Y., Hu, J. W., Dostrovsky, J. O., and Sessle, B. J. 2006. Involvement of glia in central sensitization in trigeminal subnucleus cudalis (medullary dorsal horn). Brain Behav. Immun. (in press).

This page intentionally left blank

35 Ascending Pathways: Anatomy and Physiology D Lima, Universidade do Porto, Porto, Portugal ª 2009 Elsevier Inc. All rights reserved.

35.1 35.1.1 35.1.2 35.2 35.2.1 35.2.2 35.2.3 35.2.4 35.2.5 35.3 35.3.1 35.3.1.1 35.3.1.2 35.3.1.3 35.3.1.4 35.3.1.5 35.3.1.6 35.3.1.7 35.3.2 35.3.2.1 35.3.2.2 35.3.2.3 35.3.2.4 35.3.2.5 35.3.2.6 35.3.2.7 35.3.3 35.3.3.1 35.3.3.2 35.3.3.3 35.3.3.4 35.3.3.5 35.3.3.6 35.3.4 35.3.4.1 35.3.4.2 35.3.4.3 35.3.4.4 35.3.4.5 35.3.4.6 35.4 35.4.1 35.4.1.1 35.4.1.2 35.4.1.3 35.4.1.4

Introduction Defining Nociceptive Ascending Pathways The Spinothalamic System Spinocervical Pathway Spinal Laminae of Origin and Sites of Termination Structural Types of Neurons Involved Spinal Location of Ascending Fibers Response properties Pathways Driven at the Target Spinobulbar Pathways Ventrolateral Reticular Formation Spinal laminae of origin and sites of termination Structural types of neurons involved Spinal location of ascending fibers Surface receptors Neurotransmitters Response properties Pathways driven at the target Dorsal Reticular Nucleus Spinal laminae of origin and sites of termination Structural types of neurons involved Spinal location of ascending fibers Surface receptors Neurotransmitters Response properties Pathways driven at the target Nucleus Tractus Solitarii Spinal laminae of origin and sites of termination Structural types of neurons involved Spinal location of ascending fibers Neurotransmitters Response properties Pathways driven at the target Rostral Ventromedial Medulla Spinal laminae of origin and sites of termination Structural types of neurons involved Spinal location of ascending fibers Neurotransmitters Response properties Pathways driven at the target Spinopontine Pathways Parabrachial Nuclei Spinal laminae of origin and sites of termination Structural types of neurons involved Spinal location of ascending fibers Surface receptors

479 479 480 481 481 482 482 482 483 483 483 483 484 485 485 485 486 486 487 487 488 488 488 488 488 489 489 489 489 491 491 491 491 492 492 493 493 493 493 493 494 494 494 495 495 496

477

478 Ascending Pathways: Anatomy and Physiology 35.4.1.5 35.4.1.6 35.4.1.7 35.5 35.5.1 35.5.1.1 35.5.1.2 35.5.1.3 35.5.1.4 35.5.1.5 35.5.1.6 35.5.1.7 35.6 35.6.1 35.6.1.1 35.6.1.2 35.6.1.3 35.6.1.4 35.6.1.5 35.6.1.6 35.6.1.7 35.6.2 35.6.2.1 35.6.2.2 35.6.2.3 35.6.2.4 35.6.2.5 35.6.2.6 35.6.3 35.6.3.1 35.6.3.2 35.6.3.3 35.6.3.4 35.6.3.5 35.7 35.7.1 35.7.2 35.8 35.8.1 35.8.2 35.8.3 35.8.4

Neurotransmitters Response properties Pathways driven at the target Spinomesencephalic Pathways Periaqueductal Gray Spinal laminae of origin and sites of termination Structural types of neurons involved Spinal location of ascending fibers Surface receptors Neurotransmitters Response properties Pathways driven at the target Spinodiencephalic Pathways Lateral Thalamus Spinal laminae of origin and sites of termination Structural types of neurons involved Spinal location of ascending fibers Surface receptors Neurotransmitters Response properties Pathways driven at the target Medial Thalamus Spinal laminae of origin and sites of termination Structural types of neurons involved Spinal location of ascending fibers Neurotransmitters Response properties Pathways driven at the target Hypothalamus Spinal laminae of origin and sites of termination Spinal location of ascending fibers Surface receptors Response properties Pathways driven at the target Spinothelencephalic Pathways Thelencephalic Targets of Spinal Ascending Fibers Spinal Laminae of Origin Discussion Multiple Parallel Ascending Pathways Spinal Neuronal Populations at the Origin of Nociceptive Ascending Pathways Stimulus Discrimination Nociceptive Ascending Pathways as Part of a Complex Nociceptive Integration System

References

496 496 497 497 497 497 500 500 500 500 500 501 501 502 502 504 504 505 505 505 507 507 507 508 509 509 509 509 510 510 511 512 512 512 512 512 513 514 514 516 517 517 518

Glossary anterograde tracing Staining of axonal terminal arborizations with a substance (tracer) picked up by the neuronal soma and dendrites and transported through the axon up to its terminal structures.

antidromic activation Evoking neuronal spikes by electric activation of the axon terminal field. antinociceptive action A neuronal effect that results in decrease of responses to pain

Ascending Pathways: Anatomy and Physiology

and inhibiton of neurons driven by nociceptive input. ascending pathway Neuronal tract that conveys input from caudal to rostral areas along the spinal cord and brain. contralateral pathway Pathway connecting gray matter regions (nuclei) located in opposite sides of the spinal cord or brain. dendrites The branch units of a dendritic arbor. dendritic arbor The receptive area of a neuron, organized from the perikarya as the ramifying branches of a tree. dendritic spines Small protrusions of the dendritic surface that more often appear as a knob connected to the dendritic shaft by a short pedicle. electrophysiological recording Recording of changes in the membrane potential or current in a neuron. facilitatory loop Neuronal circuit playing a positive feedback action so that neuronal activity is enhanced. fiber decussation Crossing of axons from one side to the other side of the spinal cord or the brain. high-threshold neurons Neurons responsive solely to stimuli of high intensity (noxious). ipsilateral pathway Pathway connecting gray matter regions (nuclei) located in the same side of the spinal cord or brain. low-threshold neurons Neurons responsive solely to stimuli of low intensity (innocuous). neuronal soma The central area of a neuron where the nucleus and most organelles are located. neurotransmitters Molecules that functionally connect neurons at synapses by being delivered by the presynaptic element upon depolarization and acting upon ligand-gated receptors at the postsynaptic element.

35.1 Introduction 35.1.1 Defining Nociceptive Ascending Pathways Nociceptive information traveling from the periphery in primary sensory neurons is transmitted to second-order neurons located at the spinal cord and cranial sensory nuclei. From this first relay, various pathways distribute nociceptive input through higher

479

nociresponsive Driven by the arrival of nociceptive input. noxious stimulation Presentation of stimuli that represent a potential or effective aggression to a peripheral tissue. pain inhibitory center Region in the central nervous system whose stimulation results in pain depression. primary sensory neurons Neurons that convey input from the periphery to the central nervous system. receptive field of a neuron The peripheral area whose stimulation elicits neuronal responses. retrograde tracing Staining of the neuronal soma and dendritic arbors with a substance (tracer) picked up by the respective axonal boutons and transported back through the axon. second-order neurons Neurons that transmit input from primary sensory neurons to higher order processing centers. somatotopy Structural arrangement that correlates topographic organization at different sites, either at the periphery or in the central nervous system. spinofugal transmission Input transmission away from the spinal cord. target Area where the axon terminal arborization of a neuron is distributed. transmitter receptors Plasma membrane molecules which, upon activation by a ligand (neurotransmitter), open ionic channels inducing alteration in the membrane potential. wide dynamic-range neurons Neurons responsive to stimuli of graded intensities, from innocuous to noxious, but more intensively at the noxious range.

processing centers so that pain is ultimately perceived in its multiple dimensions and adequate adaptive responses are generated. These ascending pathways are believed to terminate in the cortex with one or several relay stations in their way, although for most of the tracts, studies demonstrating that the intervening neurons are indeed serially connected from the spinal cord to the cortex are missing. The term ‘nociceptive ascending pathways’ is thus normally used in

480 Ascending Pathways: Anatomy and Physiology

a restricted sense, to designate the neuronal tracts that connect the spinal cord with supraspinal regions, each pathway being named from the brain area at which it terminates. The nociceptive nature of a pathway is classically demonstrated by recording responses to noxious stimuli from spinal neurons antidromically activated from the target (Perl, E. R. and Whitlock, D. G. 1961; Dilly, P. N. et al., 1968). More recently, detection of molecular markers of nociceptive activation (Hunt, S. P. et al., 1987) in conjunction with retrograde tracing has been largely used. By revealing large populations of putative nociceptive neurons, such a procedure allows an easy characterization of the location and morphology of neurons projecting in each pathway, and is particularly valuable to uncover varying population activation patterns as a function of stimulation conditions (Lima, D., 1998). The structural features that best describe a pathway are the topographic and morphofunctional characteristics of the spinal neurons involved and the area of termination of their axons. Studies addressing the morphology of spinal projecting neurons are particularly few and mainly related to lamina I. One of the reasons for the restricted use of this kind of evaluation is the lack of systematic models of classification of spinal neurons apart from laminae I (Gobel, S. 1978a; Lima, D. and Coimbra, A., 1983; 1986) and II (Gobel, S., 1978b). Recent studies, however, call our attention to the importance of neuronal morphology, in particular, dendritic geometry, in defining the signal-processing properties of neurons (Prescott, S. A. and De Koninck, Y. 2002; Szucs, P. et al., 2003; Mainen, Z. F. and Sejnowski, T. J. 2006), which justify taking these aspects into account when addressing the anatamophysiology of a pathway. The multitude of ascending nociceptive pathways, together with the subtleness of the anatomical and physiological features that separate them as to their origin at the spinal cord, makes it difficult to attribute a particular functional meaning to each one. A tentative way of unraveling the role of each pathway in nociceptive processing has been the elucidation of the connections established by the target. 35.1.2

The Spinothalamic System

The classical view of the ascending nociceptive system puts particular emphasis on the dual distribution of nociceptive input through a lateral pathway responsible for sharp, well-localized short lasting

pain, and a medial pathway responsible for diffuse, poorly localized persisting pain (Figure 1). From the spinal cord, nociceptive input is conveyed both to the posterior lateral sensory nuclei of the thalamus, in the lateral or neospinothalamic pathway (Bowsher, D. 1957; Mehler, W. R. 1957; Willis, W. D. et al., 1974; Giesler, G. J. et al., 1976) and to medial thalamic nuclei, in the medial or paleospinothalamic pathway (Mehler, W. R. et al., 1956; Bowsher, D. 1957; Mehler,

Medial spinothalamic system Lateral spinothalamic system Figure 1 Diagrammatic representation of the areas of termination of the lateral spinothalamic pathway and the medial spinothalamic pathway, and the spinoreticular pathways that serve as relays in the medial spinothalamic system. Brain and spinal cord photomicrographs were adapted from Paxinos, G. and Watson, C. 1998. The Rat Brain in Stereotaxic Coordinates, 4th edn. Academic Press.

Ascending Pathways: Anatomy and Physiology

W. R. 1957; Giesler, G. J. et al., 1981b). While the first is monosynaptic, made up of spinal neurons projecting directly to the thalamus (Trevino, D. L. and Carstens, E. 1975; Willis, W. D. et al., 1979; Giesler, G. J. et al., 1979a), the second is either monosynaptic or polysynaptic with a variable number of relays along the brainstem (Johnson, F. H. 1954; Mehler, W. R. et al., 1956; Rossi, G. F. and Brodal, A. 1957; Bowsher, D. 1957; Carstens, E. and Trevino, D. L. 1978b; Willis, W. D. et al., 1979; Giesler, G. J. et al., 1979a). The lateral spinothalamic pathway was proposed to be involved in the discriminative aspects of pain (Bowsher, D. 1957; Melzack, R. and Casey, K. L. 1968) based on early studies on the perception deficits resulting from lesions of lateral thalamic nuclei (Dejerine, J. and Roussy, G. 1906; Melzack, R. and Casey, K. L. 1968). This was later supported by studies showing that both spinal and thalamic neurons of the lateral spinothalamic pathway present small receptive fields (Giesler, G. J. et al., 1981b; Willis, W. D. 1988), are capable of encoding the extent of the stimulated area and the intensity of the stimulus(Kenshalo, D. R., Jr. et al., 1979; Peschanski, M. et al., 1980; Guilbaud, G. et al., 1985; Willis, W. D. 1988; Guilbaud, G. and Kayser, V. 1988), and terminate following a somatotopic pattern in the thalamus and cortex respectively (Whitsel, B. L. et al., 1978; Boivie, J. 1979). The medial spinothalamic pathway was claimed to deal with the affective and volitive aspects of pain (Bowsher, D. 1957; Melzack, R. and Casey, K. L. 1968) based on similar behavioral studies on human and experimental animals suffering from lesions of various brainstem or thalamic areas (Dejerine, J. and Roussy, G. 1906; Walker, A. E. 1942b; He´caen, H. et al., 1949). This view was again supported by studies revealing that spinal and thalamic neurons of the medial pathway present large receptive fields, responses unrelated to stimulus intensity (Giesler, G. J. et al., 1981b; Guilbaud, G. et al., 1985) and no topographical arrangement of their axonal terminal arborizations in both the thalamus (Boivie, J. 1979) and cortex (Morison, R. S. and Dempsey, E. W. 1942; Jones, E. G. and Leavitt, R. Y. 1974). In the last decades, the use of very sensitive electrophysiological and tracing techniques revealed a wide variety of brainstem loci capable of contributing as relays to the medial spinothalamic system (reviewed by (Lima, D., 1997), and uncovered ascending pathways that bypass the thalamus to terminate directly on telencephalic areas, including the cortex (Cliffer, K. D. et al., 1991). In this chapter, the various pathways

481

involved in the spinofugal transmission of nociceptive input will be referred following a caudorostral sequence.

35.2 Spinocervical Pathway The spinocervical pathway is one of the ascending putative nociceptive pathways uncovered the earliest, based on its capacity to activate cortical sensory areas (Catalano, J. V. and Lamarche, G., 1957; Mark, R. F. and Steiner, J., 1958) and on the finding that neurons of the lateral cervical nucleus (LCN) project to the ventrobasal complex of the thalamus (Ha, H. and Liu, C. N., 1966; Craig, A. D. and Burton, H., 1979; Baker, M. L. and Giesler, G. J., 1985; Giesler, G. J., et al., 1987). It has been claimed, however, to be mostly dedicated to the processing of tactile, hair movement input (Lundberg, A. and Oscarsson, O., 1961; Taub, A. and Bishop, P. O., 1965) and be mainly represented in carnivores (Flink, R. and Westman, J., 1986). The identification of a neuronal column continuing the lateral cervical nucleus caudally along the entire length of the cord (the lateral spinal nucleus), together with the finding that their neurons also send projections to the thalamus as well as to many other brain areas (see ahead ), raised the possibility that the lateral cervical nucleus is part of a more extensive spinal neuronal aggregation lying within the dorsolateral fasciculus, which serves as a relay in various ascending nociceptive pathways. Nonetheless, differences in the morphology and response properties of lateral cervical and lateral spinal neurons (Giesler, G. J. et al., 1979b; Mene´trey, D. et al., 1980) point to a specific role of the former in conveying ascending input to the lateral thalamus. 35.2.1 Spinal Laminae of Origin and Sites of Termination Neurons projecting to the lateral cervical nucleus are mainly located in the ipsilateral spinal cord at lamina IV (Figure 2) (Bryan, R. N. et al., 1973; Craig, A. D., 1976; Brown, A. G. et al., 1976; Cervero, F. et al., 1977; Brown, A. G. et al., 1977; Craig, A. D., 1978; Brown, A. G. et al., 1980a; Baker, M. L. and Giesler, G. J., 1984), where they amount to 60% of the entire population, followed by lamina III (10%) (Brown, A. G. et al., 1980a). Scattered neurons are present in other laminae such as laminae I, V, VI, and VII (Craig, A. D., 1976; Craig, A. D., 1978; Brown, A. G. et al., 1980a;

482 Ascending Pathways: Anatomy and Physiology

1984), but neurons with large round soma have also been observed in lamina IV (Craig, A. D., 1978). They present dorsally oriented dendrites (Brown, A. G. et al., 1976; Jankowska, E. et al., 1976; Brown, A. G. et al., 1977; Craig, A. D., 1978; Brown, A. G. et al., 1980b), which extend rostrocaudally for up to 2000 mm without penetrating lamina II (Brown, A. G. et al., 1977; Brown, A. G. et al., 1980b).

C1

35.2.3 Spinal Location of Ascending Fibers

C5

Spinal axons targeting the lateral cervical nucleus course ipsilaterally in the dorsal part of the lateral funiculus (Figure 2) (Brown, A. G. et al., 1977; Baker, M. L. and Giesler, G. J., 1984; Giesler, G. J. et al., 1988). According to Ha and Liu (Ha, H. and Liu, C. N., 1966), they are often collaterals of fibers coursing to more rostral levels. 35.2.4

Response properties

L5 Spino-LCN

Figure 2 Diagram representing the spinal laminae of origin, ascendingb course in the spinal cord, and areas of termination of the spino-LCN pathway. Note the somatotopic arrangement of the axon terminal fields according to their rostrocaudal origin. (in this figure and figures 3, 7, 10, 12, 13, 15, 17, 19, 21 and 24, the left side is ipsilateral to the side of arrival of peripheral input) Brain and spinal cord photomicrographs were adapted from Paxinos, G. and Watson, C. 1998. The Rat Brain in Stereotaxic Coordinates, 4th edn. Academic Press.

Baker, M. L. and Giesler, G. J., 1984). Axonal terminals are somatotopically organized, fibers originated in caudal levels terminating in the dorsolateral aspect of the caudal portion of the lateral cervical nucleus, and fibers originated in rostral levels in the medial aspect of its rostral portion (Figure 2) (Svensson, B. A. et al., 1985).

35.2.2 Structural Types of Neurons Involved Neurons targeting the lateral cervical nucleus are commonly described as small-sized (10–20 mm) (Craig, A. D., 1978; Baker, M. L. and Giesler, G. J.,

Nociceptive neurons at the origin of the spinocervical pathway present background activity in bursts (Brown, A. G. and Franz, D. N., 1969). They are activated by A, A, and C primary afferent fibers (Taub, A. and Bishop, P. O., 1965), A fibers exciting the entire neuronal population either alone (29%) or in convergence with C fibers (71%) (Brown, A. G. et al., 1975). They belong in the low-threshold (LT), wide-dynamic range (WDR) and high-threshold (NS) classes (Brown, A. G. and Franz, D. N., 1969; Bryan, R. N. et al., 1973; Bryan, R. N. et al., 1974; Cervero, F. et al., 1977; Downie, J. W. et al., 1988). Neurons receiving high-threshold input were reported to make up between 60% and 86% of the entire projecting population (Cervero, F. et al., 1977; Kajander, K. C. and Giesler, G. J., 1987). Highthreshold input is generated either by pressure, pinch, heat, or cold (Brown, A. G. and Franz, D. N., 1969; Bryan, R. N. et al., 1973; Bryan, R. N. et al., 1974; Cervero, F. et al., 1977; Downie, J. W. et al., 1988), while low-threshold input is mainly originated in hair follicle afferent receptors (Brown, A. G. and Franz, D. N., 1969). Receptive fields are small and located in hairy as well as glabrous skin (Bryan, R. N. et al., 1974; Kunze, W. A. A. et al., 1987; Downie, J. W. et al., 1988). They are organized somatotopically so that cells located more laterally have receptive fields in the dorsal surface of the body and cells located more medially in the ventral surface (Bryan, R. N. et al., 1973; Bryan, R. N. et al., 1974; Brown, A. G. et al.,

Ascending Pathways: Anatomy and Physiology

1980a). Inhibitory receptive fields were described adjacent to the excitatory receptive field (Brown, A. G. et al., 1987; Short, A. D. et al., 1990) or in the contralateral limb (Brown, A. G. and Franz, D. N., 1969). Natural stimuli causing neuronal inhibition include hair movement, pressure, and squeezing (Brown, A. G. and Franz, D. N., 1969; Brown, A. G. et al., 1987; Short, A. D. et al., 1990). Convergence of cutaneous and deep tissues input has been reported (Kniffki, K. D. et al., 1977; Hamann, W. C. et al., 1978; Harrison, P. J. and Jankowska, E., 1984). Only cells responsive to both hair movement and skin pressure were shown to receive group III and IV muscle afferent input (Hamann, W. C. et al. 1978). Muscle and joint primary afferent activation can also elicit neuronal inhibition (Hamann, W. C. et al. 1978; Harrison, P. J. and Jankowska, E. 1984). 35.2.5

Pathways Driven at the Target

Axons from neurons in the lateral cervical nucleus join the medial lemniscus contralaterally and terminate in the midbrain, the ventral posterial lateral nucleus (VPL), and the posterior complex (PO) of the thalamus (Ha, H. and Liu, C. N., 1966). In the midbrain, the lateral part of the periaqueductal gray (PAG) receives afferents from the lateral two-thirds of the lateral cervical nucleus (Mouton, L. J. and Holstege, G., 2000; Mouton, L. J. et al., 2004). In the VPL, fibers ascending from the lateral cervical nucleus are topographically arranged so that those originated in its dorsolateral portion terminate in the VPL, pars lateralis, and those originated in its ventromedial portion terminate in the VPL, pars medialis (Craig, A. D. and Burton, H., 1979).

483

similarities with the rat, pointing to a high degree of phylogenetic conservation.

35.3.1

Ventrolateral Reticular Formation

35.3.1.1 Spinal laminae of origin and sites of termination

Spinal cells projecting to the caudal ventrolateral reticular formation (VLM) are distributed through laminae I, II, IV–VII, VIII, X, and the lateral spinal nucleus (Figure 3) (Mene´trey, D. et al., 1983; Mene´trey, D. et al., 1984; Leah, J. et al., 1988; Lima, D. et al., 1991; Galhardo, V. et al., 2000). Projections were first described to be mainly contralateral (Mene´trey, D. et al., 1983; Mene´trey, D. et al., 1984; Thies, R., 1985), but an important ipsilateral component was revealed by the use of more sensitive retrograde tracers (Mene´trey, D. et al., 1982; Lima, D. et al., 1991; Mene´trey, D. et al., 1992b; Galhardo, V. et al., 2000). There is, however, a large variability in the proportion of cells labeled in each spinal side, particularly with respect to cells located in the superficial dorsal horn. Both ipsilateral and contralateral predominance have been observed, in a few cases in the same animal at different rostrocaudal levels (Lima, D. et al., 1991). The occurrence of subtle differences in the area of termination of each spinal side along the cord length was proposed as a tentative explanation, but experiments designed to clarify a putative somatotopic arrangement are missing.

35.3 Spinobulbar Pathways Most spinobulbar pathways were uncovered relatively recently and are not as thoroughly studied as the more rostrally terminating pathways such as the spinomesencephalic and the spinothalamic. With the exception of the rostral ventromedial medulla (RVM), the majority of the studies dealing with spinobulbar pathways were performed in the rat. An anecdotic study addressing the spinal pathways terminating in the caudal medulla of the pigeon (Galhardo, V. et al., 2000), however, reveals remarkable

Spino-VLMlat Spino-LRT (lateral) Spino-LRT (medial)

Figure 3 Diagram representing the spinal laminae of origin, ascending course in the spinal cord, and areas of termination of the spino-VLM pathway. Note the contribution of lamina II neurons. Brain and spinal cord photomicrographs were adapted from Paxinos, G. and Watson, C. 1998. The Rat Brain in Stereotaxic Coordinates, 4th edn. Academic Press.

484 Ascending Pathways: Anatomy and Physiology

Spino-VLM axons appear to give axonal collaterals to various sites within the brainstem (Thies, R., 1985), such as the parabrachial nuclei (PBN) and the PAG (Spike, R. C. et al., 2003). The use of discrete injections, which became possible with the advent of particularly sensitive tracing methods, clearly demonstrated that the spino-VLM system is composed of three pathways originating in three distinct spinal regions (Figure 3). The pathway originating in the superficial dorsal horn (laminae I–III) and lateral spinal nucleus was observed in the rat (Lima, D. and Coimbra, A., 1991; Tavares, I. et al., 1993), cat, and monkey (Craig, A. D., 1995) to terminate in the lateral-most portion of the VLM (VLMlat), in between the spinal trigeminal nucleus and the ventral tip of the lateral reticular nucleus (LRt). The pathways originating in the deep dorsal horn (laminae IV–VI) and intermediate/ventral horn (laminae VII and X) terminate, respectively, in the lateral half and the medial half of the LRt (Lima, D. et al., 1991). A curious aspect of the spino-VLMlat projection is the participation of a large amount of cells of the substantia gelatinosa, or lamina II (Figure 4) (Lima, D. et al., 1991; Lima, D. and Coimbra, A., 1991), an area that was not shown to participate significantly in any other ascending pathway and is therefore usually taken as involved in nociceptive modulatory local or propriospinal circuits (see Chapter Spinal Cord Physiology of Nociception). Lamina II neurons project, together with neurons in lamina I and the lateral spinal nucleus, to the VLMlat (Figure 3), contributing to almost one-third of the entire spinal-VLMlat projection in the cervical enlargement, and to onefifth in the lumbar enlargement. (Lima, D. and Coimbra, A., 1991). There are still no clues on the physiological meaning of this unique lamina II projection to the VLMlat. Studies aimed at clarifying whether these cells participate in inhibitory circuits similar to those described in the superficial dorsal horn failed to reveal GABA content in these neurons (Tavares, I. and Lima, D., 2002). 35.3.1.2 Structural types of neurons involved

Lamina I neurons projecting in the spino-VLM pathway were characterized in the rat, based on the comparison of the structural features of neurons retrogradely labeled with CTb at various spinal cord levels in the three anatomical planes (Lima, D. et al., 1991). In the rat, as in the pigeon (Galhardo, V. et al., 2000), spino-VLM neurons belong in three (fusiform,

Figure 4 Superficial dorsal horn neurons labeled retrogradely with cholera toxin subunit B (CTb) from the VLMlat. (a) Lamina I neuron of the fusiform type, subtype B, in horizontal view. (b) Lamina I fusiforn neurons and lamina II neurons in transverse view. Note the ventrally oriented dendrites of fusiform B neurons (large arrows in (b)). DF – Dorsal funiculus. Scale bar ¼ 30 mm. Adapted from figure 3 of Lima, D., Mendes-Ribeiro, J. A., and Coimbra, A. 1991. The spino-latero-reticular system of the rat: projections from the superficial dorsal horn and structural characterization of marginal neurons involved. Neuroscience 45, 137–152.

Ascending Pathways: Anatomy and Physiology

pyramidal, and flattened) of the four structural neuronal groups present in lamina I. The majority (around 80%) are of the fusiform type, a neuronal group whose main characteristic is the strict longitudinal spiny dendritic arbor. Some fusiform neurons present a few dendrites oriented ventrally and penetrating the entire width of lamina II (Figure 4). These neurons, classified as fusiform B by Lima and Coimbra (Lima, D. and Coimbra, A., 1986), represent a large fraction of VLMlat-projecting fusiform cells (20%) when compared to the small contribution of this neuronal subtype (6%) to the entire lamina I fusiform neuronal population (Lima, D. and Coimbra, A., 1986). Curiously, fusiform B neurons could not be observed in other spinofugal pathways. This finding is particularly interesting in the light of the contribution of lamina II neurons to this pathway (Figure 4). It may indicate that neurons of the fusiform B subtype cooperate with lamina II neurons in transmitting to the VLMlat primary input arriving at lamina II. The remaining 20% VLM-projecting lamina I neurons belong to the flattened and pyramidal types in similar amounts. These two cell groups have in common long practically aspiny dendrites coursing horizontally, parallel to the dorsal surface of lamina I. Pyramidal neurons have, in addition, dendrites that ramify inside the white matter overlying lamina I. VLM-projecting lamina II neurons present ovoid, rostrocaudally elongated dendritic arbors that extend as parasagittal sheets through the entire width of lamina II (Lima, D. and Coimbra, A., 1991), resembling the central and the limiting cells of Ramo´n y Cajal (Ramo´n y Cajal, S., 1909).

35.3.1.3 fibers

485

Spinal location of ascending

According to the intense fiber staining occurring in the dorsolateral fasciculus after retrograde tracer injections in theVLMlat (Lima, D. et al., 1991), VLM projections from laminae I–III course in the dorsal portion of the lateral funiculus (Figure 3), as is the case of the spinomesencephalic (McMahon, S. B. and Wall, P. D., 1985; Hylden, J. L. K. et al., 1986b) and spinothalamic (Apkarian, A. V. et al., 1985; Apkarian, A. V. and Hodge, C. J., 1989c) pathways. 35.3.1.4

Surface receptors Large numbers of lamina I neurons projecting to the VLM express neurokinin I (NK1) (Figure 5) (Todd, A. J. et al., 2000; Spike, R. C. et al., 2003; Castro, A. R. et al., 2006) and GABAB receptors (Castro, A. R. et al., 2006), the co-localization of both being relatively frequent (Castro, A. R. et al., 2006). In addition, 90% of the large deep dorsal horn neurons with dendrites entering superficial laminae and exhibiting the NK1 receptor project to the VLM (Todd, A. J. et al., 2000). Appositions of serotonin (5HT) and noradrenalin-containing axonal boutons upon VLM-projecting lamina I neurons are common (Tavares, I. et al., 1996a; Polgar, E. et al., 2002). Serotoninergic boutons establish symmetrical synaptic contacts and are more abundant upon neurons expressing the NK1 receptor (Polgar, E. et al., 2002). 35.3.1.5

Neurotransmitters As in most ascending pathways conveying nociceptive input, studies addressing the neurochemical content of

(a)

(b)

(c)

(d)

Figure 5 Flattened (a, b) and pyramidal (c, d) lamina I neurons, in horizontal view, retrogradely labeled with cholera toxin subunit B (CTb) from the VLM (red) and immunoreactive for the NK1 receptor (green). Scale bar ¼ 50 mm. Adapted from figure 9 of Spike, R. C., Puskar, Z., Andrew, D., and Todd, A. J. 2003. A quantitative and morphological study of projection neurons in lamina I of the rat lumbar spinal cord. Eur. J. Neurosci. 18, 2433–2448.

486 Ascending Pathways: Anatomy and Physiology

the neurons of origin of the spino-VLM pathway have focused on neuropeptides. The exhaustive study of Leah and collaborators (Leah, J. et al., 1988) revealed a relatively large amount of vasoactive intestinal peptide (VIP), bombesin, dynorphin, and substance Pimmunoreactive VLM-projecting neurons in the lateral spinal nucleus. A few enkephalin immunoreactive neurons were observed in lamina X. Calbindin is present in particularly large numbers of lumbosacral cells projecting to the VLM-bilaterally, especially within lamina I and the lateral spinal nucleus, but also in lamina X (Mene´trey, D. et al., 1992b). Although fusiform neurons in lamina I (Lima, D. et al., 1993) and neurons in lamina II (Todd, A. J. and Spike, R. C., 1993) are known to contain GABA, GABA-immunostaining of neurons retrogradely labeled from the VLM could not be observed (Tavares, I. and Lima, D., 2002). Response properties The response properties of neurons projecting to the ventrolateral reticular formation were studied in the rat (Mene´trey, D. et al., 1984) and cat (Thies, R., 1985). A high proportion of VLM-projecting neurons are spontaneously active (Mene´trey, D. et al., 1984; Thies, R., 1985). NS neurons make up about half of the entire population of VLM-projecting neurons (Mene´trey, D. et al., 1984; Thies, R., 1985). The remaining are either WDR or LT/proprioceptive neurons (Mene´trey, D. et al., 1984; Thies, R., 1985). They often present bilateral symmetrical receptive fields as well as cutaneous inhibitory receptive fields (Mene´trey, D. et al., 1984). Convergence of cutaneous, visceral, and muscle input is frequently observed (Thies, R., 1985). By monitoring noxiousevoked c-fos induction (Tavares, I. et al., 1993), 10% to 20% of VLM-projecting neurons were shown to be activated by heat or mechanical stimulation in laminae I and IIo. In lamina IIi, neurons were activated in fewer numbers and only after thermal stimulation.

the VLM region that establishes connections with other supraspinal pain inhibitory centers (Tavares, I. et al., 1996b; Cobos, A. et al., 2003), pointing to a role of the superficial dorsal horn-VLMlat pathway in driving the potent descending inhibition that can be elicited upon stimulation of VLM (Gebhart, G. F. and Ossipov, M. H., 1986). At the RVM and the pontine A5 noradrenergic group, terminal arborizations of VLM axons appose spinal-projecting neurons (Figure 6), indicating that pain control actions from those areas are indeed under the control of the VLM (Tavares, I. et al., 1996b).

(a)

35.3.1.6

Pathways driven at the target The VLM projects to several brain areas also receiving nociceptive input from the spinal cord and involved in pain control as well as cardiovascular, endocrine, or limbic functioning. Among these areas stand the RVM; the dorsal reticular nucleus (DRt); the A5, A6, and A7 pontine noradrenergic groups (Tavares, I. et al., 1996b); the hypothalamus (Calaresu, F. R. et al., 1984; Malick, A. et al., 2000); and the central nucleus of the amygdala (Zardettosmith, A. M. and Gray, T. S., 1995). Studies focused on the brainstem showed that the VLMlat is

(b)

35.3.1.7

Figure 6 RVM (a) and A5 (b) neurons retrogradely labeled with cholera toxin subunit B (CTb) from the spinal cord (brown granules) and receiving appositions (arrows) from axonal boutons anterogradely labeled with biotinilated dextran amine (BDA) from the VLM. Neuron in (b) is immunoreactive for dopamine--Hydroxylase (DBH; blue). Scale bar ¼ 20 mm. (Adapted from figure 3 of Tavares, I., Lima, D., and Coimbra, A. 1996b. The ventrolateral medulla of the rat is connected with the spinal cord dorsal horn by an indirect descending pathway relayed in the A5 noradrenergic cell group. J. Comp. Neurol. 374, 84–95).

Ascending Pathways: Anatomy and Physiology

In the A5, spinal-projecting neurons contacted by VLMlat fibers are noradrenergic (Figure 6) and postsynaptic in asymmetric, putative excitatory synaptic contacts (Tavares, I. et al., 1996b). This was taken as suggestive that the spinal 2 adrenoreceptormediated antinociceptive action triggered in the VLM is dependent on VLMlat activation and relayed in the A5 group. The VLM also sends direct descending projections to the spinal cord (Tavares, I. and Lima, D., 1994). Projections to both the superficial and deep dorsal horn originate in the VLMlat (Tavares, I. and Lima, D., 1994). Data from several studies indicate that noradrenaline is not used in the direct VLMspinal pathway (Westlund, K. N. et al., 1981; Westlund, K. N. et al., 1983; Tavares, I. et al., 1996b). VLMlat axons targeting lamina I make up a reciprocal closed VLM-spino-VLM loop which is entirely excitatory at the VLM level, and both excitatory and inhibitory at the spinal level (Tavares, I. et al., 1998; Tavares, I. and Lima, D., 2002). The cerebellar connections of the LRt (Cledenin, M. et al., 1974; Parenti, R. et al., 1996), together with the fact that, contrary to the VLMlat, the LRt does not contribute descending projections to the spinal cord dorsal horn (Tavares, I. and Lima, D., 1994), point to a role of the deep dorsal horn/ventral hornLRt pathways in the control of motor activity in response to pain.

35.3.2

487

Dorsal Reticular Nucleus

35.3.2.1 Spinal laminae of origin and sites of termination

The medullary dorsal reticular nucleus (DRt) was first shown in the rat to be the site of termination of an important, mainly ipsilateral, pathway ascending from the spinal cord (Lima, D. and Coimbra, A., 1985; Lima, D., 1990; Villanueva, L. et al., 1991). By the same time, neurons in the DRt were shown to be exclusively or preferentially activated by noxious stimuli from the skin and viscera (Villanueva, L. et al., 1988). The spino-DRt pathway was later uncovered in other species such as the cat, monkey (Craig, A. D., 1995), and pigeon (Galhardo, V. et al., 2000). It is constituted by a dorsal and ventral component differing in the area of termination within the DRt (Figure 7). The dorsal pathway terminates at the dorsal-most portion of the DRt, immediately above the level of the central canal and surrounding the ventral border of the cuneate nucleus (Almeida, A. et al., 1995; Almeida, A. et al., 2000). It originates from the medial-most part of laminae I–III ipsilaterally, with a marked predominance of lamina I, and from lamina X, bilaterally (Figure 7) (Lima, D., 1990). The ventral pathway terminates ventrally to the area of termination of the dorsal pathway, within both sides of the DRt (Almeida, A. et al., 1995; Almeida, A. et al., 2000).

Spinodorsal DRt Spinoventral DRt

Figure 7 Diagram representing the spinal laminae of origin, ascending course in the spinal cord, and areas of termination of the spino-DRt pathway. Note the preferential medial location of dorsal horn neurons. Fibers of the spinodorsal DRt pathway course in the dorsal funiculus. Brain and spinal cord photomicrographs were adapted from Paxinos, G. and Watson, C. 1998. The Rat Brain in Stereotaxic Coordinates, 4th edn. Academic Press.

488 Ascending Pathways: Anatomy and Physiology

Its cells of origin prevail ipsilaterally in the medial portion of laminae IV–VI, with additional bilateral participation from laminae VII and X (Figure 7) (Lima, D., 1990). Interestingly, retrograde labeling from the superficial or deep dorsal horn demonstrated descending pathways arising, respectively, from the ipsilateral dorsal-most part of the DRt or from both sides of the ventral DRt (Tavares, I. and Lima, D., 1994). The DRt is thus part of two distinct reciprocal loops connecting its dorsal part with the superficial dorsal horn ipsilaterally, and ventral part with the deep dorsal horn bilaterally (Almeida, A. et al., 1993; Almeida, A. et al., 2000). 35.3.2.2 Structural types of neurons involved

Lamina I neurons projecting to the dorsal DRt were structurally characterized in the rat based on observations of neurons retrogradely filled with CTb in the three anatomical planes (Lima, D. and Coimbra, A., 1990). As to other spinal laminae, no data have been collected so far. In the rat, about 30% of lamina I neurons projecting to the DRt belong in the pyramidal and flattened types in similar amounts. The remaining 70% are of the multipolar type, a finding particularly curious taking into account that multipolar neurons were not seen to project in other ascending pathways. These cells are rather peculiar due to the typical lamina II crossing of the dendritic arbor, the bush pattern of the highly ramified proximal dendritic branches and the profusion and large variety of dendritic spines (Lima, D. and Coimbra, A., 1986). Another interesting feature of multipolar cells is their preferential location in the medial third of lamina I in the rat (Lima, D. and Coimbra, A., 1983; Lima, D. and Coimbra, A., 1986). The same structural types of lamina I neurons were seen to project to the DRt in the pigeon, although flattened and pyramidal neurons were relatively more abundant in this species (Galhardo, V. et al., 2000).

was completely abolished in ipsilateral laminae I–III and markedly diminished in the deep dorsal horn at segments caudal to the lesion. Anterograde tracing later revealed that numerous fibers are labeled in the dorsal funiculus after injections in superficial laminae, and in the dorsolateral fasciculus after injections in deep dorsal horn laminae (Almeida, A. et al., 1995). Accordingly, injections in the dorsal funiculus resulted in DRt labeling restricted to its ipsilateral dorsal part, while injections in the dorsolateral fasciculus produced ipsilateral ventral DRt labeling (Almeida, A. et al., 1995). These findings not only confirm a dual ascending tract for the dorsal and ventral DRt pathways, but also indicate that fiber decussation in the ventral pathway takes place near the segment of origin, as in most other pathways. 35.3.2.4

Surface receptors A significant amount of lamina I neurons projecting to the DRt express the NK1 receptor alone (Todd, A. J. et al., 2000; Castro, A. R. et al., 2006) or together with the GABAB receptor (Castro, A. R. et al., 2006). DRtprojecting neurons expressing only the GABAB receptor are, however, much more numerous (Castro, A. R. et al., 2006). In laminae III–IV, about 20% of NK1expressing neurons project to the DRt (Todd, A. J. et al., 2000). 35.3.2.5

Neurotransmitters So far, there are no studies addressing the possible neurotransmitters used in the spino-DRt pathway. Nevertheless, it is interesting to note that, although immunoreactions for GABA revealed immunostaining of lamina I neurons of the multipolar type, (Lima, D. et al., 1993), even in the early 2000s, GABA could not be detected in projecting spinal neurons (Gamboa-Esteves, F. O. et al., 2001b; Tavares, I. and Lima, D., 2002). 35.3.2.6

35.3.2.3 fibers

Spinal location of ascending

An interesting aspect of the spino-DRt pathway, apparently only shared with the spino-NTS pathway (Gamboa-Esteves, F. O. et al., 2001c), is the course of their axons in the dorsal funiculus. This was first suggested by the dorsal orientation of axonal processes of lamina I neurons labeled retrogradely from the DRt and by comparing retrograde labeling rostrally and caudally to lesions of the dorsal funiculus (Lima, D., 1990). Retrograde labeling

Response properties The few data regarding the response characteristics of spino-DRt neurons rely on the induction of the c-fos proto-oncogene as a marker of activation of spinal neurons following noxious stimulation (Hunt, S. P. et al., 1987). This kind of approach only permitted to conclude on the activation by various kinds of cutaneous and visceral noxious stimulation of DRt-projecting lamina I neurons of all the three structural groups involved, namely multipolar, flattened, and pyramidal (Almeida, A. and Lima, D., 1997). The rate of activation of DRt-projecting

Ascending Pathways: Anatomy and Physiology

lamina I neurons varied from 20% to 80% depending on the kind of stimulation applied and the neuronal cell group (Almeida, A. and Lima, D., 1997). In the deep dorsal horn, although high levels of c-fos expression were observed, the amount of activation of projecting neurons did not exceed 5%. Electrophysiological studies are absolutely needed to further characterize the response properties of spino-DRt neurons and to clarify the involvement of the deep dorsal horn in the transmission of nociceptive input to the DRt. 35.3.2.7

Pathways driven at the target Projections from the DRt reach the parafascicular, ventromedial, and reunions thalamic nuclei (Figure 8) in the rat (Villanueva, L. et al., 1998), which in turn are connected with telencephalic areas involved in emotional/affective and cognitive control. A putative spinoreticulothalamocortical projection relayed at the DRt has been proposed (Desbois, C. and Villanueva, L., 2001). Widespread projections to other brain targets of nociceptive ascending pathways have also been described. These include the VLM; the NTS; the rostral ventromedial medulla; the pontine noradrenergic cell groups A5, A6, and A7 (PBN); the PAG; the posterior thalamus; the hypothalamus; the septal nuclei; the globus pallidus; and the amygdala (Figure 8) (Bernard, J. F. and Besson, J. M., 1990; Bernard, J. F. et al., 1990; Villanueva, L. et al., 1998; Leite-Almeida, H. et al., 2006). Important projections to the orofacial motor nuclei (Bernard, J. F. et al., 1990; Leite-Almeida, H. et al., 2006) as well as to the deep cerebellar nuclei (Leite-Almeida, H. et al., 2006) favor an important role in the organization of facial expressions and vocalization triggered by noxious stimulation. The DRt also projects to the spinal cord superficial (Tavares, I. and Lima, D., 1994) and deep dorsal horn (Tavares, I. and Lima, D., 1994; Villanueva, L. et al., 1995) as well as to the intermediate/ventral horn (Villanueva, L. et al., 1995). DRt axons terminating in lamina I participate in a closed reciprocal spinodorsal DRt-spinal loop which, based on the asymmetric structure of synapses, is likely to be excitatory at both the spinal and medullary levels (Figure 9) (Almeida, A. et al., 1993; Almeida, A. et al., 2000; Lima, D. and Almeida, A., 2002). Nociceptive input arriving at the DRt is thus thought to drive a reverberating, lamina I centered pain facilitatory circuit, which is in accordance with the high proportion of c-fos activated spino-DRt neurons when compared to that of activated cells projecting to other targets

489

(Lima, D., 1998). A ventral DRt-deep dorsal horn pain facilitatory loop is also likely to be established as indicated by the increased responsiveness of WDR deep dorsal horn neurons upon DRt stimulation (Dugast, C. et al., 2003). 35.3.3

Nucleus Tractus Solitarii

35.3.3.1 Spinal laminae of origin and sites of termination

The spino-NTS pathway was demonstrated in the rat (Mene´trey, D. and Basbaum, A. I., 1987; Leah, J. et al., 1988; Esteves, F. et al., 1993) and pigeon (Galhardo, V. et al., 2000). It originates in laminae I, IV–VI, VII, X, and the lateral spinal nucleus, mainly contralaterally, but with an important ipsilateral component (Figure 10) (Esteves, F. et al., 1993). In the rat, the thoracic and sacral autonomic cell columns were also shown to participate (Mene´trey, D. and Basbaum, A. I., 1987; Mene´trey, D. and DePommery, J., 1991). In addition, an important contribution from the superficial laminae of the spinal trigeminal nucleus, pars caudalis, was revealed (Mene´trey, D. and Basbaum, A. I., 1987). The spinoNTS pathway terminates in the caudal part of the NTS, the general visceral zone (Figure 10) (Loewy, A. D., 1990). Based on restricted retrograde tracer injections, cells projecting to the lateral subnucleus are fewer than those targeting the medial NTS, and do not include lamina I cells (Figure 10) (Esteves, F. et al., 1993). Anterograde tracing confirmed this finding by showing that fibers originating in the superficial dorsal horn terminate bilaterally in the medial part of the commissural subnucleus, while fibers originating in the deep dorsal horn terminate ipsilaterally in the lateral subnucleus, with a few fibers distributed to the dorsomedial subnucleus (Gamboa-Esteves, F. O. et al., 2001c). 35.3.3.2 Structural types of neurons involved

Again, studies referring to the structural characteristics of spino-NTS neurons only addressed lamina I. Similar to what was observed for the VLM, lamina I neurons projecting to the NTS belong in the fusiform, pyramidal, and flattened groups. However, contrary to the VLM, fusiform neurons contribute a small fraction. In spite of constituting half of the lamina I neuronal population (Lima, D. and Coimbra, A., 1983; Lima, D. and Coimbra, A., 1986), fusiform neurons amount only to 25% of NTS-projecting lamina I neurons, whereas flattened and pyramidal neurons make up

490 Ascending Pathways: Anatomy and Physiology

(a)

(f)

(b)

(c)

(g)

(h)

(i) (d)

(e)

(j)

Figure 8 Distribution of DRt efferents anterogradely labeled with phaseolus vulgaris leucoagglutinin (PHA-L) in the diencephalon and telencephalon, in horizontal view. Adapted from figure 6 of Villanueva, L., Desbois, C., Le Bars, D., and Bernard, J. F. 1998. Organization of diencephalic projections from the medullary subnucleus reticularis dorsalis and the adjacent cuneate nucleus: a retrograde and anterograde tracer study in the rat. J. Comp. Neurol. 390, 133–160.

about 35–40% each. Similar relative amounts were observed in the pigeon, although pyramidal cells prevailed followed by flattened and fusiform cells (Galhardo, V. et al., 2000). The abundant participation

of flattened cells in the spino-NTS pathway deserves particular attention since it may be related to the specific role of this pathway in pain processing. Flattened cells make up 10% of the entire lamina I

Ascending Pathways: Anatomy and Physiology

(a)

(b)

Figure 9 Anterogradely labeled axonal bouton () in the DRt (a) and superficial dorsal horn (b) establishing asymmetric synaptic contacts (arrows) upon retrogradely labeled dendrites after injecting cholera toxin subunit B (CTb) in the superficial dorsal horn (a) or horseradish peroxidase (HRP) in the dorsal DRt (b). In (b), tracer deposits are pointed by cuved arrows. Scale bar 0.3 mm (a) Adapted from figure 3 of Almeida, A., Tavares, I., and Lima, D. 2000. Reciprocal connections between the medullary dorsal reticular nucleus and the spinal dorsal horn in the rat. Eur. J. Pain. 4, 373–387. (b) Adapted from figure 3 of Almeida, A., Tavares, I., Lima, D., and Coimbra, A. 1993. Descending projections from the medullary dorsal reticular nucleus make synaptic contacts with spinal cord lamina I cells projecting to that nucleus: an electron microscopic tracer study in the rat. Neuroscience 55, 1093–1106.

neuronal population and participate in a similar proportion in the spino-VLM (Lima, D. et al., 1991) and the spino-DRt (Lima, D. and Coimbra, A., 1990) pathways. Their relative amount in the NTS system is, however, particularly high surpassing the one observed in the lateral spinothalamic system (25–30% at the spinal enlargements). 35.3.3.3 fibers

Spinal location of ascending

By comparing anterograde tracing produced by injections centered in the dorsal funiculus or the dorsolateral fasciculus with that obtained from superficial or deep dorsal horn laminae, it was concluded that fibers from lamina I neurons course in the dorsal funiculus and fibers from deep dorsal horn neurons in the dorsolateral fasciculus (Figure 10) (GamboaEsteves, F. O. et al., 2001c). 35.3.3.4

Neurotransmitters A small fraction of the neurons projecting to the NTS was found, in immunocytochemical studies, to contain dynorphin in lamina I, VIP in the lateral spinal

491

nucleus, and bombesin in lamina X (Leah, J. et al., 1988). Calbindin was immunodetected in spinal NTS-projecting neurons located mainly in lamina I (Figure 11) and the lateral spinal nucleus (Mene´trey, D. et al., 1992b; Gamboa-Esteves, F. O. et al., 2001a), as well as in lamina I of the spinal trigeminal nucleus, pars caudalis (Mene´trey, D. et al., 1992a). In lamina I, about 40% of fusiform NTS-projecting neurons contain calbindin. Pyramidal and flattened neurons also exhibit calbindin (Figure 11), but in smaller fractions (Gamboa-Esteves, F. O. et al., 2001a). Glutamate also occurs mainly in fusiform neurons followed by pyramidal neurons, and co-localizes extensively with calbindin (Gamboa-Esteves, F. O. et al., 2001a). Nitric oxide synthase is present in fewer cells, almost all of them the fusiform type (Gamboa-Esteves, F. O. et al., 2001a). Calbindin-immunoreactive NTS-projecting neurons are c-fos activated by visceral and cutaneous stimulation (Gamboa-Esteves, F. O. et al., 2001b). Glutamate-positive and nitric oxide synthase-positive neurons are c-fos activated only by visceral stimulation (Gamboa-Esteves, F. O. et al., 2001b). About 5% neurons of NTS-projecting neurons of the pyramidal group are immunoreactive for substance P (GamboaEsteves, F. O. et al., 2001a). 35.3.3.5

Response properties By the use of the c-fos approach, spino-NTS neurons located in lamina I were shown to be activated by cutaneous and visceral noxious stimulation (Mene´trey, D. and DePommery, J., 1991; Lima, D. et al., 1994; Gamboa-Esteves, F. O. et al., 2001b). They belong in the three neuronal groups that participate in the pathway (Esteves, F. et al., 1993) irrespective of the kind of cutaneous or visceral noxious stimulation employed (Lima, D. et al., 1994). However, cells activated by visceral input prevail over those activated by cutaneous input, and neurochemical differences between cutaneous- and visceral-activated cells were found (Gamboa-Esteves, F. O. et al., 2001b). 35.3.3.6

Pathways driven at the target The caudal NTS projects to several brain areas involved in pain processing such as the caudal ventrolateral reticular formation (Cobos, A. et al., 2003), the dorsal reticular nucleus (Almeida, A. et al., 2002), the rostral ventromedial medulla (Sim, L. J. and Joseph, S. A., 1994), the PBN (Cechetto, D. F. et al., 1985), the PAG (Bandler, R. and Tork, I., 1987; Herbert, H. and Saper, C. B., 1992), and the hypothalamus (Reis, L. C. et al., 2000). The NTS is also connected with the medullary vasopressor (Agarwal, S. K. and Calaresu,

492 Ascending Pathways: Anatomy and Physiology

Spino-NTS (commissural subnucleus) Spino-NTS (lateral subnucleus)

Figure 10 Diagram representing the spinal laminae of origin, ascending course in the spinal cord, and areas of termination of the spino-NTS pathway. Note the deep dorsal horn location of neurons terminating in the lateral subnucleus. Brain and spinal cord photomicrographs were adapted from Paxinos, G. and Watson, C. 1998. The Rat Brain in Stereotaxic Coordinates, 4th edn. Academic Press.

F. R., 1990) and vasodepressor (VLM) areas (Cobos, A. et al., 2003). Although the NTS–VLM pathway is potentially involved in nociceptive/cardiovascular integration (Tavares, I. et al., 1997), different VLM neurons are likely to mediate the antinociceptive and vasodepressive effects (Lima, D. et al., 2001). The caudal NTS also gives rise to projections descending directly to the spinal cord (Loewy, A. D. and Burton, H., 1978; Mtui, E. P. et al., 1993; Tavares, I. and Lima, D., 1994). NTS fibers targeting the dorsal horn originate in the commissural subnucleus and terminate in superficial laminae (Tavares, I. and Lima, D., 1994).

35.3.4

Rostral Ventromedial Medulla

35.3.4.1 Spinal laminae of origin and sites of termination

Spinal cells projecting in the spino-RVM pathway predominate in laminae V, VII, VIII, and X (Figure 12) in the rat (Maunz, R. A. et al., 1978; Kevetter, G. A. and Willis, W. D., 1982; Kevetter, G. A. et al., 1982; Kevetter, G. A. and Willis, W. D., 1983; Chaouch, A. et al., 1983; Peschanski, M. and Besson, J. M., 1984; Nahin, R. L. and Micevych, P. E., 1986;

Nahin, R. L. et al., 1986), cat (Abols, I. A. and Basbaum, A. I., 1981; Ammons, W. S., 1987), and monkey (Haber, L. H. et al., 1982; Kevetter, G. A. et al., 1982). The pathway is mainly contralateral, although a large number of ipsilaterally and bilaterally projecting cells have also been reported (Figure 12) (Haber, L. H. et al., 1982; Thies, R. and Foreman, R. D., 1983; Foreman, R. D. et al., 1984; Ammons, W. S., 1987). Cells are distributed throughout the entire length of the spinal cord, but are much more numerous at the upper cervical level due to an important contribution of the ipsilateral ventral horn (Kevetter, G. A. and Willis, W. D., 1983). Scattered neurons were observed in lamina I (Foreman, R. D. et al., 1984; Leah, J. et al., 1988) and the lateral spinal nucleus in the rat (Leah, J. et al., 1988). The axonal termination domain distributes through the nucleus reticularis gigantocellularis and the nucleus paragigantocellularis (Figure 12) (Bowsher, D. and Westman, J., 1970; Kerr, F. W. L., 1975; Peschanski, M. and Besson, J. M., 1984). In the cat and monkey, fibers originating in lamina I were seen to extend medially through the reticular formation to terminate in nucleus raphe magnus (Craig, A. D., 1995).

Ascending Pathways: Anatomy and Physiology

(a)

(b)

(c)

(d)

493

Neurons in lamina X were also shown to contain cholecystokinin (CCK), somatostatin and, in fewer numbers, bombesin (Leah, J. et al., 1988). In the lateral spinal nucleus, a relatively large neuronal population is immunoreactive to VIP, while bombesin and dynorphin are expressed in just a few neurons (Leah, J. et al., 1988). Scarce somatostatin-immunoreactive neurons occur in lamina V (Leah, J. et al., 1988). 35.3.4.5

(e)

(f)

Figure 11 Lamina I neurons of the flattened (a, b), pyramidal (c, d), and fusiform (e, f ) types retrogradely labeled with cholera toxin subunit B (CTb) from the NTS, in parasagittal view. In (b, d, and f ), retrogradely labeled neurons present immunoreactivity for calbindin (green). Scale bar ¼ 50 mm. (Adapted from figures 3 and 5 of Gamboa-Esteves, F. O., Kaye, J. C., McWilliam, P. N., Lima, D., and Batten, T. F. 2001a. Immunohistochemical profiles of spinal lamina I neurons retrogradely labelled from the nucleus tractus solitarii in rat suggest excitatory projections. Neuroscience 104, 523–538).

35.3.4.2 Structural types of neurons involved

Spino-RVM neurons located in lamina VII in the monkey were structurally relatively small as compared to spinothalamic neurons, with multipolar or, less frequently, fusiform or round perikarya and long dendrites across the lateromedial axis (Kevetter, G. A. et al., 1982). 35.3.4.3 fibers

Spinal location of ascending

Spino-RVM axons course in the contralateral ventrolateral quadrant in the spinal cord (Figure 12) and follow ventrolaterally in the caudal medulla oblongata before they turn medially to reach their sites of termination (Rossi, G. F. and Brodal, A., 1957; Anderson, F. D. and Berry, C. M., 1959; Mehler, W. R. et al., 1960; Kerr, F. W. L., 1975; Nahin, R. L. et al., 1986). Neurotransmitters Immunocytochemical staining for enkephalin was observed in spino-RVM neurons located in laminae VII and X (Nahin, R. L. and Micevych, P. E., 1986).

Response properties Spino-RVM neurons are excited by stimulation of A and C fibers from the skin, muscles, and viscera (Maunz, R. A. et al., 1978; Thies, R. and Foreman, R. D., 1983; Foreman, R. D. et al., 1984; Ammons, W. S., 1987). Both noxious and innocuous stimulation are effective, but the majority of RVM-projecting neurons are nociceptive (Maunz, R. A. et al., 1978; Haber, L. H. et al., 1982; Thies, R. and Foreman, R. D., 1983; Foreman, R. D. et al., 1984). Neurons responding only to cutaneous input belong in the LT, WDR, and NS classes (Fields, H. L. et al., 1977). Receptive fields vary from limited (Fields, H. L., et al., 1977) to large and complex, often including inhibitory regions (Fields, H. L. et al., 1977; Maunz, R. A. et al., 1978; Cervero, F. and Wolstencroft, J. H., 1984). Neurons responding to stimulation of deep structures are particularly numerous. They are mostly activated by deep noxious stimulation (Cervero, F. and Wolstencroft, J. H., 1984) and may receive convergent noxious or innocuous input from the skin (Fields, H. L. et al., 1977; Cervero, F. and Wolstencroft, J. H., 1984). Neurons responsive to cutaneous, deep, and visceral noxious stimulation have also been reported (Foreman, R. D. et al., 1984; Blair, R. W. et al., 1984a, 1984b; Ammons, W. S., 1987). The majority of these cells belong in the high-threshold class, the remaining being WDR neurons (Thies, R. and Foreman, R. D., 1983; Foreman, R. D. et al., 1984). Similar to pure somatic neurons, spinoreticular neurons with visceral input present either well-delimited or complex receptive fields, the latter including areas resulting in innocuous- or noxious-evoked inhibition (Thies, R. and Foreman, R. D., 1983; Foreman, R. D. et al., 1984). Ten percent to 20% of the neurons projecting to the RVM also target the lateral thalamus (Haber, L. H. et al., 1982; Foreman, R. D. et al., 1984).

35.3.4.4

35.3.4.6

Pathways driven at the target The RVM was shown to project to the medial thalamus, including the intralaminar complex (Giesler, G.

494 Ascending Pathways: Anatomy and Physiology

Spino-RVM

Figure 12 Diagram representing the spinal laminae of origin, ascending course in the spinal cord, and areas of termination of the spino-RVM pathway. Brain and spinal cord photomicrographs were adapted from Paxinos, G. and Watson, C. 1998. The Rat Brain in Stereotaxic Coordinates, 4th edn. Academic Press.

J. et al., 1981b; Peschanski, M. and Besson, J. M., 1984), and hence was proposed to function as a relay station in a spinoreticulothalamic pathway involved in motor responses to noxious stimulation. It is also at the origin of an important pain control descending pathway that terminates in the superficial and deep dorsal horn and includes pain inhibitory and facilitatory neurons (Fields, H. L. et al., 1995; Fields, H. L., 2000).

35.4 Spinopontine Pathways The search for spinal fibers terminating in the brainstem (Craig, A. D., 1995), in particular in catecholaminergic nuclei (Westlund, K. N. and Craig, A. D., 1996), revealed various pontine spinal targets, which include the ventrolateral pons (A5), the locus coeruleus (A6), the subcoerulear region, the Ko¨lliker–Fuse nucleus, and the PBN (Figure 13). These studies were, however, focused on lamina I ascending fibers, and, except for the PBN,

such putative nociceptive pathways were not thoroughly investigated. This section will, therefore, deal only with the spino-PBN system.

35.4.1

Parabrachial Nuclei

35.4.1.1 Spinal laminae of origin and sites of termination

Injections centered in the PBN in both the rat (Cechetto, D. F. et al., 1985; Lima, D. and Coimbra, A., 1989; Hylden, J. L. et al., 1989; Mene´trey, D. and DePommery, J., 1991; Traub, R. J. and Murphy, A., 2002) and cat (Panneton, W. M. and Burton, H., 1985; Hylden, J. L. K. et al., 1986a; 1986b) produce dense bilateral retrograde labeling in lamina I, mainly near the dorsal root entry zone, as well as in the lateral reticular portion of lamina V and laminae VIII and X (Figure 13). Additional labeling was observed in the intermediolateral column at thoracic levels, and in the parasympathetic column at sacral levels (Mene´trey, D. and DePommery, J. 1991). Spino-PBN neurons with

Ascending Pathways: Anatomy and Physiology

495

Spino-PBN

Figure 13 Diagram representing the spinal laminae of origin, ascending course in the spinal cord, and areas of termination of the spino-PBN pathway. Note the preferential lateral location of dorsal horn neurons. Spinal axonal termination areas in the locus coeruleus (LC), nucleus subcoeruleus (subCA) and the A5 noradrenergic group are also represented. Brain and spinal cord photomicrographs were adapted from Paxinos, G. and Watson, C. 1998. The Rat Brain in Stereotaxic Coordinates, 4th edn. Academic Press.

axonal collaterals to the lateral thalamus were observed in all spinal areas with a marked prevalence in lamina I (Hylden, J. L. K. et al., 1985; Hylden, J. L. et al., 1989). A large percentage of spino-PBN neurons also project to the VLM (Spike, R. C. et al., 2003). The areas of termination of spinal fibers in the PBN are distributed bilaterally through the dorsal part of the lateral parabrachial nucleus, namely the dorsal, central, internal, and superior lateral subnuclei and the Ko¨lliker–Fuse (Figure 13) (Cechetto, D. F. et al., 1985; Blomqvist, A. et al., 1989; Slugg, R. M. and Light, A. R., 1994). The medial and ventral lateral subnuclei are not targeted by spinal axons (Cechetto, D. F. et al., 1985). No topographical arrangement has been disclosed (Blomqvist, A. et al., 1989). 35.4.1.2 Structural types of neurons involved

Lamina I neurons labeled retrogradely in the rat following CTb injections centered in the PBN

(although extending to the cuneiform nucleus) belonged in the fusiform (65–70%) and pyramidal (30–35%) groups (Lima, D. and Coimbra, A., 1989). In the cat, lamina I neurons antidromically activated from mesencephalic sites with similar location and intracellularly stained resembled fusiform neurons (Figure 14) both from the description of their longitudinally extended spiny dendritic arbors and from their camera lucida drawings (Hylden, J. L. K. et al., 1986a; see Figure 5). 35.4.1.3 fibers

Spinal location of ascending

In the cat, spino-PBN fibers course bilaterally in the dorsolateral fasciculus and ipsilaterally in the ventrolateral and ventral funiculi (Figure 13) (Hylden, J. L. K. et al., 1986b; Hylden, J. L. et al.. 1989). Fibers originated in lamina I were shown to ascend through the dorsal aspect of the dorsolateral fasciculus (Hylden, J. L. K. et al., 1986b). About one-fifth of

496 Ascending Pathways: Anatomy and Physiology

(a)

(b)

et al., 2003), and most lamina I neurons expressing the NK1 receptor and receiving synaptic contacts from TRPV1 immunoreactive primary afferent fibers project to the PBN (Hwang, S. J. et al., 2003). Lamina I PBN-projecting Giant cells (lamina I cells three times larger than the remaining, amounting to about 5% in each lamina I structural group) (Lima, D. and Coimbra, A., 1983, 1986) of the pyramidal type were shown to lack the NK1 receptor and exhibit instead the glycine receptor-associated protein gephyrin (Puskar, Z. et al., 2001). These cells are apposed by nitric oxide synthase and GABA-containing axonal boutons (Puskar, Z. et al., 2001). In the deep dorsal horn, about 60% of NK1-immunoreacive neurons project to the PBN (Todd, A. J. et al., 2000). 35.4.1.5

Neurotransmitters Around half of the lamina I neuronal population projecting to the PBN immunostains for either dynorphin or enkephalin. Staining of sequential sections did not reveal co-localization of the two peptides (Standaert, D. et al., 1986). According to Lima and colleagues (Lima, D. and Coimbra, A., 1989; Lima, D. et al., 1993), lamina I enkephalinergic PBN-projecting cells should belong in the pyramidal group, whereas dynorphinergic cells could be either pyramidal or fusiform. Lumbosacral neurons projecting both ipsi- and contralaterally, mainly from lamina I and the lateral spinal nucleus, are immunoreactive for calbindin (Mene´trey, D. et al., 1992b). 35.4.1.6

Figure 14 Lamina I PBN-projecting neurons retrogradely labeled with CTb (a) or intracellularly stained during antidromic activation (b), in horizontal (a) and parasagittal (b) views. In (a), arrows point to thin distal dendritic branches. In (b), the arrow points to the axon and the open arrow to the cell body. Scale bars ¼ 30 mm. (a) Adapted from figure 4 of Lima, D. and Coimbra, A. 1989. Morphological types of spinomesencephalic neurons in the marginal zone (lamina I) of the rat spinal cord, as shown after retrograde labeling with cholera toxin subunit B. J. Comp. Neurol. 279, 327–339. (b) Adapted from figure 5 of Hylden, J. L. K., Hayashi, H., Dubner, R., and Bennett, G. J. 1986a. Physiology and morphology of the lamina I spinomesencephalic projections. J. Comp. Neurol. 247, 505–515).

lamina I neurons project bilaterally along the spinal cord (Hylden, J. L. K. et al., 1986a). 35.4.1.4

Surface receptors Most spino-PBN neurons located in lamina I express the NK1 receptor (Todd, A. J. et al., 2000; Spike, R. C.

Response properties Neurons antidomically activated from the PBN in lamina I of the lumbar spinal cord of the rat (Bester, H. et al., 2000) and cat (Hylden, J. L. K. et al., 1985; Hylden, J. L. K. et al., 1986a) belong mostly in the NS class (75–90%), the remaining being WDR neurons. They present extremely low spontaneous activity and small receptive fields, respond to stimulation of A and C primary afferent fibers and conduct in the C–A range (Hylden, J. L. K. et al., 1986a; Bester, H. et al., 2000). The large majority respond to both mechanical and heat-noxious stimulation and a few also to noxious cold stimulation. C-fos studies identified thoracolumbar spino-PBN neurons located preferentially in the superficial dorsal horn that were activated by visceral input (Mene´trey, D. and DePommery, J., 1991; Traub, R. J. and Murphy, A., 2002). In whole-cell patch-clamp recordings, most lamina I neurons projecting to the PBN present a gap firing pattern, with a voltage-dependent delay in action potential firing, which was only shared by part

Ascending Pathways: Anatomy and Physiology

of the neurons projecting to the PAG and not by neurons that were not labeled from these two sites (Ruscheweyh, R. et al., 2004). 35.4.1.7

Pathways driven at the target

By combining antidromic activation from the thalamus with orthodromic activation from the periphery, Bourgeais and coworkers (Bourgeais, L. et al., 2001b) demonstrated that neurons in the parabrachial internal lateral nucleus responding exclusively, with sustained firing, to noxious stimulation of large receptive fields, project to the paracentral thalamic nucleus. This spino-PBN-paracentral thalamic pathway was claimed to be responsible for triggering the aversive reactions to pain at the prefrontal cortex. By the use of a similar approach as well as by anatomical tracing, a spino-PBN-amygdaloid pathway with relay neurons in the external pontine parabrachial area and terminating in the lateral capsular division of the central nucleus of the amygdala was demonstrated (Ma, W. and Peschanski, M., 1988; Bernard, J. F. and Besson, J. M., 1990). This pathway was confirmed by retrograde transneuronal tracing from the amygdala with pseudorabies virus, and found to originate mainly in lamina I neurons (Jasmin, L. et al., 1997).

35.5 Spinomesencephalic Pathways Spinomesencephalic pathways target a multitude of regions located close to each other, which include the PAG, the intercollicular nucleus, the superior colliculus, the cuneiform nuclei, the posterior and anterior pretectal nuclei, and the nucleus of Darkschewitsch (Wiberg, M. and Blomqvist, A., 1984; Bjo¨rkeland, M. and Boivie, J., 1984; Yezierski, R. P., 1988). The PAG itself, the major target of spinofugal mesencephalic pathways, has its spinal afferents distributed through several areas, each one playing particular integrative roles (Yezierski, R. P., 1988). Most retrograde tracing studies that refer to the spino-PAG pathway are based on injections that encompass different areas of the PAG as well as part of the above referred neighbor regions. Since the PAG is the principal site of termination of the spinomesencephalic tract, this chapter, will focus on the spino-PAG pathway without separating the various mesencephalic targets, as a large number of studies addressing this ascending system do. However, it should be kept in mind that it comprises several parallel systems that

497

are likely to deal with different aspects of pain processing. 35.5.1

Periaqueductal Gray

35.5.1.1 Spinal laminae of origin and sites of termination

Neurons of origin of the spino-PAG pathway are located in lamina I, the reticular region of laminae IV–V, laminae VI–VIII, lamina X, and the lateral spinal nucleus (Figure 15) in the rat (Mene´trey, D. et al., 1982; Beitz, A. J., 1982; Liu, R. P., 1983; Swett, J. E. et al., 1985; Yezierski, R. P., 1988; Lima, D. and Coimbra, A., 1989; Yezierski, R. P. and Broton, J. G., 1991; Yezierski, R. P. and Mendez, C. M., 1991), cat (Wiberg, M. and Blomqvist, A., 1984; Yezierski, R. P., 1988), and monkey (Trevino, D. L., 1976; Mantyh, P. W., 1982; Wiberg, M. et al., 1987; Yezierski, R. P., 1988; Zhang, D. et al., 1990). In the cat, cells located in lamina I were found to account for the majority of spino-PAG neurons in the cervical and lumbar enlargements, but only to around 30% in the remaining spinal segments (Mouton, L. J. et al., 2001). In the rat, an additional important projection, apparently exclusive of this pathway, originates from neurons located inside the white matter overlying lamina I, at the dorsal funiculus (Lima, D. and Coimbra, A., 1989). Projections originated in the dorsal horn are mainly contralateral, especially from lamina I, the lateral spinal nucleus, and the dorsal funiculus (Trevino, D. L., 1976; Wiberg, M. et al., 1987; Lima, D. and Coimbra, A., 1989), although a significant ipsilateral projection from lumbosacral spinal segments has been reported (Mene´trey, D. et al., 1992b). Projections originated in lamina X and the ventral horn are bilateral (Figure 15) (Trevino, D. L., 1976; Wiberg, M. et al., 1987; Lima, D. and Coimbra, A., 1989). The upper cervical cord makes a major additional bilateral contribution both from the ventral horn and the lateral cervical nucleus (Yezierski, R. P. and Mendez, C. M., 1991; Mouton, L. J. and Holstege, G., 2000). Spino-PAG neurons were shown to leave axonal collaterals in the DRt, RVM, and locus coeruleus in the rat (McMahon, S. B. and Wall, P. D., 1985; Pechura, C. and Liu, R., 1986), and to collateralize a lot within the mesencephalon (Hylden, J. L. K. et al., 1985; Yezierski, R. P. and Schwartz, R. H., 1986). Projections to both the mesencephalon and thalamus were reported in the rat (Harmann, P. A. et al., 1988; Yezierski, R. P. and Mendez, C. M., 1991), cat (Hylden, J. L. K. et al., 1986a; Yezierski, R. P. and Broton, J. G., 1991) and

498 Ascending Pathways: Anatomy and Physiology

Spinomesencephalic

Figure 15 Diagram representing the spinal laminae of origin, ascending course in the spinal cord, and areas of termination of the spinomesencephalc pathway. (Only the caudal termination area is represented) Brain and spinal cord photomicrographs were adapted from Paxinos, G. and Watson, C. 1998. The Rat Brain in Stereotaxic Coordinates, 4th edn. Academic Press.

monkey (Price, D. D. et al., 1978; Yezierski, R. P. et al., 1987; Zhang, D. et al., 1990). Thalamic sites of termination are mainly located in the ventrobasal complex, but collateralization to the posterior complex and medial thalamic nuclei has also been observed (Yezierski, R. P. and Mendez, C. M., 1991). The mesencephalic sites of termination of the fibers ascending from the spinal cord and the spinal trigeminal nucleus were depicted in the rat (Yezierski, R. P., 1988), cat (Wiberg, M. and Blomqvist, A., 1984;

Bjo¨rkeland, M. and Boivie, J., 1984; Wiberg, M. et al., 1987; Yezierski, R. P., 1988), and monkey (Kerr, F. W. L., 1975; Wiberg, M. et al., 1987; Yezierski, R. P., 1988). The termination pattern is very similar in the three species (Figure 15). With the exception of the nucleus of Darkschewitsch, terminal arborizations are sparse in the most rostral part of the mesencephalon (Yezierski, R. P., 1988; Lima, D. and Coimbra, A., 1989). Fibers are mainly distributed through the middle and caudal part of the PAG, nucleus cuneiformis,

Ascending Pathways: Anatomy and Physiology

deep and intermediate gray layers of the superior colliculus, and intercollicular nucleus (Wiberg, M. et al., 1987; Yezierski, R. P., 1988). In the caudalmost PAG of the monkey, but not in the rat and cat (Figure 16), spinal afferents contribute to two distinct dorsolateral and ventrolateral dense arborizations, while immediately rostrally, in the intercollicular region, they concentrate in a sole domain located laterally (Wiberg, M. et al., 1987; Yezierski, R. P., (a) IC

AQ

(b) IC CG

AQ

(c) IC

AQ

Figure 16 Anterograde labeling in the caudal midbrain following injection of wheat grem agglutinin–horseradish peroxidase (WGA-HRP) in the lumbosacral spinal cord of the rat (a), cat (b), and monkey (c). AQ, Cerebral aqueduct; CG , Periaqueductal gray; IC, Inferior colliculus. Adapted from figure 3 of Yezierski, R. P. 1988. Spinomesencephalic tract: projections from the lumbosacral spinal cord of the rat, cat, and monkey. J. Comp. Neurol. 267, 131–146.

499

1988), with additional labeling dorsally to the aqueduct (Yezierski, R. P., 1988). This is an interesting finding in the light of data showing that the dorsolateral/lateral PAG is involved in aversive/defense behavior and vasopressor responses, and the vantrolateral PAG in immobility, positive reinforcing, and vasodepression (Lovick, T. A., 1993). The possibility that the spino-PAG pathway is a composite of multiple pathways subserving the various functions in which the PAG is involved is supported by studies showing that different regions in the PAG receive afferents from distinct spinal neuronal populations (Keay, K. A. and Bandler, R., 1992; VanderHorst, V. G. J. M. et al., 1996; Mouton, L. J. and Holstege, G.., 2000). Neurons at spinal segments C1–C3 that project to the lateral part of the PAG are mainly located in lamina I, whereas those projecting to the ventrolateral part of the PAG prevail in laminae VII–VIII (Keay, K. A. and Bandler, R., 1992). In the lumbosacral spinal cord, neurons in medial lamina VII and lamina VIII terminate in the lateral part of the lateral PAG and adjacent tegmentum, whereas neurons distributed thoughout laminae I and V terminate diffusely in the dorsal and lateral PAG (VanderHorst, V. G. J. M. et al., 1996). In the cat, Mouton and Holstege (Mouton, L. J. and Holstege, G., 2000) described five distinct spinal neuronal groups based on their clustering pattern in the spinal cord and termination pattern in the PAG: (1) neurons located in laminae I and V along the entire length of the spinal cord and terminating in all parts of the intermediate and caudal PAG; (2) neurons located bilaterally in lateral laminae VI–VII and dorsolateral lamina VIII of segments C1–C3 and terminating in the ventrolateral and lateral part of the entire PAG and deep tectum; (3) neurons located in lamina X of the thoracic and upper lumbar cord and terminating in the ventrolateral and lateral PAG and deep tectum; (4) neurons located in medial laminae VI–VII of segments L5–S3 and terminating in the lateral and ventrolateral intermediate and caudal PAG; and (5) neurons located laterally in lamina I of segments L6– S2 and laminae V–VII and X of segments S1–S3 and terminating in the medial part of the ventrolateral intermediate and caudal PAG. According to electrophysiologcal studies using antidromic activation (Yezierski, R. P. and Schwartz, R. H., 1986), spinal cells projecting to the rostral-most part of the PAG are located more ventrally, in laminae V–VII, than those projecting to the intercollicular and caudal levels, to where lamina I neurons project.

500 Ascending Pathways: Anatomy and Physiology

35.5.1.2 Structural types of neurons involved

Spinomesencephalic neurons were characterized as to the size and shape of the soma both in the rat and cat (Mene´trey, D. et al., 1980; VanderHorst, V. G. J. M. et al., 1996). Neurons in lamina I are smaller than in other laminae and present oval to fusiform soma in transverse view (VanderHorst, V. G. J. M. et al., 1996). Neurons in the lateral spinal nucleus and lamina X present oval to fusiform soma of variable sizes. Deep dorsal horn and ventral horn neurons are large and multipolar (Mene´trey, D. et al., 1980; VanderHorst, V. G. J. M. et al., 1996). A detailed structural characterization was obtained for lamina I neurons retrogradely labeled with CTb in the rat (Lima, D. and Coimbra, A., 1989). Large numbers of fusiform and pyramidal neurons were shown to participate. However, all injections were directed to the ventrolateral caudal PAG and encompassed part of the PBN. Injections hitting mainly the PBN failed to stain as many pyramidal neurons as those targeting the ventrolateral PAG, while still labeling a relatively large number of fusiform neurons. Pyramidal neurons were therefore taken as projecting mainly to the ventrolateral PAG and fusiform neurons to the PBN (Lima, D. and Coimbra, A., 1989). Some fusiform neurons projecting to the PAG were shown to have myelinated axons and give off collaterals inside lamina I (Hylden, J. L. K. et al., 1986a).

35.5.1.3 fibers

Spinal location of ascending

Fibers of the spinomesencephalic pathway are classically considered to travel in the ventrolateral quadrant of the spinal white matter (Mehler, W. R. et al., 1960; Kerr, F. W. L., 1975). More recent data using antidromic activation revealed that fibers arising from lamina I decussate near their level of origin and course in the dorsal part of the dorsolateral fasciculus (McMahon, S. B. and Wall, P. D., 1985; Hylden, J. L. K. et al., 1986b).

35.5.1.4

Surface receptors The majority of spino-PAG neurons in lamina I, but not in the deep dorsal horn, express the NK1 receptor (Todd, A. J. et al., 2000). Their amounts are, however, smaller than those of neurons projecting to the VLM or the PBN (Spike, R. C. et al., 2003).

35.5.1.5

Neurotransmitters In the lateral spinal nucleus and lamina X, neurons containing various neuropeptides and projecting to a mesencephalic area centered in the PAG (but extending to the parabrachial nuclei) were observed (Leah, J. et al., 1988). Neurons in the lateral spinal nucleus were immunoreactive for VIP, bombesin, and substance P, while those located in lamina X were immunoreactive for bombesin and enkephalin. A few VIP-immunoreactive neurons were located in lamina I. At lumbosacral spinal levels, calbindin immunoreactive PAG-projecting neurons were observed bilaterally in all spinal areas of origin of the pathway, with a particularly high concentration in lamina I and the lateral spinal nucleus (Mene´trey, D. et al., 1992b). 35.5.1.6

Response properties The response properties of spinal neurons projecting to the PAG were recorded in the rat (Mene´trey, D. et al., 1980), cat (Yezierski, R. P. and Schwartz, R. H., 1986; Yezierski, R. P. and Broton, J. G., 1991), and monkey (Yezierski, R. P. et al., 1987). PAG-projecting neurons belong in the LT, WDR, and NS classes. Both WDR and NS neurons respond to mechanical and heat stimuli at the noxious range. WDR neurons largely prevail over the other neuronal classes, representing about half of the population recorded. Many WDR cells were found to respond to both cutaneous and visceral/deep tissue stimulation (Yezierski, R. P. and Schwartz, R. H., 1986; Yezierski, R. P. et al., 1987). In the rat, NS neurons are predominant in lamina I, WDR neurons are distributed through both lamina I and the deep dorsal horn, and LT cells prevail in the deep dorsal horn (Mene´trey, D. et al., 1980). In the cat and monkey, neurons are distributed evenly through the dorsal horn and around the central canal irrespective of the physiological class they belong to (Yezierski, R. P. and Schwartz, R. H., 1986; Yezierski, R. P. et al., 1987). C-fos studies (Clement, C. I. et al., 2000; Keay, K. A. et al., 2002) revealed neurons at the thoracic spinal cord that project to the rostral ventrolateral PAG to be activated by noxious visceral stimulation. Neurons at both the lumbosacral and upper cervical spinal cord and projecting to the caudal ventrolateral PAG were activated by hind limb muscle noxious stimulation. Lamina I neurons projecting to the caudal ventrolateral PAG at the lumbar enlargement and expressing c-fos following either mechanical, thermal, or chemical noxious stimulation of the skin or noxious stimulation of the urinary bladder belong in

Ascending Pathways: Anatomy and Physiology

both the fusiform and pyramidal groups (Lima, D. et al., 1992; Lima, D., 1998). Most spino-PAG neurons, including those few cells projecting to both the PAG and the ventrobasal complex of the thalamus, present small excitatory receptive fields confined to a single limb (Yezierski, R. P. et al., 1987). However, neurons with extensive and complex receptive fields have also been observed, in particular in the upper cervical cord and in deep spinal laminae, including lamina X (Mene´trey, D. et al., 1980; Yezierski, R. P. and Schwartz, R. H., 1986; Yezierski, R. P., 1990; Yezierski, R. P. and Broton, J. G., 1991). Both groups present complex inhibitory receptive fields and include NS and WDR neurons (Yezierski, R. P. and Schwartz, R. H., 1986; Yezierski, R. P. et al., 1987; Yezierski, R. P. and Broton, J. G., 1991). Spino-PAG lamina I neurons have slow conducting velocities, at the A range, while those in the deep dorsal horn and ventral horn conduct at the low A range (Yezierski, R. P. et al., 1987). Neurons in the lateral spinal nucleus present particularly slow axons, which belong in the unmyelinated and thin myelinated classes (Mene´trey, D. et al., 1980). A recent study using whole-cell patch-clamp in spinal slices showed that spino-PAG neurons present either gapfiring or burst-firing patterns, contrary to neurons that were not labeled from either the PAG or the PBN (Ruscheweyh, R. et al., 2004). 35.5.1.7

Pathways driven at the target The spinomesencephalic pathway was first uncovered as a relay station of the medial spinothalamic tract. Early anatomical studies revealed a projection from the mesencephalon to the intralaminar nuclei of the thalamus (Bowsher, D., 1957). Later anterograde tracing studies confirmed this connection as well as important projections to the hypothalamus, striatum, and amygdala (Eberhart, J. A. et al., 1985; Meller, S. T. and Dennis, B. J., 1991). Discrete injections confined to different portions of the PAG in the rabbit showed that the ventral portion is the main source of afferent systems (Meller, S. T. and Dennis, B. J., 1991). Two distinct ascending systems were recognized: a periventricular system terminating in intralaminar and midline thalamic nuclei and along the hypothalamus, and a ventrolateral system terminating in the ventral tegmental area, ventral thalamus, zona incerta, amygdala, substantia innonimata, lateral preopric nucleus, diagonal band of Broca, and the lateral septal nucleus. This multitude of pathways is likely to reflect the morphofunctional complexity of the PAG and is

501

taken as indicative of a PAG role in motor responses, escape/avoidance, aversive versus positive reinforcing, and neuroendocrine and autonomic responses to pain (Lovick, T. A., 1993). A dense descending projection connects the ventrolateral portion of the caudal PAG with the ipsilateral nucleus raphe magnus (NRM) and adjacent reticular formation, locus coeruleus (LC), nucleus subcoeruleus, and the ventral reticular formation of the medulla (Meller, S. T. and Dennis, B. J., 1991). Sparse fibers originated in the dorsal PAG and superior colliculus also terminate in the locus coeruleus/subcoeruleus area (Cowie, R. J. and Holstege, G., 1992). Since PAG projections to the spinal cord are limited and restricted to laminae VII–VIII (Behbehani, M. M., 1995), the analgesic effects elicited from PAG stimulation are likely to be mediated by these PAG-pontine and PAG-medullary pathways (Lovick, T. A., 1993).

35.6 Spinodiencephalic Pathways Of the pathways terminating in the diencephalon, the spinothalamic are by far those known for longer and therefore more thoroughly investigated. Although a large proportion of the studies dealing with the spinothalamic system address together the lateral and medial pathways, it turned clear from clinical (Dejerine, J. and Roussy, G., 1906; Walker, A. E., 1942a; He´caen, H. et al., 1949), electrophysiological (Kenshalo, D. R., Jr. et al., 1979; Giesler, G. J. et al., 1981b), and anatomical (Boivie, J., 1979) studies that each pathway is engaged in particular aspects of nociceptive processing. The medial pathway has been implicated in arousal, motivational, affective, and motor responses to pain, and the lateral pathway in stimulus discrimination. Accordingly, in this chapter, the two pathways will be dealt with separately in spite of the difficulties raised by being often assessed as a whole, particularly in retrograde tracing studies. There are, nonetheless, common aspects that will be more thoroughly described in the context of the lateral spinothalamic pathway. Also, a relatively large percentage of spinothalamic neurons (around 15%) of various species and different spinal laminae projects to both the lateral and medial thalamus (Giesler, G. J. et al., 1981b; Kevetter, G. A. and Willis, W. D., 1983; Stevens, R. T. et al., 1989; Craig, A. D. et al., 1989). These neurons share, however, all the properties of lateral spinothalamic neurons

502 Ascending Pathways: Anatomy and Physiology

(Giesler, G. J. et al., 1981b) and are therefore considered as part of the lateral spinothalamic pathway. 35.6.1

Lateral Thalamus

The lateral spinothalamic pathway was the first nociceptive spinofugal pathway described (Edinger, L., 1890). Its identification, at the turning of the nineteenth century, was based on the observation in necropsia tissue from humans, of degenerating profiles at the lateral sensory thalamus after ventrolateral cordotomy that disrupted pain sensation (Quensel, F., 1898; Kohnstamm, O., 1900; Thiele, F. H. and Horsley, V., 1901; Collier, J. and Buzzard, E. F., 1903; Foerster, O. and Gagel, O., 1932; Clark, W. E.

L., 1936). Only much later, with the advent of neurophysiology and tracing techniques, this pathway was revealed in detail. Nevertheless, early clinical studies (Dejerine, J. and Roussy, G., 1906; Melzack, R. and Casey, K. L., 1968) correlated the lateral spinothalamic pathway with the discriminative processing of nociceptive input. 35.6.1.1 Spinal laminae of origin and sites of termination

The lateral spinothalamic pathway takes origin on the contralateral spinal cord in laminae I, IV–VI, VII–VIII, X, and the lateral spinal nucleus (Figure 17) in the rat, cat, and monkey (Trevino, D. L. and Carstens, E., 1975; Carstens, E. and Trevino, D. L.,

Lateral spinothalamic

Figure 17 Diagram representing the spinal laminae of origin, ascending course in the spinal cord and areas of termination of the lateral spinothalamic pathway. Note the cluster appearance of axon termination in the VPL. Brain and spinal cord photomicrographs were adapted from Paxinos, G. and Watson, C. 1998. The Rat Brain in Stereotaxic Coordinates, 4th edn. Academic Press.

Ascending Pathways: Anatomy and Physiology

1978b; Willis, W. D. et al., 1979; Giesler, G. J. et al., 1979a; Berkley, K. J., 1980; Leah, J. et al., 1988; Lima.D. and Coimbra, A., 1988; Burstein, R. et al., 1990b). In laminae I and IV, a somatotopic arrangement has been described, neurons receiving input from extensor surfaces being located more laterally than neurons receiving input from flexor surfaces (Willis, W. D. et al., 1974). The amount of spinothalamic neurons varies considerably along the rostrocaudal extent of the spinal cord due to additional intense labeling in particular areas at various spinal levels. This is the case of the deep dorsal horn contralaterally, and the intermediate/ventral horn, bilaterally, in spinal segments C1–C2 (Carstens, E. and Trevino, D. L., 1978a; Carstens, E. and Trevino, D. L., 1978b; Giesler, G. J. et al., 1979a; Lima.D. and Coimbra, A., 1988; Burstein, R. et al., 1990b), and the intermediate basilar nucleus of Cajal, contralaterally, in the rat (Giesler, G. J. et al., 1979a; Lima.D. and Coimbra, A., 1988; Burstein, R. et al., 1990b). Due to this regional variability, together with the fact that the multiple spinal groups projecting to the lateral thalamus also project to many other supraspinal targets, the erroneous assumption that thalamic projections from certain areas, such as lamina I, to the main lateral spinal target, the VPL, are not sufficiently relevant gained credit (Blomqvist, A. et al., 2000; Craig, A. D. et al., 2002; Klop, E. M. et al., 2004). However, although the relative participation of lamina I neurons is below 10% in the cat (Klop, E. M. et al., 2004) and rat (Burstein, R. et al., 1990b) when the spinal cord is considered as a whole, small relative amounts are only found in segments where additional labeling occurs in particular spinal groups, as is the case of the upper cervical and lumbar cord (Burstein, R. et al., 1990b). Notably, in the cervical enlargement of the rat, numbers of lamina I spinothalamic neurons equal those in the deep dorsal horn (Burstein, R. et al., 1990b). Moreover, many lamina I neurons in the contralateral spinal and medullary dorsal horn of the monkey project to the ventrobasal complex of the thalamus, amounting to one-third of the entire dorsal horn labeled population (Willis, W. D. et al., 2001). Although the spinothalamic lateral pathway is classically considered to project contralaterally except for the ventral horn in segments C1–C2 (Trevino, D. L. and Carstens, E., 1975; Carstens, E. and Trevino, D. L., 1978a; Carstens, E. and Trevino, D. L., 1978b; Willis, W. D. et al., 1979; Giesler, G. J. et al., 1979a), the use of very sensitive tracers such as

503

CTb disclosed an important ipsilateral component (Lima.D. and Coimbra, A., 1988). Ipsilateral neurons amounted to about half the neurons labeled in the contralateral side in the lateral spinal nucleus and the deep dorsal horn in almost all the spinal segments examined. In the ventral horn, ipsilateral neurons equalized in number contralateral neurons, except in the cervical enlargement, where they were more abundant. Only in lamina I and the intermediate basilar nucleus of Cajal, contralateral neurons largely surpassed ipsilateral neurons. The need of using a very sensitive tracing technique to reveal the ipsilateral neuronal population suggests that these neurons may actually be contralaterally projecting neurons that send axonal collaterals to the ipsilateral thalamus. However, there is evidence from ventral spinal lesions in primates that nociceptive input is also conveyed supraspinally in the ipsilateral anterolateral quadrant (Vierck, C. J. and Luck, M. M., 1979). The areas of spinal axon arborization in the lateral thalamus (Figure 17) were thoroughly studied in primates, including the monkey (Mehler, W. R. et al., 1960; Bowsher, D., 1961; Mehler, W. R., 1966; Mehler, W. R., 1969; Kerr, F. W. L. and Lippman, H. H., 1974; Boivie, J., 1979; Berkley, K. J., 1980; Mantyh, P. W., 1983a; Apkarian, A. V. and Hodge, C. J., 1989a) and humans (Mehler, W. R., 1962; Mehler, W. R., 1974). In these species, as in the rat (Lund, R. D. and Webster, K. E., 1967; Mehler, W. R., 1969; Zemlan, F. P. et al., 1978; Peschanski, M. et al., 1983; Cliffer, K. D. et al., 1991), the VPL is the major recipient of spinal fibers. In the VPL, spinal afferents are somatotopically arranged in rostrocaudally oriented clusters so that axons arriving from the lumbosacral spinal cord terminate in the lateral part of the nucleus and axons from the cervical enlargement terminate in the medial part (Boivie, J., 1979; Mantyh, P. W., 1983a). Such a somatotopic arrangement supports the ability of the lateral spinothalamic pathway to process spatial discrimination. Other important lateral thalamic areas of spinal termination are the posterior complex (PO), the ventral posteroinferior nucleus (VPI) and the zona incerta (ZI) ((Mehler, W. R., 1974; Boivie, J., 1979; Apkarian, A. V. and Hodge, C. J., 1989a; Cliffer, K. D. et al., 1991). In the cat, fibers in the lateral spinothalamic pathway appear to be fewer and terminate in the ZI, the posterior complex, and in a shell area surrounding the VPL ventrolaterally (Boivie, J., 1971; Jones, E. G. and Burton, H., 1974; Berkley, K. J., 1980; Mantyh, P. W., 1983b; Craig, A. D. and Burton, H., 1985). Recently, Craig and colleagues claimed that a region located posteromedially to the VPL,

504 Ascending Pathways: Anatomy and Physiology

which they called VMpo, is the site of termination of the lamina I spinothalamic fibers (Craig, A. D. et al., 1994, 2002; Blomqvist, A. et al., 2000). However, besides the fact that the so-called VMpo was most probably included in the area of termination of spinal and trigeminal thalamic afferents described by Mehler (Mehler, W. R., 1966) in humans, numerous retrograde and anterograde studies have proved that lamina I neurons project to many other areas in the thalamus (references given earlier), including a study by Craig (Craig, A. D., 2003) using anterograde tracing with phaseolus vulgaris leucoagglutinin. Moreover, this assumption was based on the dense calbindin-staining observed in the VMpo, but neither is the calbindin-immunoreactive region restricted to the VMpo lying within the medial aspect of the ventral posterior medial nucleus (Graziano, A. and Jones, E. G., 2004), nor are calbindin-immonoreactive projecting cells exclusively located in lamina I (Mene´trey, D. et al., 1992b). 35.6.1.2 Structural types of neurons involved

Spinothalamic cells were shown, in retrograde labeling studies, to have cell bodies that vary in shape from roundish or flattened to polygonal (Willis, W. D. et al., 1979). They are mainly small in lamina I and include cells with fusiform, pyriform, and triangular shapes in transverse view, beyond the classic Waldeyer cells. In deep dorsal horn as well as the ventral horn, they are medium to large sized and polygonal in shape. Similar data were obtained by Apkarian and Hodge (Apkarian, A. V. and Hodge, C. J., 1989d), although in this case, tracer injections included the medial thalamus. Spinothalamic cells intracellularly stained in laminae IV–VIII of the cat (Meyers, D. E. R. and Snow, P. J., 1982) and monkey (Surmeier, D. J. et al., 1988) presented long dendritic branches that could reach the lateral funiculus, lamina I and lamina X. In the intermediomedial gray matter, spinothalamic cells presented spheroidal cell bodies and narrow dendrites (Milne, R. J. et al., 1982). Around the central canal, neuropeptide-containing spinothalamic cells had oval cell bodies and dendrites oriented transversely, reaching the central canal medially (Leah, J. et al., 1988). Injections of CTb confined to the VPL in the rat revealed that VPL-projecting lamina I neurons belong in the pyramidal and flattened groups (Lima.D. and Coimbra, A., 1988). Pyramidal cells prevailed over flattened cells in the cervical and lumbar enlargements (70% and 77%, respectively), the reverse occurring at

C1 and C2 (40%) (Lima.D. and Coimbra, A., 1988). In the cat (Zhang, E. T. et al., 1996) and monkey (Zhang, E. T. and Craig, A. D., 1997), large tracer injections filling both the lateral and medial thalamus, resulted in labeling of fusiform neurons, beyond pyramidal and flattened neurons. Although the authors explained their labeling of fusiform neurons by putative species differences, fusiform neurons were most probably labeled from the medial thalamus (see further). It should be emphasized that, in the studies by Craig and co-workers (Zhang, E. T. et al., 1996; Zhang, E. T. and Craig, A. D., 1997), flattened neurons were designated ‘multipolar’ due to their appearance in horizontal view, on which the authors based their observations. However, this designation is misleading and should be avoided since a neuronal group completely distinct in dendritic geometry and specializations was previously designated ‘multipolar’ in the rat (Lima, D. and Coimbra, A., 1986), and subsequently observed in the cat (Galhardo, V. and Lima, D., 1999), monkey (Lima, D. et al., 2002), and pigeon (Galhardo, V. et al., 2000) as well. When compared to flattened neurons, multipolar neurons have ventrally oriented rather than horizontal dendritic arbors and highly spiny rather than smooth dendritic branches. This kind of misuse of nomenclature already led some authors to disregard the occurrence of flattened neurons as an independent group in the cat and monkey, based on the results of retrograde labeling and immunostaining (Yu, X. H. et al., 1999), despite the fact that flattened neurons were clearly identified in both species by the use of Golgi impregnation (Galhardo, V. and Lima, D., 1999; Lima, D. et al., 2002). 35.6.1.3 fibers

Spinal location of ascending

Axons of the lateral spinothalamic tract travel in the ventral, ventrolateral, and dorsolateral funiculi after decussating the spinal cord within a short distance from the cell body (Applebaum, A. E. et al., 1975; Willis, W. D. et al., 1979; Giesler, G. J. et al., 1981a; Jones, M. W. et al., 1985; Surmeier, D. J. et al., 1988; Stevens, R. T. et al., 1989; Apkarian, A. V. and Hodge, C. J., 1989a,b). Spinothalamic axons from lamina I cells were shown to project through the dorsolateral fasciculus in the cat (Apkarian, A. V. et al., 1985; Stevens, R. T. et al., 1989) and monkey (Apkarian, A. V. and Hodge, C. J., 1989a,b,c). Neurons located in the deep dorsal horn and ventral horn project through the ventrolateral fasciculus and ventral funiculus (Stevens, R. T. et al., 1989; Apkarian, A. V. and Hodge, C. J., 1989b; Zhang, X. J. et al., 2000). In the

Ascending Pathways: Anatomy and Physiology

ventrolateral quadrant of the spinal cord white matter, axons are arranged somatotopically so that those originating in more caudal levels are located dorsolaterally to the more rostral ones (Horrax, G., 1929; Foerster, O. and Gagel, O., 1932; Hyndman, O. R. and Van Epps, C., 1939; Walker, A. E., 1940; Applebaum, A. E. et al., 1975). The termination sites of the dorsolateral and ventrolateral fibers are equally distributed in the lateral thalamus, except for VPI and the ZI whose spinal afferents course mainly in the dorsolateral fasciculus and the ventral spinal quadrant, respectively (Apkarian, A. V. and Hodge, C. J., 1989a). 35.6.1.4

Surface receptors Enkephalin immunoreactive varicosities were shown to establish asymmetric synaptic contacts upon medullary and spinal neurons retrogradely labeled from large HRP injections centered in the lateral thalamus of the cat and monkey (Ruda, M. A. et al., 1984). These neurons make up 30% of lamina I and 50% of lamina V labeled neurons. In transverse sections, neurons present bipolar configuration in lamina I (equivalent to flattened neurons of Lima, D. and Coimbra, A., 1986) and multipolar configuration in lamina V (Ruda, M. A. et al., 1984). Spinothalamic neurons exhibiting immunostaining for the NMDA receptor (Zou, X. Y. et al., 2000) and metabotropic glutamate receptor subtype 1 (mGluR1) (Millis, C. D. and Hulsebosch, C. E., 2002) have been described in studies. A study focused on lamina I neurons retrogradely labeled from large injections comprising both the lateral and medial thalamus revealed NK1 receptors in flattened (called ‘multipolar’ by the authors) and pyramidal neurons, the latter being relatively few, however (Yu, X. H. et al., 1999). This was taken as supporting the nonnociceptive nature of pyramidal neurons, although large amounts of pyramidal neurons expressing the NK1 receptor were observed by other authors (Todd, A. J. et al., 2002), and pyramidal neurons are c-fos-activated following various kinds of noxious stimulation (Lima, D., 1998). 35.6.1.5

Neurotransmitters Most studies addressing the neurochemical nature of spinothalamic neurons looked for the presence of neuropeptides in the rat. Neuropeptide-containing lateral spinothalamic neurons were preferentially observed in the lateral spinal nucleus and around the central canal (including lamina X). Both VIP (Nahin, R. L., 1988) and bombesin (Leah, J. et al.,

505

1988) were observed in the lateral spinal nucleus at the lumbar cord. In lamina X, neurons immunoreactive for bombesin (Leah, J. et al., 1988), CCK (Ju, G. et al., 1987; Leah, J. et al., 1988), and galanin (Ju, G. et al., 1987) were described. Galanin and CCK were seen to co-localize in lamina X neurons projecting to the VPL (Ju, G. et al., 1987). Neurons containing glutamate or glutaminase were described in the lateral trigeminothalamic system in areas where WDR and low-threshold neurons predominate (Magnusson, K. R. et al., 1987). Calbindin was claimed to be present in the majority of lamina I spinothalamic neurons of all structural groups projecting to the thalamus (Craig, A. D. et al., 2002), although anterograde tracing combined with immunocytochemical staining failed to reveal calbindin-immunostaining in lamina I axons terminating in the thalamus (Graziano, A. and Jones, E. G., 2004). 35.6.1.6

Response properties Spinothalamic cells were shown to present background activity at variable firing rates depending on the species and their laminar location in the spinal cord. Only few lamina I cells present background activity (Craig, A. D. and Kniffki, K. D., 1985) in the cat as compared to lamina I cells in the monkey (Ferrington, D. G. et al., 1987) and to laminae IV–V cells in both species (Giesler, G. J. et al., 1981b; Ferrington, D. G. et al., 1986). Most spinothalamic cells respond to stimulation of C primary afferent fibers (Chung, J. M. et al., 1979), but many of them respond to volleys in A and A fibers of somatic nerves as well (Foreman, R. D. et al., 1975; Beall, J. E. et al., 1977; Chung, J. M. et al., 1979). Spinothalamic cells also respond to A and C-fiber volleys in visceral nerves (Foreman, R. D. and Weber, R. N., 1980; Blair, R. W. et al., 1981; Foreman, R. D. et al., 1981, 1984; Rucker, H. K. and Holloway, J. A., 1982; Ammons, W. S., 1987) and to group II, III, and IV muscle afferents (Foreman, R. D. et al., 1979). Lateral spinothalamic neurons were found to be activated by mechanical and/or thermal noxious stimulation of the skin in the rat (Giesler, G. J. et al., 1976), cat (Fox, R. E. et al., 1980; Ferrington, D. G. et al., 1986), and monkey (Willis, W. D. et al., 1974, 1979; Applebaum, A. E. et al., 1975; Price, D. D. et al., 1978; Kenshalo, D. R., Jr. et al., 1979; Giesler, G. J. et al., 1981b; Surmeier, D. J. et al., 1986a,b; Ferrington, D. G. et al.. 1987) as well as by noxious chemical stimulation (Simone, D. A. et al., 1991) and low-threshold mechanical (Willis, W. D. et al., 1974; Applebaum, A. E. et al., 1975; Giesler, G. J. et al., 1976; Price, D. D. et al., 1978) cooling

506 Ascending Pathways: Anatomy and Physiology

(Dostrovsky, J. O. and Craig, A. D., 1996; Craig, A. D. et al., 2001) and warming (Andrew, D. and Craig, A. D., 2001) stimulation. Nociceptive neurons belong in both the NS and WDR classes (Willis, W. D. et al., 1974; Giesler, G. J. et al., 1981b; Ferrington, D. G. et al., 1986). NS neurons are equally distributed throughout laminae I and IV–V, while WDR neurons predominate in laminae IV–V (Willis, W. D. et al., 1974) and neurons responsive to cooling are located in lamina I (Craig, A. D. et al., 2001). Thermal-responsive neurons belonging in either the NS or the WDR neuronal classes were shown to be capable of encoding noxious heat intensity (Figure 18) irrespective of their location in lamina I or the deep dorsal horn (Kenshalo, D. R., Jr. et al., 1979; Ferrington, D. G. et al., 1986; Surmeier, D. J. et al., 1986a, b). Neurons with convergent input from the skin and viscera also contribute to the lateral spinothalamic

50 43° 30 10 50 47°

Spikes/bin

30 10

50 51° 30 10

50 55° 30 10 18

54

90

Time (s) Figure 18 Responses of a lateral spinothalamic neuron to heat stimulation of increasing intensities. Adapted from figure 1 of Surmeier, D. J., Honda, C. N., and Willis, W. D. 1986a. Temporal features of the responses of primate spinothalamic neurons to noxious thermal stimulation of hairy and glabrous skin. J. Neurophysiol. 56, 351–369.

pathway (Foreman, R. D. and Weber, R. N., 1980; Blair, R. W. et al., 1981; Foreman, R. D. et al., 1984; Ammons, W. S. et al.. 1984; Ammons, W. S., 1987; AlChaer, E. D. et al., 1999; Chandler, M. J. et al., 2000). Curiously, in lamina X, neurons of the postsynaptic dorsal column tract were shown to receive viscerosomatic input and reported to be more numerous than those of the spinothalamic tract (Al-Chaer, E. D. et al., 1999; Dorsal Columns and Visceral Pain).These neurons belong in the WDR, NS, or high-threshold inhibitory classes, and present cutaneous receptive fields that occupy regions to which pain is frequently referred (Foreman, R. D. and Weber, R. N., 1980; Foreman, R. D. et al., 1984; Ammons, W. S. et al., 1984). Some of these neurons were shown to leave axonal collaterals in the medial medullary reticular formation (Foreman, R. D. et al., 1984). Some spinothalamic neurons receive convergent input from the skin and deep tissues (Willis, W. D. et al., 1974; Giesler, G. J. et al., 1981b; Ferrington, D. G. et al., 1986). These neurons are thought to have a proprioceptive function (Milne, R. J. et al., 1982). They are mainly located in the lateral part of lamina V and intermediomedial gray matter (Stilling’s nucleus) and respond to either weak or intense cutaneous stimulation (Willis, W. D. et al., 1974). Lateral spinothalamic neurons normally present ipsilateral receptive fields that vary from very small (less than one digit) to moderate (the entire limb) (Willis, W. D. et al., 1974; Giesler, G. J. et al., 1981b), as well as additional inhibitory receptive fields (Gerhart, K. D. et al., 1981; Giesler, G. J. et al., 1981b; Ammons, W. S., 1987). In a few cells, convergent inhibitory cutaneous or visceral receptive fields were reported (Willis, W. D. et al., 1974; Blair, R. W. et al., 1981; Milne, R. J. et al., 1982). Receptive fields tend to be smaller in high-threshold neurons and in lamina I neurons (Applebaum, A. E. et al., 1975; Giesler, G. J. et al., 1981b; Ferrington, D. G. et al., 1987). The relatively small size of the receptive fields of lateral spinothalamic neurons favors a role in discriminating the size of the stimulated area (Giesler, G. J. et al., 1981b). C-fos induction after noxious cutaneous or visceral stimulation was observed in spinothalamic neurons in laminae I, III–VII, and X (Palecek, J. et al., 2003). Curiously, neurons projecting in the postsynaptic dorsal column pathway were activated in similar proportions by the noxious cutaneous stimuli and in even higher proportions by the visceral stimuli (Palecek, J. et al., 2003). In lamina I, both flattened and pyramidal neurons projecting to the

Ascending Pathways: Anatomy and Physiology

VPL were c-fos-activated following cutaneous mechanical, thermal, and chemical noxious stimulation, and, in smaller amounts, following visceral chemical stimulation (Lima, D. et al., 1992; Lima, D., 1998). 35.6.1.7

Pathways driven at the target

The VPL is long-known for sending nociceptive input to the parietal somatosensory cortex (Burton, H. and Jones, E. G., 1976; Whitsel, B. L. et al., 1978; Kenshalo, D. R., Jr. et al., 1980). Combined anterograde tracing from the spinal cord and retrograde tracing from the somatosensory cortex in the monkey revealed that overlapping between spinal thalamic afferents and thalamic neurons projecting to cortical areas SI or SII occurs in the VPL, but also in the VPI and PO, the VPL being the area where the number of overlapping neurons is smaller (Stevens, R. T. et al., 1993; Shi, T. and Apkarian, A. V., 1995). VPL afferents in cortical areas SI and SII are arranged in a somatotopic fashion (Burton, H. and Jones, E. G., 1976; Whitsel, B. L. et al., 1978) so that the more posterior the thalamic source of afferents, the more posterior the cortical termination sites. Sparse cells in the lateral part of the VPL and the ventral part of the VPI target the cingulated cortex (Apkarian, A. V. and Shi, T., 1998). The PO projects to the granular insular and retroinsular cortex in primates (Burton, H. and Jones, E. G., 1976) and was therefore proposed to be involved in nociceptive visceral processing (Cechetto, D. F. and Saper, C. B., 1987). PO neurons projecting to the anterior insula were seen to clearly overlap with spinothalamic axonal arborizations (Apkarian, A. V. and Shi, T., 1998). Neurons in the VPI also show insular projections, but with no overlapping. Moreover, neurons projecting to the insula do not overlap with neurons projecting to SI (Apkarian, A. V. and Shi, T., 1998). 35.6.2

Medial Thalamus

The medial spinothalamic pathway was described at the middle 1960s as an ascending nociceptive system especially devoted to the processing of the affective and motivational aspects of pain (Melzack, R. and Casey, K. L., 1968). While anatomical degeneration studies demonstrated the termination in medial thalamic nuclei of spinal axons ascending in the ventrolateral quadrant of the spinal cord (Bowsher, D., 1957, 1961; Mehler, W. R. et al., 1960; Boivie, J., 1971), clinical studies revealed that, in patients with lesions centered in the medial thalamus, the painful

507

poorly localized unpleasant feeling was abolished (He´caen, H. et al., 1949). 35.6.2.1 Spinal laminae of origin and sites of termination

Spinal neurons projecting to medial thalamic nuclei prevail in the contralateral intermediate and ventral gray matter (Figure 19) in the rat (Giesler, G. J. et al., 1979a), cat (Carstens, E. and Trevino, D. L., 1978b), and monkey (Willis, W. D. et al., 1979; Giesler, G. J. et al., 1981b). In the cat, although a predominant location in laminae VII and VIII has been described by some authors (Carstens, E. and Trevino, D. L., 1978b; Comans, P. E. and Snow, P. J., 1981), others point to a laminar distribution similar to that observed for the lateral spinothalamic pathway, namely laminae I, IV–VI, and VII to X (Stevens, R. T. et al., 1989; Craig, A. D. et al., 1989). Lamina I was also shown to be the source of spinal afferents to the nucleus submedius in the cat and monkey (Craig, A. D. and Burton, H., 1981; Stevens, R. T. et al., 1989) and to contribute to the spinal projections to the intralaminar complex in the monkey (Albe-Fessard, D. et al., 1975; Ammons, W. S. et al., 1985). In the rat, projections from laminae IV–VII were recently shown to target the central lateral nucleus, whereas the medial dorsal nucleus was found to be mainly innervated bilaterally by the lateral spinal nucleus and, to a lesser extent, by contralateral lamina I (Gauriau, C. and Bernard.J.F., 2004). Spinal afferents ascending to the medial thalamus appear to be fewer than those reaching the lateral thalamus (Mehler, W. R. et al., 1960; Apkarian, A. V. and Hodge, C. J., 1989a). They target similar medial thalamic regions in the rat (Lund, R. D. and Webster, K. E., 1967; Mehler, W. R., 1969; Zemlan, F. P. et al., 1978; Cliffer, K. D. et al., 1991), cat (Boivie, J., 1971; Berkley, K. J., 1980; Mantyh, P. W., 1983a; Craig, A. D. and Burton, H., 1985), monkey (Mehler, W. R. et al., 1960; Boivie, J., 1979; Mantyh, P. W., 1983a; Apkarian, A. V. and Hodge, C. J., 1989a), and humans (Mehler, W. R., 1962; Mehler, W. R., 1974). These include the medial dorsal and paraventricular nuclei and the intralaminar complex, namely the central lateral, center median, paracentral, and parafascicular nuclei (Figure 19). In the monkey, the medial dorsal nucleus (except for its dorsomedial part) and the central lateral nucleus are the major sites of termination of spinal fibers (Apkarian, A. V. and Hodge, C. J., 1989a). The nucleus submedius is also a consistent site of spinal axon arborization in the cat (Boivie, J., 1971; Craig, A. D. and Burton, H., 1981; Mantyh, P.

508 Ascending Pathways: Anatomy and Physiology

Medial spinothalamic

Figure 19 Diagram representing the spinal laminae of origin, ascending course in the spinal cord and areas of termination of the medial spinothalamic pathway. Brain and spinal cord photomicrographs were adapted from Paxinos, G. and Watson, C. 1998. The Rat Brain in Stereotaxic Coordinates, 4th edn. Academic Press.

W., 1983b; Craig, A. D. and Burton, H., 1985) and monkey (Boivie, J., 1979; Mantyh, P. W., 1983a; Apkarian, A. V. and Hodge, C. J., 1989a), but in relatively small amounts (Mantyh, P. W., 1983a; Apkarian, A. V. and Hodge, C. J., 1989a). Contrary to the lateral thalamus, no somatotopic arrangement of spinal terminals could be detected in the intralaminar complex (Boivie, J., 1979), which agrees with electrophysiological studies (Giesler, G. J. et al., 1981b; Guilbaud, G. et al., 1985) as to the inadequacy of the medial spinothalamic system to process information related to stimulus discrimination. In the nucleus submedius, however, a somatotopic organization was described, with fibers from more rostral spinal levels terminating more rostrally in the nucleus (Craig, A. D. and Burton, H., 1985).

35.6.2.2 Structural types of neurons involved

Although there are no descriptions of the morphology of spinal neurons labeled from injections restricted to medial thalamic nuclei, data on laminae VI–X spinothalamic cells revealed medium to largesized soma of polygonal or occasionally flattened configuration (Willis, W. D. et al., 1979). Following injections filling both the lateral and medial thalamus in the cat and monkey (Zhang, E. T. et al., 1996; Zhang, E. T. and Craig, A. D., 1997), lamina I neurons belonging in the fusiform, pyramidal, and flattened groups were labeled. As to pyramidal and flattened neurons, the possibility that labeled neurons picked up the tracer in the lateral thalamus can not be ruled out, since they were shown to project to the VPL in

Ascending Pathways: Anatomy and Physiology

509

the rat (Lima, D. and Coimbra, A., 1988). Fusiform neurons, however, most probably project to medial thalamic nuclei as they could not be labeled from the VPL in the rat (Lima, D. and Coimbra, A., 1988). 35.6.2.3 fibers

Spinal location of ascending

Spinal axons targeting the medial thalamus were early shown to course in the ventral quadrant of the spinal cord (Mehler, W. R. et al., 1960; Bowsher, D., 1961; Mehler, W. R., 1969). In the rat this appears to be the way taken by all spinothalamic axons (Giesler, G. J. et al., 1981a), whereas in the monkey axons were shown to distribute through the lateral funiculus also (Giesler, G. J. et al., 1981b; Apkarian, A. V. and Hodge, C. J., 1989a). Studies using anterograde tracing after lesioning either the contralateral spinal ventral quadrant or the contralateral dorsolateral fasciculus (Apkarian, A. V. and Hodge, C. J., 1989a) revealed that the termination pattern of fibers coursing in both pathways is similar except for the fibers targeting the dorsolateral region of the medial dorsal nucleus, which course mostly in the ventral quadrant. The ventral quadrant also contributes with particularly large amounts of fibers to the central lateral nucleus afferents, mainly in its more anterior portion. 35.6.2.4

Neurotransmitters Enkephalin (Coffield, J. A. and Miletiæ, V., 1987; Nahin, R. L., 1988) and dynorphin (Nahin, R. L., 1988) were immunodetected in deep dorsal horn and intermediate gray spinal neurons projecting to the medial thalamus. Enkephalin-immunoreactive neurons amount to 10% of the entire spinothalamic population (Coffield, J. A. and Miletiæ, V., 1987). Spinothalamic lamina X neurons immunoreactive for CCK (Ju, G. et al., 1987; Leah, J. et al., 1988) and galanin (Ju, G. et al., 1987) are likely to terminate in the parafascicular nucleus, which was shown to contain fibers immunoreactive to both neuropeptides (Ju, G. et al., 1987). 35.6.2.5

Response properties Neurons projecting to the medial thalamus respond, although weakly, to activation of A ( to ) and C primary afferent fibers with sustained afterdischarges (Giesler, G. J. et al., 1981b). Their background activity is practically nil. They conduct at relatively low velocities, which amount to about half those of lateral spinothalamic neurons (Giesler, G. J. et al., 1981b). Most medial spinothalamic neurons belong in the NS class (around two-third vs. one-

Figure 20 Receptive fields of spinal cells projecting to the medial thalamus in the monkey. Adapted from figure 3 of Giesler, G. J., Yezierski, R. P., Gerhart, K. D., and Willis, W. D. 1981b. Spinothalamic tract neurons that project to medial and/or lateral thalamic nuclei: evidence for a physiologically novel population of spinal cord neurons. J. Neurophysiol. 46, 1285–1308.

third in the lateral spinothalamic pathway). Some are WDR neurons and a few respond to deep tissue stimulation (Giesler, G. J. et al., 1981b). They normally present very large, frequently complex, receptive fields that may encompass the entire surface of the body (Figure 20). Inhibitory receptive fields are rare (Giesler, G. J. et al., 1981b). Viscerosomatic convergence has been reported (Rucker, H. K. and Holloway, J. A., 1982). 35.6.2.6

Pathways driven at the target Intralaminar nuclei, in particular the central lateral nucleus, project to widely distributed areas of the cerebral cortex, including sensorimotor areas, and to the basal ganglia (Jones, E. G. and Leavitt, R. Y., 1974). Ascending pathways terminating in the intralaminar nuclei have hence been proposed to be involved in motor and arousal nociceptive responses. Nociceptive pathways from the medial dorsal nucleus and the central lateral nucleus terminate, respectively, in the anterior cingulated cortex and frontal motor cortex (Wang, C. C. and Shyu, B. C., 2004). The posterior cingulated cortex also receives projections from restricted areas of both, the medial dorsal and the central lateral nuclei (Apkarian, A. V. and Shi, T., 1998). These connections are consonant with the role of the medial thalamic pathway in the emotional aspects of nociception (Wang, C. C. and Shyu, B. C., 2004). The medial dorsal nucleus and the nucleus submedius, which are similar in the response properties of their nociceptive neurons (Dostrovsky,

510 Ascending Pathways: Anatomy and Physiology

J. O. et al., 1987), project to adjacent regions in the orbital cortex (Krettek, J. E. and Price, J. L., 1977; Craig, A. D. et al., 1982; Yoshida, A. et al., 1992). 35.6.3

Hypothalamus

35.6.3.1 Spinal laminae of origin and sites of termination

A direct spinohypothalamic pathway (Figure 21) was uncovered in the rat (Burstein, R. et al., 1987; Burstein, R. et al., 1990a; Burstein, R. et al., 1990b; Mene´trey, D. and DePommery, J., 1991) and cat (Katter, J. T. et al., 1991) by the use of both electrophysiologic and tracing methods. It originates bilaterally, although with a slight contralateral prevalence, from the entire extent

of the spinal cord (Figure 22) (Burstein, R. et al., 1987, 1990a; 1990b) as well as from the spinal trigeminal nucleus, mainly the pars caudalis (Malick, A. and Burstein, R., 1998). Neurons in the deep dorsal horn make up the largest population of spinohypothalamic neurons, especially at upper cervical segments (around 50%), followed by the lateral spinal nucleus (around 30%), laminae I and X (around 10% each), and the intermediate ventral horn (Burstein, R. et al., 1990a). An additional contribution from the parasympathetic cell column was described in the rat (Burstein, R. et al., 1990a; Mene´trey, D. and DePommery, J., 1991). In the cat, the spinohypothalamic tract appears to be much smaller and to contain fewer lamina I

Spinohypothalamic

Figure 21 Diagram representing the spinal laminae of origin, ascending course in the spinal cord, and areas of termination of the spinohypothalamic pathway. Note that ipsilaterally terminating axons course contralaterally in the spinal cord. Brain and spinal cord photomicrographs were adapted from Paxinos, G. and Watson, C. 1998. The Rat Brain in Stereotaxic Coordinates, 4th edn. Academic Press.

Ascending Pathways: Anatomy and Physiology

Nuc. caud.

C1 – 2

T4

511

L1 – 3

T6

L4 – 5 C4 – 5

C7 – 8

T8

T12 L6 – S2

Figure 22 Distribution in the spinal cord and spinal trigeminal nucleus, pars caudalis, of neurons retrogradely labeled from injection of fluorogold encompassing the lateral and medial hypothalamus. (Adapted from figure 4 of Burstein, R., Cliffer, K. D., and Geisler, G. J. 1990b. Cells of origin of the spinohypothalamic tract in the rat. J. Comp. Neurol. 291, 329–344).

neurons than in the rat (Katter, J. T. et al., 1991). No differences in spinal distribution were found between the medial and lateral hypothalamic pathways, except for the sacral parasympathetic nucleus, which appears to project mainly to medial nuclei (Burstein, R. et al., 1990a). According to a recent study by Braz and coworkers (Braz, J. M. et al., 2005) in which transgenic mice expressing a transneuronal tracer in a subset of nociceptors were used, nociceptive input conveyed by nonpeptidergic primary afferent neurons is relayed to lamina V neurons projecting to the ventromedial hypothalamus by spinal neurons located in the dorsal part of lamina II. Consonant with retrograde and antidromic stimulation studies, terminal arborizations of spinal axons were shown to distribute massively through the lateral hypothalamus, although important labeling was also observed in the medial hypothalamus (Figure 21) (Burstein, R. et al., 1987; Cliffer, K. D. et al., 1991). In the lateral hypothalamus, fibers terminate bilaterally along its rostrocaudal extent, and throughout the course of the supraoptic decussation. In the medial hypothalamus, fibers terminate mainly contralaterally in the posterior and dorsal hypothalamic areas, the

dorsomedial, paraventricular and suprachiasmatic nuclei, and the preoptic area (Cliffer, K. D. et al., 1991). Anterograde tracer injections restricted to the superficial or deep dorsal horn confirmed that the latter contributes much more fibers to the spinohypothalamic pathway, the main areas of termination being the posterior hypothalamic area, the posterior part of the lateral hypothalamic area, and the ventral part of the paraventricular hypothalamic nucleus (Gauriau, C. and Bernard. J. F., 2004). 35.6.3.2 fibers

Spinal location of ascending

A few studies based on degeneration following spinal lesions revealed the termination in the lateral (Anderson, F. D. and Berry, C. M., 1959; Ring, G. and Ganchrow, D., 1983) and medial (Kerr, F. W. L., 1975) hypothalamus of spinal fibers coursing in the ventral funiculus. However, electrophysiological studies using antidromic activation from the supraoptic decussation showed that only 5% of the spinohypothalamic axons course in the ventral funiculus (Burstein, R. et al., 1991). The remaining travel through the lateral funiculus, mainly in the

512 Ascending Pathways: Anatomy and Physiology

dorsolateral fasciculus (57%), irrespective of their origin in the superficial or deep dorsal horn (Figure 21) (Burstein, R. et al., 1991). Although spinal and trigeminal neurons project to the hypothalamus bilaterally, their axons ascend contralaterally in the spinal cord (Burstein, R. et al., 1991) and brainstem (Kostarczyk, E. et al., 1997). Those terminating ipsilaterally cross the midline within the supraoptic decussation (Burstein, R. et al., 1991). Extensive collateralization along the entire brainstem has been reported (Kostarczyk, E. et al., 1997). 35.6.3.3

Surface receptors A particularly high number of spinal neurons projecting to the hypothalamus are apposed by profiles immunoreactive to nitric oxide synthase or to interferon- receptor in the lateral spinal nucleus (Kayalioglu, G. et al., 1999). 35.6.3.4

Response properties The majority of the neurons antidromically activated from the hypothalamus both in the spinal cord and the spinal trigeminal nucleus belong in the WDR and NS classes and also respond to noxious heat or cooling (Burstein, R. et al., 1987, 1991; Malick, A. et al., 2000; Zhang, X. J. et al., 2002). Incremental responses to increasingly intense noxious heat stimulation were observed (Burstein, R. et al., 1987). Low-threshold neurons make up 20% of the trigeminohypothalamic neurons (Malick, A. et al. 2000) and only 4% of the spinohypothalamic neurons (Burstein, R. et al., 1991). The cutaneous receptive fields are particularly small indicating that this pathway may convey relatively precise information about the stimulated area (Burstein, R. et al., 1991; Malick, A. et al., 2000). About half of the spinohypothalamic neurons recorded in the thoracic spinal cord were activated by visceral distension with responses that increased with increasing stimulus intensities (Zhang, X. J. et al., 2002). Eight percent of lumbar spinohypothalamic neurons respond to deep low-threshold input (Burstein, R. et al., 1991). 35.6.3.5

Pathways driven at the target Projections from the hypothalamus, namely the dorsomedial nucleus, descend through a dorsal pathway to the PAG, and through a ventral smaller pathway to the NTS (Thompson, R. H. et al., 1996). According to c-fos studies (Snowball, R. K. et al., 2000), neurons projecting to the ventrolateral PAG receive visceral input in the lateral hypothalamus, presumably in convergence with somatic input, and neurons

projecting to the NTS are concentrated in the posterolateral hypothalamus and the paraventricular nucleus. Projections connecting the paraventricular nucleus with the ventrolateral medulla were also reported (Hardy, S. G. P., 2001).

35.7 Spinothelencephalic Pathways During the last decade, evidence accumulated about the existence of ascending nociceptive pathways that connect the spinal cord directly with various telencephalic regions in the rat. Although data are mainly based on anatomic retrograde and anterograde tracing studies, both the location of the spinal cells of origin, the demonstration of cells responding to noxious stimulation in areas such as the amygdala (Miyagama, T. et al., 1986), and a recent study using genetic-controlled transneuronal tracing initiated in IB4-positive putative nociceptive primary afferent fibers (Braz, J. M. et al., 2005) suggest that some of these areas are spinal targets of nociceptive input. The data on spinotelencephalic pathways collected till the early years of 2000 are still few and each study deals with several systems. Therefore, notwithstanding their probable functional individuality, they will be described together although tentatively grouped according to their putative functions. 35.7.1 Thelencephalic Targets of Spinal Ascending Fibers Studies using very sensitive anterograde tracers, such as phaseolus vulgaris leucoagglutinin or dextran (Burstein, R. et al., 1987; Cliffer, K. D. et al., 1991; Gauriau, C. and Bernard.J. F., 2004), revealed axonal terminal arborizations in various regions of the basal forebrain and cortex (Figure 23), which can be grouped as areas involved in motor control and areas of the limbic system. The first group includes the globus pallidus, substantia nigra, and nucleus accumbens, in particular its medial part. A participation in the striatopallidal system as well as a role in innate motor patterns triggered by noxious stimuli has been proposed for the spinal–globus pallidus projection (Braz, J. M. et al., 2005). Limbic spinal targets include nuclei of the septal complex, thought to be involved in motivation and emotion, but also in attention, arousal, learning, and memory (Burstein, R. et al., 1987; Cliffer, K. D. et al., 1991). Positive and negative reinforcement

Ascending Pathways: Anatomy and Physiology

(a)

(d)

(g)

innonimata and stria terminalis as well as the posterior hypothalamus (Bourgeais, L. et al., 2001a).

35.7.2 (b)

(e)

(h)

(c)

(f)

(i)

Figure 23 Distribution of spinal fibers labeled anterogradely with phaseolus vulgaris leucoagglutinin in the diencephalon and telencephalon, in horizontal view. Adapted from figure 3 of Cliffer, K. D., Burstein, R., and Giesler, G. J. 1991. Distributions of spinothalamic, spinohypothalamic, and spinotelencephalic fibers revealed by anterograde transport of PHA-L in rats. J. Neurosci. 11, 852–868.

associated with learning trials during nociceptive processing have been claimed to be accomplished by this pathway (Cliffer, K. D. et al., 1991). The central nucleus of the amygdala together with what has been called the ‘extended amygdala’, namely the substantia innonimata and the Bed Nucleus of the stria terminalis, also receive direct projections from the spinal cord (Cliffer, K. D. et al., 1991; Gauriau, C. and Bernard.J.F., 2004), as do the medial orbital and infralimbic cortices (Cliffer, K. D. et al., 1991). Projections to the orbital cortex may affect autonomic, endocrine, and behavioral functions in relation to pain (Burstein, R. and Potrebic, S., 1993). The horizontal and vertical limbs of the diagonal band of Broca are also targeted by spinal axons (Burstein, R. et al., 1987; Cliffer, K. D. et al., 1991). These direct spinotelencephalic projections appear to be paralleled by ascending polysynaptic pathways relaying not only in the brainstem, as is the case of the spinoparabrachialamygdaloid pathway (Ma, W. and Peschanski, M., 1988; Bernard, J. F. and Besson, J. M., 1990; Jasmin, L. et al., 1997), but also within the telencephalon. Anterograde tracer injections in the central and basolateral anterior nuclei of the amygdala revealed projections from there to the substantia

513

Spinal Laminae of Origin

Based on anterograde labeling from restricted injections in various spinal laminae, Gauriau and Bernard (Gauriau, C. and Bernard. J. F., 2004) concluded that cells of origin of spinopallidal fibers are located in the deep dorsal horn, laminae VII and X and, in smaller amounts, in the superficial dorsal horn (Table 1). Marked labeling was obtained in the lateral aspect of the globus pallidus from neurons located in lamina V, as revealed by transneuronal tracing with wheat germ agglutinin synthesized by IB4-positive primary afferents in mice (Braz, J. M. et al., 2005). Spinal fibers projecting to the nucleus accumbens and the septal nuclei have similar bilateral origins at the reticulated portion of the deep dorsal horn, the lateral spinal nucleus, and lamina X throughout the entire length of the spinal cord (Burstein, R. and Giesler, G. J., 1989). Deep dorsal horn neurons account to half of the entire projection population, followed by the lateral spinal nucleus, and lamina X (about 15% each). Neurons in lamina I and the intermediate/ventral horn are very few, but the first are slightly more numerous in the spinoseptal pathway (Table 1). Spinal neurons projecting to the amygdala present similar laminar distribution (Mene´trey, D. and DePommery, J., 1991; Burstein, R. and Potrebic, S., 1993). Neurons in the reticulated region of the deep dorsal horn also make up about half of the entire spinoamygdala population, but they are located in its dorsal portion in cervical segments and ventral portion in thoracolumbar segments. The lateral spinal nucleus contributes to 25% of the projection, lamina X to 13% (mainly at upper lumbar segments), and the intermediate and ventral horn to 10%, at upper cervical and lumbar segments (Table 1). Neurons in lamina V receiving primary afferent input through lamina II neurons activated by IB4-positive primary afferents also send projections to the amygdala, as well as to the bed nucleus of stria terminalis (Braz, J. M. et al., 2005). A projection to the dorsal part of substantia innonimata from the superficial and deep dorsal horn, contralaterally, and from the lateral spinal nucleus, ipsilaterally, has been described (Gauriau, C. and Bernard. J.F., 2004).

514 Ascending Pathways: Anatomy and Physiology Table 1

Relative participation of spinal cord laminae in the various nociceptive ascending pathways LSN

II

III

IV

V

VI

VII

&

&

&

& (60%)

&

&

& (10%) &

& (Medial)

& (Medial)

& (Medial)

&

&

&

&

& (Medial) &

& (Medial) & & & (Lateral) & (Lateral) &

& (Medial) &

&

&

LCN VLMlat LRt DRt dorsal

I

&

DRt ventral NTS RVM PBN

&

&

PAG

&

& (Lateral) &

Lateral thalamus Medial thalamus Hypothalamus

& & & (30%)

N. Pallidus N. Accumbens Septal nucleus Amygdala Subst. inonimata Orbital cortex

& (25%) & (15%) & (25%)

& & & (10%) & &

& (15%)

& (Lateral) &

& &

VIII

X

&

& & & &

& &

& & &

&

&

&

&

&

& &

& &

&

& & & (- - - - - - - - - - 50%- - - - - - - - - - ) & & & & & & (- - - - - - - - - - 50%- - - - - - - - - - ) & & & (- - - - - - - - - - 50%- - - - - - - - - - ) & & (- - - - - 50%- - - - - ) & & & & & (- - - - - 62%- - - - - )

& & (–10%–)

& (10%) & & (10%) & (15%) & (10%)

& & (–13%–)

& (10%)

&

Relative amounts refer to each pathway and do not allow comparisons between pathways. Whenever quantified, the relative contribution to each pathway is referred between brackets. LSN, lateral spinal nucleus; LCN, lateral cervical nucleus; VLMlat, caudal ventrolateral reticular formation, lateral portion; LRt, lateral reticular nucleus; DRt dorsal, dorsal reticular nucleus, dorsal portion; DRt ventral, dorsal reticular nucleus – ventral portion; NTS, nucleus tractus solitarii; RVM, rostral ventromedial medulla; PBN, parabrachial nuclei; PAG, periaqueductal gray; I–X, spinal laminae.

The orbital cortex receives its major spinal projections from the contralateral reticulated area of the deep dorsal horn (62%) at the cervical level or its ventromedial aspect at the thoracic and lumbar levels. The lateral spinal nucleus contributes to 15% of the projection, but mainly at lumbar segments, while the intermediate/ventral horn and lamina X contribute to 13% and 10%, respectively, both at the upper cervical and lower thoracic/upper lumbar segments (Table 1) (Burstein, R. and Potrebic, S., 1993).

35.8 Discussion 35.8.1 Multiple Parallel Ascending Pathways The main feature that stands out is the multiplicity of the ascending nociceptive system in terms of the

variety of supraspinal regions that are targeted (Figure 24). This has been interpreted as the anatomical substrate for the triggering of a multitude of responses to the noxious event, from autonomic and motor reactions to affective and cognitive behaviors. Nevertheless, it is curious to note that, contrary to what was thought in the middle of the twentieth century, nociceptive input does not necessarily arrive to high processing motor, affective, and cognitive centers in the thelencephalon through multisynaptic chains capable of filtering information at various successive levels, but can reach those areas through direct spinofugal pathways. Another aspect that emerges is that multiple polysynaptic pathways seem to parallel monosynaptic connections between the spinal cord and each supraspinal target. So far, this organization pattern was demonstrated only for a few systems, such as the medial paracentral spinothalamic and the spinoamygdaloid

Ascending Pathways: Anatomy and Physiology

515

Spinopallidus/accumbens

Spinolimbic

Spinohypothalamic Lateral spinothalamic Medial spinothalamic

Spinomesencephalic

Spinopontine

Spino-RVM

Spino-NTS Spino-DRt Spino-VLM

Spino-LCN

Figure 24 Diagram illustrating the termination areas of the various ascending nociceptive pathways. The laterality of the ascending tracts and termination fields with respect to the side of arrival of primary afferent input is represented, the left side being ipsilateral and the right side contralateral. Brain and spinal cord photomicrographs were adapted from Paxinos, G. and Watson, C. 1998. The Rat Brain in Stereotaxic Coordinates, 4th edn. Academic Press.

516 Ascending Pathways: Anatomy and Physiology

systems, served by a direct pathway and a disynaptic pathway with a relay in the PBN (Ma, W. and Peschanski, M., 1988; Bernard, J. F. and Besson, J. M., 1990; Jasmin, L. et al., 1997). However, the fact that most spinal targets send projections to other brain areas that are also targeted by spinal fibers strongly suggests a similar architecture for most systems, with the participation of parallel monosynaptic and multisynaptic chains of different lengths. Such an arrangement may imply that the responses to the noxious event generated at each site evolve along time according to postarriving of noxious-evoked input generated in other pain-processing centers. Notwithstanding the extensive anatomical and electrophysiological data that are still needed to corroborate this hypothesis, it is worth to take it into consideration in future investigation. 35.8.2 Spinal Neuronal Populations at the Origin of Nociceptive Ascending Pathways When facing such a variety of nociceptive ascending pathways, it is tempting to assume that they differ by either channeling different sensory modalities to brain regions specifically dedicated to their processing, or by the responses they induce to whatever stimulus through activation of a particular supraspinal region. For the first assumption to be correct, the spinal source of input should differ between different pathways. The overview of the ascending nociceptive system here presented clearly shows that this is not the case. On the contrary, if one compares the contribution of the various spinal laminae to each pathway (Table 1), the first emerging picture is that of a strong similarity, which favors the second assumption that the functional properties of a pathway depend on the functional engagement of its target. However, in spite of a large overlap, there are subtle dissimilarities between pathways consisting of a preponderance of some laminae over others or differences in the location of the projecting neurons in each lamina (Table 1). Also the electrophysiological response properties of spinal neurons participating in the various pathways overlap considerably (Table 2): all pathways including nociceptive specific, wide-dynamic-range and low-threshold neurons, as well as neurons responding to cutaneous, visceral, and deep noxious stimuli. Again, subtle differences are likely to occur about the proportion of neurons of each kind that take part in each pathway (Table 2). Differences between pathways over the

Table 2 Relative participation of low threshold (LT), wide-dynamic-range (WDR) and nociceptive specific (NS) spinal cord neurons in the various nociceptive ascending pathways LT

WDR 60–86%

VLM NTS RVM PBN

Mainly hair movement 25% þ þ 

PAG

þ (DDH)

Lateral thalamus Medial thalamus Hypothalamus

þ

25% 50% The majority The majority þ þ (75– 90% in lamina I) 50% þ (lamina I) (Lamina I þ DDH þ 35%

þ

þ

4%

The majority

LCN

NS

70%

DDH, deep dorsal horn. Other abbreviations as in Table 1.

amount of projecting neurons they involve have also been pointed out (Apkarian, A. V. and Hodge, C. J., 1989d; Burstein, R. et al., 1990b; Mouton, L. J. and Holstege, G., 1998; Willis, W. D. et al., 2001) but a complete picture of the quantitative variations is still hard to attain due to the use of tracers of variable sensitivity. As to the possibility that each pathway identity relies on a particular neurochemical architecture at the spinal relay, data are too scarce to allow any sort of considerations. The difficulty in concealing this anatomofunctional organization with the well-known capacity of modality discrimination during acute physiological pain led some authors to ascribe discrimination capacity to a particular spinal region, leaving the remaining spinal cord with a secondary, largely unknown but eventually not important role in pain processing. The high concentration of nociceptive specific neurons in lamina I, together with the convergence of input of various nature and peripheral origin to this lamina and the easy separation of its structural neuronal groups (see Chapter Spinal Cord Physiology of Nociception) brought it into focus during the last decade. However, lamina I does not contribute to all spinofugal nociceptive pathways while participating similarly in many others (Table 1). Moreover, an appraisal of the participation of the various lamina I structural cell groups in a sample of nociceptive ascending pathways revealed

Ascending Pathways: Anatomy and Physiology Table 3

517

Relative amounts of supraspinally projecting lamina I neurons

VLM DRt NTS PBN PAG Thalamus VBC

Fusiform

Flattened

Pyramidal

80%

10% 10–30% 40%

10% 5–20% 35% 30% 70% 70–75% (enlargements)

25% 70% 30%

25–30% (enlargements)

Multipolar

60–85%

VBC, ventrobasal complex of the thalamus.

large superposition, although again slight differences as to their relative amount in each pathway and the specific involvement or noninvolvement of certain groups were detected (Table 3). What is noteworthy is that when taken together, the various electrophysiological studies on the response properties of lamina I neurons do not support a clear-cut structural–functional correlation based on stimulusmodality processing (see discussion in Galhardo, V. et al., 2000). The possibility that stimulus characterization at the central nervous system depends on a combinatory activation process rather than on the activation of specific channels should be addressed in the future. As a working hypothesis, it could be postulated at this point that each pathway has particular characteristics that depend on both, the kind of input it transmits (defined by the relative contribution of the various spinal neurons) and the functional properties of the target. Ultimately, for each noxious event, ascending transmission of nociceptive input would be the result of the relative activation of the various pathways.

35.8.3

Stimulus Discrimination

A clear separation between the lateral and the medial spinothalamic nociceptive pathways as to the ability of the former to discriminate between stimulus location and intensity has been established, based mainly on the electrophysiological properties of neurons projecting in each pathway. Amongst the supporting data stand out the relatively small size of the receptive fields, the stimulus intensity-encoding capacity, and the somatotopic organization of the spinal, thalamic, and cortical neurons in the lateral pathway, as opposed to the medial pathway. It should be noted, however, that early studies pointed out that the medial spinothalamic system conveys spinal input either directly or through a brainstem relay, but spinal

neurons projecting to brainstem regions connected to the medial thalamus do not necessarily share the same properties of the medial spinothalamic neurons. Receptive fields of spino-RVM and spino-PAG neurons vary from small, confined to a sole limb, to very large and complex. PBN-projecting spinal neurons were shown to present small receptive fields (Bester, H. et al., 2000), contrary to PBN neurons projecting to the paracentral nucleus of the thalamus, which have large receptive fields (Bourgeais, L. et al., 2001b). Also noteworthy in this respect is the fact that neurons in the RVM and PAG send axonal collaterals to the lateral thalamus, while neurons projecting through the lateral spinothalamic or the spinocervical pathways send collaterals to the medial thalamus. As a whole, the data suggest that, although the lateral spinothalamic pathway as well as the spinocervical and the spinohypothalamic pathways appear to be morphofuntionally organized to allow stimulus location and intensity discrimination, an extensive cross-talk between the various nociceptive ascending pathways is likely to take place.

35.8.4 Nociceptive Ascending Pathways as Part of a Complex Nociceptive Integration System Although the ascending transmission system and the descending endogenous pain control system (see Chapter Descending Control Mechanisms) are normally dealt with separately, evidence has been accumulated to prove that they are both part of a sole nociceptive system buildup in such a way that information is treated at different brain levels in order to integrate nociception and various brain functions. The brain areas of termination of the ascending nociceptive pathways are those and the same from where pain-control actions are elicited upon local stimulation (Jones, S. L., 1992). These areas are intimately connected with each other, and

518 Ascending Pathways: Anatomy and Physiology

each of them with the spinal cord dorsal horn, in most cases through direct descending projections that very often participate in spino-brain-spinal reciprocal loops (Lima, D. et al., 1998). Descending pain-control actions appear to be triggered not only by arriving of nociceptive input, but also by the current state of processing of other functions carried out at those brain areas, as blood pressure variations at the caudal ventrolateral reticular formation (Tavares, I. and Lima, D., 2002). The so-called ascending and descending systems are arranged as an intricate network of neuronal pathways that interchange information and dynamically control, through modulation of spinal dorsal horn activity, the level of activation of the perception and response centers. Pain perception and pain reactions are thus adapted to autonomic, affective, and cognitive states, which in turn are short- or long-term modified in response to the noxious event. The various nociceptive ascending pathways must not be viewed as static separate lines that allow the passage of nociceptive signals to distinct brain regions, but rather as an ensemble of spinal transmission neurons that tune pain perception and reactions according to peripheral and central conditions through a constant and dynamic interplay with the brain.

References Abols, I. A. and Basbaum, A. I. 1981. Afferent connections of the rostral medulla of the cat: a neural-substrate for midbrainmedullary interactions in the modulation of pain. J. Comp. Neurol. 201, 285–297. Agarwal, S. K. and Calaresu, F. R. 1990. Reciprocal connections between nucleus tractus solitarii and rostral ventrolateral medulla. Brain Res. 523, 305–308. Al-Chaer, E. D., Feng, Y., and Willis, W. D. 1999. Comparative study of viscerosomatic input onto postsynaptic dorsal column and spinothalamic tract neurons in the primate. J. Neurophysiol. 82, 1876–1882. Albe-Fessard, D., Boivie, J., Grant, G., and Levante, A. 1975. Labelling of cells in the medulla oblongata and the spinal cord of the monkey after injections of horseradish peroxidase in the thalamus. Neurosci. Lett. 1, 75–80. Almeida, A. and Lima, D. 1997. Activation by cutaneous or visceral noxious stimulation of spinal neurons projecting to the medullary dorsal reticular nucleus in the rat: a c-fos study. Eur. J. Neurosci. 9, 686–695. Almeida, A., Cobos, A., Tavares, A., and Lima, D. 2002. Brain afferents to the medullary dorsal reticular nucleus: a retrograde and anterograde tracing study in the rat. Eur. J. Neurosci. 16, 81–95. Almeida, A., Tavares, I., and Lima, D. 1995. Projection sites of superficial or deep dorsal horn in the dorsal reticular nucleus. Neuroreport 6, 1245–1248. Almeida, A., Tavares, I., and Lima, D. 2000. Reciprocal connections between the medullary dorsal reticular nucleus and the spinal dorsal horn in the rat. Eur. J. Pain. 4, 373–387.

Almeida, A., Tavares, I., Lima, D., and Coimbra, A. 1993. Descending projections from the medullary dorsal reticular nucleus make synaptic contacts with spinal cord lamina I cells projecting to that nucleus: an electron microscopic tracer study in the rat. Neuroscience 55, 1093–1106. Ammons, W. S. 1987. Characteristics of spinoreticular and spinothalamic neurons with renal input. J. Neurophysiol. 50, 480–495. Ammons, W. S., Blair, R. W., and Foreman, R. D. 1984. Responses of primate T1–T5 spinothalamic neurons to gallbladder distension. Am. J. Physiol. 247, R995–R1002. Ammons, W. S., Girardot, M. N., and Foreman, R. D. 1985. T2– T5 spinothalamic neurons projecting to medial thalamus with viscerosomatic input. J. Neurophysiol. 54, 73–89. Anderson, F. D. and Berry, C. M. 1959. Degeneration studies of long ascending fiber systems in the cat brain stem. J. Comp. Neurol. 111, 195–229. Andrew, D. and Craig, A. D. 2001. Spinothalamic lamina I neurons selectively responsive to cutaneous warming in cats. J. Physiol. 537, 489–495. Apkarian, A. V. and Hodge, C. J. 1989a. The primate spinothalamic pathways: III. Thalamic terminations of the dorsolateral and ventral spinothalamic pathways. J. Comp. Neurol. 288, 493–511. Apkarian, A. V. and Hodge, C. J. 1989b. The primate spinothalamic pathways: II. The cells of origin of the dorsolateral and ventral spinothalamic pathways. J. Comp. Neurol. 288, 474–492. Apkarian, A. V. and Hodge, C. J. 1989c. A dorsolateral spinothalamic tract in macaque monkey. Pain 37, 323–333. Apkarian, A. V. and Hodge, C. J. 1989d. The primate spinothalamic pathways: I. A quantitative study of the cells of origin of the spinothalamic pathway. J. Comp. Neurol. 288, 447–473. Apkarian, A. V. and Shi, T. 1998. Thalamocortical Connections of the Cingulate and Insula in Relation to Nociceptive Inputs to the Cortex. In: Pain Mechanisms and Management (eds. S. N. Ayrapetyan and A. V. Apkarian), pp. 212–220. IOS Press. Apkarian, A. V., Stevens, R. T., and Hodge, C. J. 1985. Funicular location of ascending axons of lamina L cells in the cat spinal-cord. Brain Res. 334, 160–164. Applebaum, A. E., Beall, J. E., Foreman, R. D., and Willis, W. D. 1975. Organization and receptive fields of primate spinothalamic tract neurons. J. Neurophysiol. 38, 572–586. Baker, M. L. and Giesler, G. J. 1984. Anatomical studies of the spinocervical tract of the rat. Somatosens. Res. 2, 1–18. Bandler, R. and Tork, I. 1987. Midbrain periaqueductal grey region in the cat has afferent and efferent connections with solitary tract nuclei. Neurosci. Lett. 74, 1–6. Beall, J. E., Foreman, R. D., Willis, W. D., and Applebaum, A. E. 1977. Spinal cord potentials evoked by cutaneous afferents in the monkey. J. Neurophysiol. 40, 199–211. Behbehani, M. M. 1995. Functional characteristics of the midbrain periaqueductal gray. Prog. Neurobiol. 46, 575–605. Beitz, A. J. 1982. The organization of afferent-projections to the midbrain periaqueductal gray of the rat. Neuroscience 7, 133–159. Berkley, K. J. 1980. Spatial relationships between the terminations of somatic sensory and motor pathways in the rostral brainstem of cats and monkeys. I. Ascending somatic sensory inputs to lateral diencephalon. J. Comp. Neurol. 193, 283–317. Bernard, J. F. and Besson, J. M. 1990. The spino(trigemino)pontoamygdaloid pathway: electrophysiological evidence for an involvement in pain processes. J. Neurophysiol. 63, 473–490. Bernard, J. F., Villanueva, L., Carroue´, J., and Le Bars, D. 1990. Efferent projections from the subnucleus reticularis dorsalis

Ascending Pathways: Anatomy and Physiology (SRD): a Phaseolus vulgaris leucoagglutinin study in the rat. Neurosci. Lett. 116, 257–262. Bester, H., Chapman, V., Besson, J. M., and Bernard, J. F. 2000. Physiological properties of the lamina I spinoparabrachial neurons in the rat. J. Neurophysiol. 83, 2239–2259. Bjo¨rkeland, M. and Boivie, J. 1984. The termination of spinomesencephalic fibers in cat. An experimental anatomical study. Anat. Embryol. 170, 265–277. Blair, R. W., Ammons, W. S., and Foreman, R. D. 1984a. Responses of thoraric spinothalamic and spinoreticular cells to coronary artery occlusion. J. Neurophysiol. 51, 636–648. Blair, R. W., Weber, R. N., and Foreman, R. D. 1981. Characteristics of primate spinothalamic tract neurons receiving viscerosomatic convergent inputs in the T3–T5 segments. J. Neurophysiol. 46, 797–811. Blair, R. W., Weber, R. N., and Foreman, R. D. 1984b. Responses of thoracic spinoreticular and spinothalamic cells to intracardiac bradykinin. Am. J. Physiol. 246, H500–H507. Blomqvist, A., Ma, W., and Berkley, K. J. 1989. Spinal input to the parabrachial nucleus in the cat. Brain Res. 480, 29–36. Blomqvist, A., Zhang, E. T., and Craig, A. D. 2000. Cytoarchitectonic and immunohistochemical characterization of a specific pain and temperature relay, the posterior portion of the ventral medial nucleus, in the human thalamus. Brain 123, 601–619. Boivie, J. 1971. The termination of the spinothalamic tract in the cat. An experimental study with silver degeneration methods. Exp. Brain Res. 12, 331–353. Boivie, J. 1979. An anatomical reinvestigation of the termination of the spinothalamic tract in the monkey. J. Comp. Neurol. 186, 343–370. Bourgeais, L., Gauriau, C., and Bernard, J. F. 2001a. Projections from the nociceptive area of the central nucleus of the amygdala to the forebrain: a PHA-L study in the rat. Eur. J. Neurosci. 14, 229–255. Bourgeais, L., Monconduit, L., Villanueva, L., and Bernard, J. F. 2001b. Parabrachial internal lateral neurons convey nociceptive messages from the deep laminas of the dorsal horn to the intralaminar thalamus. J. Neurosci. 21, 2159–2165. Bowsher, D. 1957. Termination of the central pain pathway in man: the conscious appreciation of pain. Brain 80, 606–622. Bowsher, D. 1961. The termination of secondary somatosensory neurons within the thalamus of Macaca mulatta: an experimental degeneration study. J. Comp. Neurol. 117, 213–227. Bowsher, D. and Westman, J. 1970. The gigantocellular reticular region and its spinal afferents: a light and electron microscopic study in the cat. J. Anat. 106, 23–36. Braz, J. M., Nassar, M. A., Wood, J. N., and Basbaum, A. I. 2005. Parallel ‘pain’ pathways arise from subpopulations of primary afferent nociceptor. Neuron 47, 787–793. Brown, A. G. and Franz, D. N. 1969. Responses of spinocervical tract neurones to natural stimulation of identified cutaneous receptors. Exp. Brain Res. 7, 231–249. Brown, A. G., Fyffe, R. E., Noble, R., Rose, P. K., and Snow, P. J. 1980a. The density, distribution and topographical of spinocervical tract neurones in the cat. J. Physiol. 300, 409–428. Brown, A. G., Hamann, W. C., and Martin, H. F. 1975. Effects of activity in non-myelinated afferent fibres on the spinocervical tract. Brain Res. 98, 243–259. Brown, A. G., House, C. R., Rose, P. K., and Snow, P. J. 1976. The morphology of spinocervical tract neurones in the cat. J. Physiol. 260, 719–738. Brown, A. G., Koerber, H. R., and Noble, R. 1987. An intracellular study of spinocervical tract cell responses to natural stimuli and single hair afferent fibres in cats. J. Physiol. 382, 331–354.

519

Brown, A. G., Rose, P. K., and Snow, P. J. 1977. The morphology of spinocervical tract neurones revealed by intracellular injection of horseradish peroxidase. J. Physiol. 270, 747–764. Brown, A. G., Rose, P. K., and Snow, P. J. 1980b. Dendritic trees and cutaneous receptive fields of adjacent spinocervical tract neurones in the cat. J. Physiol. 300, 429–440. Bryan, R. N., Coulter, J. D., and Willis, W. D. 1974. Cells of origin of the spinocervical tract in the monkey. Exp. Neurol. 42, 574–586. Bryan, R. N., Trevino, D. L., Coulter, J. D., and Willis, W. D. 1973. Location and somatotopic organization of the cells of origin of the spino-cervical tract. Exp. Brain Res. 17, 177–189. Burstein, R. and Giesler, G. J. 1989. Retrograde labeling of neurons in spinal cord that project directly to nucleus accumbens or the septal nuclei in the rat. Brain Res. 497, 149–154. Burstein, R. and Potrebic, S. 1993. Retrograde labelling of neurons in the spinal cord that project directly to the amygdala or the orbital cortex in the rat. J. Comp. Neurol. 335, 469–485. Burstein, R., Cliffer, K. D., and Giesler, G. J. Jr. 1987. Direct somatosensory projections from the spinal cord to the hypothalamus and telencephalon. J. Neurosci. 4159–4164. Burstein, R., Cliffer, K. D., and Giesler, G. J. 1990a. Cells of origin of the spinohypothalamic tract in the rat. J. Comp. Neurol. 291, 329–344. Burstein, R., Dado, R. J., Cliffer, K. D., and Giesler, G. J., Jr. 1991a. Physiological characterization of spinohypothalamic tract neurons in the lumbar enlargement of rats. J. Neurophysiol. 66, 261–284. Burstein, R., Cliffer, K. D., and Geisler, G. J. 1990b. Cells of origin of the spinohypothalamic tract in the rat. J. Comp. Neurol. 291, 329–344. Burton, H. and Jones, E. G. 1976. The posterior thalamic region and its cortical projection in new world and old world monkeys. J. Comp. Neurol. 168, 249–301. Calaresu, F. R., Ciriello, J., Caverson, M. M., Chechetto, D. F., and Krukoff, T. L. 1984. Functional neuroanatomy of central pathways controlling the circulation. In: Hypertension and the brain (eds. G. P. Guthrie, Jr. and T. A. Kotchen), pp. 3–22. Futura Publishing. Carstens, E. and Trevino, D. L. 1978a. Anatomical and physiological properties of ipsilaterally projecting spinothalamic neurons in the second cervical segment of the cat’s spinal cord. J. Comp. Neurol. 182, 167–184. Carstens, E. and Trevino, D. L. 1978b. Laminar origins of spinothalamic projections in the cat as determined by the retrograde transport of horseradish peroxidase. J. Comp. Neurol. 182, 151–166. Castro, A. R., Morgado, C., Lima, D., and Tavares, I. 2006. Differential expression of NK1 and GABAB receptors in spinal neurons projecting to antinociceptive or pronociceptive medullary centers. Brain Res Bull. 69, 266–275. Catalano, J. V. and Lamarche, G. 1957. Central pathway for cutaneous impulses in the cat. Am. J. Physiol. 189, 141–144. Cechetto, D. F. and Saper, C. B. 1987. Evidence for a viscerotopic sensory representation in the cortex and thalamus in the rat. J. Comp. Neurol. 262, 27–45. Cechetto, D. F., Standaert, D. G., and Saper, C. B. 1985. Spinal and trigeminal dorsal horn projections to the parabrachial nucleus in the rat. J. Comp. Neurol. 240, 153–160. Cervero, F. and Wolstencroft, J. H. 1984. A positive feeedback loop between spinal cord nociceptive pathways and antinociceptive areas of the cat’s brain stem. Pain 20, 125–138. Cervero, F., Iggo, A., and Molony, V. 1977. Responses of spinocervical tract neurones to noxious stimulation of the skin. J. Physiol. 267, 537–558.

520 Ascending Pathways: Anatomy and Physiology Chandler, M. J., Zhang, J., Qin, C., Yuan, Y., and Foreman, R. D. 2000. Intrapericardiac injections of algogenic chemicals excite primate C1-C2 spinothalamic tract neurons. Am. J. Physiol. Regul. Integr. Comp. Physiol. 279, R560–R568. Chaouch, A., Mene´trey, D., Binder, D., and Besson, J. M. 1983. Neurons at the origin of the component of the bulbopontine spinoreticular tract in the rat: an anatomical study using horseradish peroxidase retrograde transport. J. Comp. Neurol. 214, 309–320. Chung, J. M., Kenshalo, D. R., Gerhart, K. D., and Willis, W. D. 1979. Excitation of primate spinothalamic neurons by cutaneous C-fiber volleys. J. Neurophysiol. 42, 1354–1369. Clark, W. E. L. 1936. The termination of ascending tracts in the thalamus of the thalamus of the macaque monkey. J. Anat. 71, 7–40. Cledenin, M., Ekerot, C. F., Oscarsson, O., and Rose´n, I. 1974. The lateral reticular nucleus in the cat. II: Organization of component activated from bilateral ventral flexor reflex tract (bVFRT). Exp. Brain Res. 21, 487–500. Clement, C. I., Keay, K. A., Podzebenko, K., Gordon, B. D., and Bandler, R. 2000. Spinal sources of noxious visceral and noxious deep somatic afferent drive onto the ventrolateral periaqueductal gray of the rat. J. Comp. Neurol. 425, 323–344. Cliffer, K. D., Burstein, R., and Giesler, G. J. 1991. Distributions of spinothalamic, spinohypothalamic, and spinotelencephalic fibers revealed by anterograde transport of PHA-L in rats. J. Neurosci. 11, 852–868. Cobos, A., Lima, D., Almeida, A., and Tavares, I. 2003. Brain afferents to the lateral caudal ventrolateral medulla: a retrograde and anterograde tracing study in the rat. Neuroscience 120, 485–498. Coffield, J. A. and Miletiæ, V. 1987. Immunoreactive enkephalin is contained within some trigeminal and spinal neurons projecting to the rat medial thalamus. Brain Res. 425, 380–383. Collier, J. and Buzzard, E. F. 1903. The degenerations resulting from lesions of posterior nerve roots and away from transverse lesions of the spinal cord in man. Brain 26, 559–591. Comans, P. E. and Snow, P. J. 1981. Ascending projections to nucleus parafascicularis of the cat. Brain Res. 230, 337–341. Cowie, R. J. and Holstege, G. 1992. Dorsal mesencephalic projections to pons, medulla, and spinal-cord in the cat limbic and nonlimbic components. J. Comp. Neurol. 319, 536–559. Craig, A. D. 1976. Spinocervical tract cells in cat and dog, labeled by the retrogade transport of horseradish peroxidase. Neurosci. Lett. 3, 173–177. Craig, A. D. 1978. Spinal and medullary input tothe lateral cervical nucleus. J. Comp. Neurol. 181, 729–744. Craig, A. D. 1995. Distribution of brainstem projections from spinal lamina I neurons in the cat and the monkey. J. Comp. Neurol. 361, 225–248. Craig, A. D. 2003. Distribution of trigeminothalamic and spinothalamic lamina I, terminations in the cat. Somatosens. Mot. Res. 20, 209–222. Craig, A. D. and Burton, H. 1979. The lateral cervical nucleus in the cat: anatomic organization of cervico-thalamic neurons. J. Comp. Neurol. 185, 329–346. Craig, A. D. and Burton, H. 1981. Spinal and medullary lamina I projection to nucleus submedius in medial thalamus: a possible pain center. J. Neurophysiol. 45, 443–466. Craig, A. D. and Burton, H. 1985. The distribution and topographical organization in the thalamus of antegradelytransported horseradish peroxidase after spinal injections in cat and raccoon. Exp. Brain Res. 58, 227–254. Craig, A. D. and Kniffki, K. D. 1985. Spinothalamic lumbosacral lamina I cells responsive to skin and muscle stimulation in the cat. J. Physiol. 365, 197–221.

Craig, A. D., Bushnell, M. C., Zhang, E. T., and Blomqvist, A. 1994. A thalamic nucleus specif for pain and temperature sensation. Nature 372, 770–773. Craig, A. D., Krout, K., and Andrew, D. 2001. Quantitative response characteristics of thermoreceptive and nociceptive lamina I spinothalamic neurons in the cat. J. Neurophysiol. 86, 1459–1480. Craig, A. D., Linington, A. J., and Kniffki, K. D. 1989. Cells of origin of spinothalamic tract projections to the medial and lateral thalamus in the cat. J. Comp. Neurol. 289, 568–585. Craig, A. D., Wiegand, S. J., and Price, J. L. 1982. The thalamocortical projection of the nucleus submedius in the cat. J. Comp. Neurol. 206, 28–48. Craig, A. D., Zhang, E. T., and Blomqvist, A. 2002. Association of spinothalamic lamina I neurons and their ascending axons with calbindin-immunoreactivity in monkey and human. Pain 97, 105–115. Dejerine, J. and Roussy, G. 1906. Le syndrome thalamique. Rev. Neurol. 14, 521–532. Desbois, C. and Villanueva, L. 2001. The organization of lateral ventromedial thalamic connecions in the rat: a link for the distribution of nociceptive signals to widespread cortical regions. Neuroscience 102, 885–898. Dilly, P. N., Wall, P. D., and Webster, K. E. 1968. Cells of origin of the spinothalamic tract in the cat and rat. Exp. Neurol. 21, 550–562. Dostrovsky, J. O. and Craig, A. D. 1996. Cooling-specific spinothalamic neurons in the monkey. J. Neurophysiol. 76, 3656–3665. Dostrovsky, J. O., Guilbaud, G., and Gautron, M. 1987. Nociceptive neurons in nucleus submedius of the arthritic rat. Pain 4, S263. Downie, J. W., Ferrington, D. G., Sorkin, L. S., and Willis, W. D. 1988. The primate spinocervicothalamic pathway: responses of cells of the lateral cervical nucleus and spinocervical tract to innocuous and noxious stimuli. J. Neurophysiol. 59, 861–885. Dugast, C., Almeida, A., and Lima, D. 2003. The medullary dorsal reticular nucleus enhances the responsiveness of spinal nociceptive neurons to peripheral stimulation in the rat. Eur. J. Neurosci. 18, 580–588. Eberhart, J. A., Morrell, J. I., Krieger, M. S., and Pfaff, D. W. 1985. An autoradiographic study of projections ascending from the midbrain central gray, and from the region lateral to it, in the rat. J. Comp. Neurol. 241, 285–310. Edinger, L. 1890. Einiges vom Verlauf der Gefuehlsbahnen im centralen Nervensysteme. Deut. Med. Woch. 16, 421–426. Esteves, F., Lima, D., and Coimbra, A. 1993. Structural types of spinal cord marginal (lamina I) neurons projecting to the nucleus of the tractus solitarius in the rat. Somatosens. Mot. Res. 10, 203–216. Ferrington, D. G., Sorkin, L. S., and Willis, W. D. 1986. Responses of spinothalamic tract cells in the cat cervical spinal cord to innocuous and graded noxious stimuli. Somatosens. Res 3, 339–358. Ferrington, D. G., Sorkin, L. S., and Willis, W. D. 1987. Responses of spinothalamic tract cells in the superficial dorsal horn of the primate lumbar spinal cord. J. Physiol. 388, 681–703. Fields, H. L. 2000. Pain modulation: expectation, opioid analgesia and virtual pain. Prog. Brain Res. 122, 245–253. Fields, H. L., Clanton, C. H., and Anderson, S. D. 1977. Somatosensory properties of spinoreticular neurons in the cat. Brain Res. 120, 49–66. Fields, H. L., Malick, A., and Burstein, R. 1995. Dorsal horn projection targets of On and OFF cells in the rostral ventromedial medulla. J. Neurophysiol. 1742–1759. Flink, R. and Westman, J. 1986. Different neuron populations in the feline lateral cervical nucleus: A light and electron microscopic study with the retrograde axonal transport technique. J. Comp. Neurol. 250, 265–281.

Ascending Pathways: Anatomy and Physiology Foerster, O. and Gagel, O. 1932. Die Vorderseitenstrangdurchschneidung beim Menschens. Eine klinisch-patho-physiologisch-anatomische Studie. Z. Ges. Neurol. Psychiat. 138, 1–92. Foreman, R. D. and Weber, R. N. 1980. Responses from neurons of the primate spinothalamic tract to electrical stimulation of afferents from the cardiopulmonary region and somatic structures. Brain Res. 186, 463–468. Foreman, R. D., Applebaum, A. E., Beall, J. E., Trevino, D. L., and Willis, W. D. 1975. Responses of primate spinothalamic tract neurons to electrical stimulation of hindlimb peripheral nerve. J. Neurophysiol. 38, 132–145. Foreman, R. D., Blair, R. W., and Weber, R. N. 1984. Viscerosomatic convergence onto T2-T4 spinoreticular, spinoreticular-spinothalamic, and spinothalamic tract neurons in the cat. Exp. Neurol. 85, 597–619. Foreman, R. D., Hancock, M. B., and Willis, W. D. 1981. Responses of spinothalamic tract cells in the thoracic spinal cord of the monkey to cutaneous and visceral inputs. Pain 11, 149–162. Foreman, R. D., Kenshalo, D. R., Jr., Schmidt, R. F., and Willis, W. D. 1979. Field potentials and excitation of primate spinothalamic neurons in response to volleys in muscle afferents. J. Physiol. 286, 197–213. Fox, R. E., Holloway, J. A., Iggo, A., and Mokha, S. S. 1980. Spinothalamic neurones in the cat: some electrophysiological obhservations. Brain Res. 182, 186–190. Galhardo, V. and Lima, D. 1999. Structural characterization of marginal (Lamina I) spinal cord neurons in the cat: A Golgi Study. J. Comp. Neurol. 414, 315–333. Galhardo, V., Lima, D., and Necker, R. 2000. Spinomedullary pathways in the pigeon (Columba livia): Differential involvement of lamina I cell. J. Comp. Neurol. 423, 631–645. Gamboa-Esteves, F. O., Kaye, J. C., McWilliam, P. N., Lima, D., and Batten, T. F. 2001a. Immunohistochemical profiles of spinal lamina I neurons retrogradely labelled from the nucleus tractus solitarii in rat suggest excitatory projections. Neuroscience 104, 523–538. Gamboa-Esteves, F. O., Lima, D., and Batten, T. F. C. 2001b. Neurochemistry of superficial spinal neurones projecting to nucleus of the solitary tract that express c-fos on chemical somatic and visceral nociceptive input in the rat. Metab. Brain Dis. 16, 151–164. Gamboa-Esteves, F. O., Tavares, I., Almeida, A., Batten, T. F., McWilliam, P. N., and Lima, D. 2001c. Projection sites of superficial and deep spinal dorsal horn cells in the nucleus tractus solitarii of the rat. Brain Res. 921, 195–205. Gauriau, C. and Bernard, J. F. 2004. A comparative reappraisal of projections from the superficial laminae of the dorsal horn in the rat: the forebrain. J. Comp. Neurol. 468, 24–56. Gebhart, G. F. and Ossipov, M. H. 1986. Characterization of inhibition of the spinal nociceptive tail-flick reflex in the rat from the medullary lateral reticular nucleus. J. Neurosci. 6, 701–713. Gerhart, K. D., Yezierski, R. P., Giesler, G. J., and Willis, W. D. 1981. Inhibitory receptive fields of primate spinothalamic tract cells. J. Neurophysiol. 46, 1309–1325. Giesler, G. J. and Elde, R. P. 1985. Immunocytochemical studies of the peptidergic content of fibers and terminals within the lateral spinal and lateral cervical nuclei. J. Neurosci. 5, 833–1841. Giesler, G. J., Bjo¨rkeland, M., Xu, Q., and Grant, G. 1988. Organization of the spinocervicothalamic pathways in the rat. J. Comp. Neurol. 268, 223–233. Giesler, G. J., Mene´trey, D., and Basbaum, A. I. 1979a. Differential origins of spinothalamic tract projections to medial and lateral thalamus in the rat. J. Comp. Neurol. 184, 107–126.

521

Giesler, G. J., Mene´trey, D., Guilbaud, G., and Besson, J. M. 1976. Lumbar cord neurons at the origin of the spinothalamic tract in the rat. Brain Res. 118, 320–324. Giesler, G. J., Miller, L. R., Madsen, A. M., and Katter, J. T. 1987. Evidence for the existence of a lateral cervical nucleus in mice, guinea pigs and rabbits. J. Comp. Neurol. 263, 106–112. Giesler, G. J., Spiel, H. R., and Willis, W. D. 1981a. Organization of spinothalamic tract axons within the rat spinal cord. J. Comp. Neurol. 195, 243–252. Giesler, G. J., Urca, G., Cannon, J. T., and Liebeskind, J. C. 1979b. Response properties of neurons of the lateral cervical nucleus in the rat. J. Comp. Neurol. 186, 65–78. Giesler, G. J., Yezierski, R. P., Gerhart, K. D., and Willis, W. D. 1981b. Spinothalamic tract neurons that project to medial and/or lateral thalamic nuclei: evidence for a physiologically novel population of spinal cord neurons. J. Neurophysiol. 46, 1285–1308. Gobel, S. 1978a. Golgi studies of the neurons in layer I of the dorsal horn of the medulla (trigeminal nucleus caudalis). J. Comp. Neurol. 180, 375–394. Gobel, S. 1978b. Golgi studies of the neurons in layer II of the dorsal horn of the medulla (trigeminal nucleus caudalis). J. Comp. Neurol. 180, 395–414. Graziano, A. and Jones, E. G. 2004. Widespread thalamic terminations of fibers arising in the superficial medullary dorsal horn of monkeys and their relation to calbindin immunoreactivity. J. Neurosci. 24, 248–256. Guilbaud, G. and Kayser, V. 1988. New evidence for the involvement of the rat ventrobasal thalamic complex in nociception: electrophysiological and neuropharmacological studies. 93–107. Guilbaud, G., Peschanski, M., and Besson, J. M. 1985. Experimental Data Related to Nociception and Pain at the Supraspinal Level. In: Textbook of Pain (eds. P. D. Wall and R. Melzack), pp. 110–118. Churchill Livingston. Ha, H. and Liu, C. N. 1966. Organization of the spino-cervicothalamic system. J. Comp. Neurol. 127, 445–470. Haber, L. H., Moore, B. D., and Willis, W. D. 1982. Electrophysiological response properties of spinoreticular neurons in the monkey. J. Comp. Neurol. 207, 75–84. Hamann, W. C., Hong, S. K., Kniffki, K. D., and Schmidt, R. F. 1978. Projections of primary afferent fibres from muscle to neurones of the spinocervical tract of the cat. J. Physiol. 283, 369–378. Hardy, S. G. P. 2001. Hypothalamic projections to cardiovascular centers of the medulla. Brain Res. 894, 233–240. Harmann, P. A., Carlton, S. M., and Willis, W. D. 1988. Collaterals of spinothalamic tract cells to the periaqueductal gray: a fluorescent double-labelling study in the rat. Brain Res. 441, 87–97. Harrison, P. J. and Jankowska, E. 1984. An intracellular study of descending and non-cutaneous afferent input to spinocervical tract neurones in the cat. J. Physiol. 356, 245–261. He´caen, H., Talairach, J., David, M., and Dell, M. B. 1949. Coagulations limitees du thalamus dans les algies du syndrome thalamique – resultats therapeutiques et physiologiques. Rev. Neurol. 81, 917–931. Herbert, H. and Saper, C. B. 1992. Organization of medullary adrenergic and noradrenergic projections to the periaqueductal gray matter in the rat. J. Comp. Neurol. 315, 34–52. Horrax, G. 1929. Experiences with cordotomy. Arch. Surg. 1140–1164. Hunt, S. P., Pini, A., and Evan, G. 1987. Induction of c-fos-like protein in spinal cord neurons following sensory stimulation. Nature 328, 632–634.

522 Ascending Pathways: Anatomy and Physiology Hwang, S. J., Burette, A., and Valtschanoff, J. G. 2003. VR1positive primary afferents contact NK1-positive spinoparabrachial neurons. J. Comp. Neurol. 460, 255–265. Hylden, J. L. K., Anton, F., and Nahin, R. L. 1989. Spinal lamina I projection neurons in the rat: collateral innervation of parabrachial area and thalamus. Neuroscience 28, 27–37. Hylden, J. L. K., Hayashi, H., and Bennett, G. J. 1986b. Lamina I spinomesencephalic neurons in the cat ascend via the dorsolateral funiculi. Somatosens. Res. 4, 31–41. Hylden, J. L. K., Hayashi, H., Bennett, G. J., and Dubner, R. 1985. Spinal lamina I neurons projecting to the parabrachial area of the cat midbrain. Brain Res. 336, 195–198. Hylden, J. L. K., Hayashi, H., Dubner, R., and Bennett, G. J. 1986a. Physiology and morphology of the lamina I spinomesencephalic projections. J. Comp. Neurol. 247, 505–515. Hyndman, O. R. and Van Epps, C. 1939. Possibility of differential section of the spinothalamic tract. A clinical and histological study. Arch. Surg. 38, 1036–1053. Jankowska, E., Rastad, J., and Westman, J. 1976. Intracellular application of horseradish peroxidase and its light and electron microscopical appearance in spinocervical tract cells. Brain Res. 105, 557–562. Jasmin, L., Burkey, A. R., Card, J. P., and Basbaum, A. I. 1997. Transneuronal labeling of a nociceptive pathway, the spino(trigemino-) parabrachio-amygdaloid, in the rat. J. Neurosci. 17, 3751–3765. Johnson, F. H. 1954. Experimental study of spino-reticular connections in the cat. Anat. Rec. 118, 316. Jones, E. G. and Burton, H. 1974. Cytoarchitecture and somatic sensory connectivity of thalamic nuclei other than the ventrobasal complex in the cat. J. Comp. Neurol. 154, 395–432. Jones, E. G. and Leavitt, R. Y. 1974. Retrograde axonaltransport and demonstration of nonspecific projections to cerebral-cortex and striatum from thalamic intralaminar nuclei in rat, cat and monkey. J. Comp. Neurol. 154, 349–377. Jones, M. W., Hodge, C. J., Apkarian, A. V., and Stevens, R. T. 1985. A dorsolateral spinothalamic pathway in cat. Brain Res. 335, 188–193. Jones, S. L. 1992. Descending Control of Nociception. In: The Initial Processing of Pain and its Descending Control: Spinal and Trigeminal Systems (ed. A. R. Light), pp. 203–295. Karger. Ju, G., Melander, T., Ceccatelli, S., Ho¨kfelt, T., and Frey, P. 1987. Immunohistochemical evidence for a spinothalamic pathway co-containing cholecystokinin- and galanin-like immunoreactivities in the rat. Neuroscience 20, 439–456. Kajander, K. C. and Giesler, G. J. 1987. Responses of neurons in the lateral cervical nucleus of the cat to noxious cutaneous stimulation. J. Neurophysiol. 57, 1686–1704. Katter, J. T., Burstein, R., and Giesler, G. J. 1991. The cells of origin of the spinohypothalamic tract in cats. J. Comp. Neurol. 303, 101–112. Kayalioglu, G., Robertson, B., Kristensson, K., and Grant, G. 1999. Nitric oxide synthase and interferon-gamma receptor immunoreactivities in relation to ascending spinal pathways to thalamus, hypothalamus, and the periaqueductal grey in the rat. Somatosens. Mot. Res. 16, 280–290. Keay, K. A. and Bandler, R. 1992. Anatomical evidence for segregated input from the upper cervical spinal-cord to functionally distinct regions of the periaqueductal gray region of the cat. Neurosci. Lett. 139, 143–148. Keay, K. A., Clement, C. I., Matar, W. M., Heslop, D. J., Henderson, L. A., and Bandler, R. 2002. Noxious activation of spinal or vagal afferents evokes distinct patterns of foslike immunoreactivity in the ventrolateral periaqueductal gray of unanaesthetised rats. Brain Res. 948, 122–130.

Kenshalo, D. R., Jr., Giesler, G. J., Leonard, R. B., and Willis, W. D. 1980. Responses of neurons in the primate ventral posterior lateral nucleus to noxious stimuli. J. Neurophysiol. 43, 1594–1614. Kenshalo, D. R., Jr., Leonard, R. B., Chung, J. M., and Willis, W. D. 1979. Responses of primate spinothalamic neurons to graded and to repeated noxious heat stimuli. J. Neurophysiol. 42, 1370–1389. Kerr, F. W. L. 1975. The ventral spinothalamic tract and other ascending systems of the ventral funiculus of the spinal cord. J. Comp. Neurol. 159, 335–356. Kerr, F. W. L. and Lippman, H. H. 1974. The primate spinothalamic tract as demonstrated by anterolateral cordotomy and commissural myelotomy. Adv. Neurol. 4, 147–156. Kevetter, G. A. and Willis, W. D. 1982. Spinothalamic cells in the rat lumbar cord with collaterals to the medullary reticular formation. Brain Res. 238, 181–185. Kevetter, G. A. and Willis, W. D. 1983. Collaterals of spinothalamic cells in the rat. J. Comp. Neurol. 215, 453–464. Kevetter, G. A., Haber, L. H., Yezierski, R. P., Chung, J. M., Martin, R. F., and Willis, W. D. 1982. Cells of origin of the spinoreticular tract in the monkey. J. Comp. Neurol. 207, 61–74. Klop, E. M., Mouton, L. J., and Holstege, G. 2004. Less than 15% of the spinothalamic fibers originate from neurons in lamina I in cat. Neurosci. Lett. 360, 125–128. Kniffki, K. D., Mense, S., and Schmidt, R. F. 1977. The spinocervical tract as a possible pathway for muscular nociception. J. Physiol. (Paris) 73, 359–366. Kohnstamm, O. 1900. Ueber die Coordinationskerne des Hirnstammes und die absteigenden Spinalbahnen. Nach den Ergebnissen der combinierten Degenerationsmethode. Mschr. Psychiat. Neurol. 8, 261–293. Kostarczyk, E., Zhang, X. J., and Giesler, G. J. 1997. Spinohypothalamic tract neurons in the cervical enlargement of rats: Locations of antidromically identified ascending axons and their collateral branches in the contralateral brain. J. Neurophysiol. 77, 435–451. Krettek, J. E. and Price, J. L. 1977. The cortical projections of the mediodorsal nucleus and adjacent thalamic nuclei in the rat. J. Comp. Neurol. 171, 157–191. Kunze, W. A. A., Wilson, P., and Snow, P. J. 1987. Response of lumbar spinocervical tract cells to natural and electrical stimulation of the hindlimb footpads in cats. Neurosci. Lett. 75, 253–258. Leah, J., Mene´trey, D., and De Pommery, J. 1988. Neuropeptides in long ascending spinal tract cells in the rat: evidence for parallel processing of ascending information. Neuroscience 24, 195–207. Leite-Almeida, H., Valle-Fernandes, A., and Almeida, A. 2006. Brain projections from the medullary dorsal reticular nucleus: an anterograde and retrograde tracing study in the rat. Neuroscience 140, 577–595. Lima, D. 1990. A spinomedullary projection terminating in the dorsal reticular nucleus of the rat. Neuroscience 34, 577–589. Lima, D. 1997. Functional anatomy of spinofugal nociceptive pathways. Pain Rev. 4, 1–19. Lima, D. 1998. Anatomical basis for the dynamic processing of nociceptive input. Eur. J. Pain. 2, 195–202. Lima, D. and Almeida, A. 2002. The medullary dorsal reticular nucleus as a pronociceptive centre of the pain control system. Prog. Neurobiol. 66, 81–108. Lima, D. and Coimbra, A. 1983. The neuronal population of the marginal zone (lamina I) of the rat spinal cord. A study based on reconstructions of serially sectioned cells. Anat. Embryol. 167, 273–288.

Ascending Pathways: Anatomy and Physiology Lima, D. and Coimbra, A. 1985. Marginal neurons of the rat spinal cord at the origin of a spinobulboreticular projection. Neurosci. Lett. 22, S9. Lima, D. and Coimbra, A. 1986. A Golgi study of the neuronal population of the marginal zone (lamina I) of the rat spinal cord. J. Comp. Neurol. 244, 53–71. Lima, D. and Coimbra, A. 1988. The spinothalamic system of the rat: structural types of retrogradely labeled neurons in the marginal zone (lamina I). Neuroscience 27, 215–230. Lima, D. and Coimbra, A. 1989. Morphological types of spinomesencephalic neurons in the marginal zone (lamina I) of the rat spinal cord, as shown after retrograde labeling with cholera toxin subunit B. J. Comp. Neurol. 279, 327–339. Lima, D. and Coimbra, A. 1990. Structural types of marginal (Lamina I) neurones projecting to the dorsal reticular nucleus of the medulla oblongata. Neuroscience 34, 591–606. Lima, D. and Coimbra, A. 1991. Neurons in the substantia gelatinosa rolandi (lamina II) project to the caudal ventrolateral reticular formation of the medulla oblongata in the rat. Neurosci. Lett. 132, 16–18. Lima, D., Albino-Teixeira, A., and Tavares, I. 2001. The caudal medullary ventrolateral reticular formation in nociceptivecardiovascular integration. An experimental study in the rat. Exp. Physiol. 87.2, 267–274. Lima, D., Almeida, A., and Tavares, A. 1998. The endogenous pain control system: facilitating and inhibitory pathways. In: Pain Mechanisms and Management (eds. S. N. Ayrapetyan and A. V. Apkarian), pp. 192–210. IOS Press. Lima, D., Avelino, A., and Coimbra, A. 1992. Differential participation of marginal cells in the transmission of nociceptive input to the thalamus and mesencephalon. Eur. J. Neurosci. Suppl. 5, 2057. Lima, D., Avelino, A., and Coimbra, A. 1993. Morphological characterization of marginal (Lamina I) neurons immunoreactive for substance P, enkephalin, dynorphin and gamma-aminobutyric acid in the rat spinal cord. J. Chem. Neuroanat. 6, 43–52. Lima, D., Castro, A. R., Castro-Lopes, J. M., and Galhardo, V. 2002. Differential expression of GABAB receptors in monkey lamina I neuronal types; a Golgi and immunocytochemical study. Society Neurosci Abst 258.4. Lima, D., Esteves, F., and Coimbra, A. 1994. C-fos activation by Noxious Input of Spinal Neurons Projecting to the Nucleus of the Tractus Solitarius in the Rat. In: Proceedings of the 7th World Congress on Pain (ed. G. F. Gebhart), Vol. 2, pp. 423–434. IASP Press. Lima, D., Mendes-Ribeiro, J. A., and Coimbra, A. 1991. The spino-latero-reticular system of the rat: projections from the superficial dorsal horn and structural characterization of marginal neurons involved. Neuroscience 45, 137–152. Liu, R. P. 1983. Laminar origins of spinal projection to the periaqueductal gray of the rat. Brain Res. 264, 118–122. Loewy, A. D. 1990. Central autonomic pathways. In: Central Regulation of Autonomic Functions (eds. A. D. Loewy and K. M. Spyer), pp. 88–103. Oxford University Press. Loewy, A. D. and Burton, H. 1978. Nuclei of the solitary tract: Efferent projections to the lower brain stem and spinal cord of the cat. J. Comp. Neurol. 181, 421–450. Lovick, T. A. 1993. Integrated activity of cardiovascular and pain integratory systems: Role in adaptive behaviour. Prog. Neurobiol. 40, 631–644. Lund, R. D. and Webster, K. E. 1967. Thalamic afferents from the spinal cord and trigeminal nuclei. An experimental anatomical study in the rat. J. Comp. Neurol. 130, 313–328. Lundberg, A. and Oscarsson, O. 1961. Three ascending spinal pathways in the dorsal part of the lateral funiculus. Acta. Physiol. Scand. 51, 1–16.

523

Ma, W. and Peschanski, M. 1988. Spinal and trigeminal projections to the parabrachial nucleus in the rat-electronmicroscopic evidence of a spino-ponto-amygdalian somatosensory pathway. Somatosens. Res. 5, 247–257. Magnusson, K. R., Magnusson, K. R., Clements, J. R., Larson, A. A., Madl, J. E., and Beitz, A. J. 1987. Localization of glutamate in trigeminothalamic projection neurons: a combined retrograde transport-immunohistochemical study. Somatosens. Res. 4, 177–190. Mainen, Z. F. and Sejnowski, T. J. 2006. Influence of dendritic structure on firing pattern in model neocortical neurons. Nature 382, 363–366. Malick, A. and Burstein, R. 1998. Cell of origin of the trigeminohypothalamic tract in the rat. J. Comp. Neurol. 400, 125–144. Malick, A., Strassman, A. M., and Burstein, R. 2000. Trigeminohypothalamic and reticulohypothalamic tract in the upper cervical spinal cord and caudal medulla of the rat. J. Neurophysiol. 84, 2078–2112. Mantyh, P. W. 1982. The ascending input to the midbrain periaqueductal gray of the primate. J. Comp. Neurol. 211, 50–64. Mantyh, P. W. 1983a. The spinothalamic tract in the primate: a re-examination using wheatgerm agglutinin conjugated to horseradish peroxidase. Neuroscience 9, 847–862. Mantyh, P. W. 1983b. The terminations of the spinothalamic tract in the cat. Neurosci. Lett. 38, 119–124. Mark, R. F. and Steiner, J. 1958. Cortical projection of impulser in myelinated cutaneous afferent nerve fibres of the cat. J. Physiol. 142, 544–562. Maunz, R. A., Pitts, N. G., and Peterson, B. W. 1978. Cat spinoreticular neurons: locations, responses and changes in responses during repetitive stimulation. Brain Res. 148, 365–379. McMahon, S. B. and Wall, P. D. 1985. Electrophysiological mapping of brainstem projections of spinal cord lamina I cells in the rat. Brain Res. 19–26. Mehler, W. R. 1957. The mammalian pain tract in phylogeny. Anat. Rec. 127, 332. Mehler, W. R. 1962. The anatomy of the so-called ‘pain tract’ in man: an analysis of the course and distribution of the ascending fibers of the fasciculus anterolateralis. In: Basic Research in Paraplegia (eds. J. D. French and R. W. Porter), pp. 26–55. Thomas. Mehler, W. R. 1966. Some observations on secondary ascending afferent systems in the central nervous system. In: Pain (eds. R. S. Knighton and P. R. Dumke), pp. 11–32. Little Brown. Mehler, W. R. 1969. Some neurological species differences – a posteriori. Ann. NY Acad. Sci. 167, 424–468. Mehler, W. R. 1974. Central pain and the spinothalamic tract. Adv. Neurol. 4, 127–146. Mehler, W. R., Feferman, M. E., and Nauta, W. J. H. 1956. Ascending axon degeneration following anterolateral chordotomy in the monkey. Anat. Rec. 124, 332–333. Mehler, W. R., Feferman, M. E., and Nauta, W. J. H. 1960. Ascending axon degeneration following anterolateral cordotomy. An experimental study in the monkey. Brain 83, 718–751. Meller, S. T. and Dennis, B. J. 1991. Efferent projections of the periaqueductal gray in the rabbit. Neuroscience 40, 191–216. Melzack, R. and Casey, K. L. 1968. Sensory, motivational and central control determinants of pain. pp. 423–443. Mene´trey, D. and Basbaum, A. I. 1987. Spinal and trigeminal projections to the nucleus of the solitary tract – a possible substrate for somatovisceral and viscerovisceral reflex activation. J. Comp. Neurol. 255, 439–450.

524 Ascending Pathways: Anatomy and Physiology Mene´trey, D. and DePommery, J. 1991. Origins of spinal ascending pathways that reach central areas involved in viscenoception and visceronociception in the rat. Eur. J. Neurosci. 3, 249–259. Mene´trey, D., Chaouch, A., and Besson, J. M. 1980. Location and properties of dorsal horn neurons at origin of spinoreticular tract in lumbar enlargement of the rat. J. Neurophysiol. 44, 862–877. Mene´trey, D., Chaouch, A., Binder, D., and Besson, J. M. 1982. The origin of the spinomesencephalic tract in the rat: an anatomical study using the retrograde transport of horseradish peroxidase. J. Comp. Neurol. 206, 193–207. Mene´trey, D., DePommery, J., Baimbridge, K. G., and Thomasset, M. 1992a. Calbindin-D28K (CaBP28k)-like immunoreactivity in ascending projections.1. Trigeminal nucleus caudalis and dorsal vagal complex projections. Eur. J. Neurosci. 4, 61–69. Mene´trey, D., DePommery, J., and Besson, J. M. 1984. Electrophysiological characteristics of lumbar spinal cord neurons backfired from lateral reticular nucleus in the rat. J. Neurophysiol. 52, 595–611. Mene´trey, D., DePommery, J., Thomasset, M., and Baimbridge, K. G. 1992b. Calbindin-D28K (CaBP28k)-like immunoreactivity in ascending projections. II. Spinal Projections to brain stem and mesencephalic areas. Eur. J. Neurosci. 4, 70–76. Mene´trey, D., Roudier, F., and Besson, J. M. 1983. Spinal neurons reaching the lateral reticular nucleus as studied in the rat by retrograde transport of horseradish peroxidase. J. Comp. Neurol. 220, 439–452. Meyers, D. E. R. and Snow, P. J. 1982. The morphology of physiologically identified deep spinothalamic tract cells in the lumbar spinal cord of the cat. J. Physiol. 329, 373–388. Millis, C. D. and Hulsebosch, C. E. 2002. Increased expression of metabotropic glutamate receptor subtype 1 on spinothalamic tract neurons following spinal cord injury in the rat. Neurosci. Lett. 319, 59–62. Milne, R. J., Foreman, R. D., and Willis, W. D. 1982. Responses of primate spinothalamic neurons located in the sacral intermediomedical gray (Stilling’s nucleus) to proprioceptive input from the tail. Brain Res. 234, 227–236. Miyagawa, T., Ando, R., Sakurada, S., Sakurada, T., and Kisara, K. 1986. Effects of tooth pulp stimulation on single unit activity of the amygdala in cats. Nippon Yakurigaku Zasshi 88, 173–178. Morison, R. S. and Dempsey, E. W. 1942. A study of thalamocortical relations. Am. J. Physiol. 135, 281–292. Mouton, L. J. and Holstege, G. 1998. Three times as many lamina I neurons project to the periaqueductal gray than to the thalamus: a retrograde tracing study in the cat. Neurosci. Lett. 255, 107–110. Mouton, L. J. and Holstege, G. 2000. Segmental and laminar organization of the spinal neurons projecting to the periaqueductal gray (PAG) in the cat suggests the existence of at least five separate clusters of Spino-PAG neurons. J. Comp. Neurol. 428, 389–410. Mouton, L. J., Klop, E. M., and Holstege, G. 2001. Lamina Iperiaqueductal gray (PAG) projections represent only a limited part of the total spinal and caudal medullary input to the PAG in the cat. Brain. Res. Bull. 54, 167–174. Mouton, L. J., Klop, E. M., Broman, J., Zhang, M., and Holstege, G. 2004. Lateral cervical nucleus projections to periaqueductal gray matter in cat. J. Comp. Neurol. 471, 434–445. Mtui, E. P., et al. 1993. Projections from the nucleus tractus solitarii to the spinal cord. J. Comp. Neurol. 337, 231–252. Nahin, R. L. 1988. Immunocytochemical identification of long ascending, peptidergic lumbar spinal neurons terminating in

either the medial or lateral thalamus in the rat. Brain Res. 443, 345–349. Nahin, R. L. and Micevych, P. E. 1986. A long ascending pathway of enkephalin-like immunoreactive spinoreticular neurons in the rat. Neurosci. Lett. 65, 271–276. Nahin, R. L., Madsen, A. M., and Giesler, G. J. 1986. Funicular location of the ascending axons of neurons adjacent to the spinal cord central canal in the rat. Brain Res. 384, 367–372. Palecek, J., Paleckova, V., and Willis, W. D. 2003. Fos expression in spinothalamic and postsynaptic dorsal column neurons following noxious visceral and cutaneous stimuli. Pain 104, 249–257. Panneton, W. M. and Burton, H. 1985. Projections from the paratrigeminal nucleus and the medullary and spinal dorsal horns to the peribrachial area in the cat. Neuroscience 15, 779–797. Parenti, R., Cicirata, F., Panto, M. R., and Serapide, M. F. 1996. The projections of the lateral reticular nucleus to the deep cerebellar nuclei. An experimental analysis in the rat. Eur. J. Neurosci. 8, 2157–2167. Paxinos, G. and Watson, C. 1998. The Rat Brain in Stereotaxic Coordinates, 4th ed. Academic Press. Pechura, C. and Liu, R. 1986. Spinal neurons which project to the periaqueductal gray and the medullary reticular formation via axon collaterals: a double-label fluorescence study in the rat. Brain Res. 374, 357–361. Perl, E. R. and Whitlock, D. G. 1961. Somatic stimuli exciting spinothalamic projections to thalamic neurons in cat and monkey. Exp. Neurol. 3, 256–296. Peschanski, M. and Besson, J. M. 1984. A spino-reticulothalamic pathway in the rat: an anatomical study with reference to pain transmission. Neuroscience 12, 165–178. Peschanski, M., Guilbaud, G., Gautron, M., and Besson, J. M. 1980. Encoding of noxious heat messages in neurons of the ventrobasal thalamic complex in the rat. Brain Res. 197, 401–413. Peschanski, M., Mantyh, P. W., and Besson, J. M. 1983. Spinal afferents to the ventrobasal thalamic complex in the rat: an anatomical study using wheat-germ agglutinin conjugated to horseradish peroxidase. Brain Res. 278, 240–244. Polgar, E., Puska´r, Z., Watt, C., Matesz, C., and Todd, A. J. 2002. Selective innervation of lamina I projection neurones that possess the neurokinin 1 receptor by serotonincontaining axons in the rat spinal cord. Neuroscience 109, 799–809. Prescott, S. A. and De Koninck, Y. 2002. Four cell types with distinctive membrane properties and morphologies in lamina I of the spinal dorsal horn of the adult rat. J. Physiol. 539, 817–836. Price, D. D., Hayes, R. L., Rude, M., and Dubner, R. 1978. Spatial and temporal transformations of input to spinothalamic tract neurons and their relation to somatic sensations. J. Neurophysiol. 41, 933–947. Puskar, Z., Polgar, E., and Todd, A. J. 2001. A population of large lamina I projection neurons with selective inhibitory input in rat spinal cord. Neuroscience 102, 167–176. Quensel, F. 1898. Ein Fall von Sarcom der Dura spinalis. Beitrag zur Kenntnis der secundaeren Degenerationen nach Rueckenmarkscompression. Neurol. Zbl. 17, 482–493. Ramo´n y Cajal, S. 1909. Histologie dusyste`me nerveux de l’homme et des verte´bre´s. Maloine. Reis, L. C., Colombari, E., Canteras, N. S., and Cravo, S. L. 2000. Projections from nucleus tractus solitarii (NTS) and ventrolateral medulla (VLM) to paraventricular nucleus of the hypothalamus (PVH) and median preoptic nucleus (MnPO). Projections from nucleus tractus solitarii (NTS) and ventrolateral medulla (VLM) to paraventricular nucleus of the hypothalamus (PVH) and median preoptic nucleus (MnPO). FASEB J. 14, A66.

Ascending Pathways: Anatomy and Physiology Ring, G. and Ganchrow, D. 1983. Projections of nucleus caudalis and spinal cord to brainstem and diencephalon in the hedgehog (Erinaceus europaeus and Paraechinus aethiopicus): A degeneration study. J. Comp. Neurol. 216, 132–151. Rossi, G. F. and Brodal, A. 1957. Terminal distribution of spinoreticular fibers in the cat. Arch. Neurol. Psychiat. 78, 439–453. Rucker, H. K. and Holloway, J. A. 1982. Viscerosomatic convergence onto spinothalamic tract neurons in the cat. Brain Res. 243, 155–157. Ruda, M. A., Coffield, J., and Dubner, R. 1984. Demonstration of postsynaptic opioid modulation of thalamic projection neurons by the combined techniques of retrograde horseradish peroxidase and enkephalin immunocytochemistry. J. Neurosci. 4, 2117–2132. Ruscheweyh, R., Ikeda, H., Heinke, B., and Sandkuhler, J. 2004. Distinctive membrane and discharge properties of rat spinal lamina I projection neurons in vitro. J. Physiol. 555, 527–543. Shi, T. and Apkarian, A. V. 1995. Morphology of thalamocortical neurons projecting to the primary somatosensory cortex and their relationship to spinothalamic terminals in the squirrel monkey. J. Comp. Neurol. 361, 1–24. Short, A. D., Brown, A. G., and Maxwell, D. J. 1990. Afferent inhibition and facilitation of transmission through the spinocervical tract in the anaesthetized cat. J. Physiol. 429, 511–528. Sim, L. J. and Joseph, S. A. 1994. Efferent of the opiocortincontaining region of the commissural nucleus tractus solitarius. Peptides 15, 169–174. Simone, D. A., Sorkin, L. S., Oh, U., Chung, J. M., Owens, C., LaMotte, R. H., and Willis, W. D. 1991. Neurogenic hyperalgesia: Central neural correlates in responses of spinothalamic tract neurons. J. Neurophysiol. 66, 228–246. Slugg, R. M. and Light, A. R. 1994. Spinal cord and trigeminal projections to the pontine parabrachial region in the rat as demonstrated with phaseolus-vulgaris-leukoagglutinin. J. Comp. Neurol. 339, 49–61. Snowball, R. K., Semenenko, F. M., and Lumb, B. M. 2000. Visceral inputs to neurons in the anterior hypothalamus including those that project to the periaqueductal gray: A functional anatomical and electrophysiological study. Neuroscience 99, 351–361. Spike, R. C., Puskar, Z., Andrew, D., and Todd, A. J. 2003. A quantitative and morphological study of projection neurons in lamina I of the rat lumbar spinal cord. Eur. J. Neurosci. 18, 2433–2448. Standaert, D., Watson, S., Houghten, R., and Saper, C. 1986. Opioid peptide immunoreactivity in spinal and trigeminal dorsal horn neurons projecting to the parabrachial nucleus in the rat. J. Neurosci. 6, 1220–1226. Stevens, R. T., Hodge, C. J., and Apkarian, A. V. 1989. Medial, intralaminar and lateral terminations of lumbar spinothalamic tract neurons: a fluorescent double label study. Somatosens. Mot. Res. 6, 285–308. Stevens, R. T., London, S. M., and Apkarian, A. V. 1993. Spinothalamocortical projections to the secondary somatosensory cortex (SII) in squirrel monkey. Brain Res. 631, 241–246. Surmeier, D. J., Honda, C. N., and Willis, W. D. 1986a. Temporal features of the responses of primate spinothalamic neurons to noxious thermal stimulation of hairy and glabrous skin. J. Neurophysiol. 56, 351–369. Surmeier, D. J., Honda, C. N., and Willis, W. D. 1986b. Responses of primate spinothalamic neurons to noxious thermal stimulation of glabrous and hairy skin. J. Neurophysiol. 56, 328–350.

525

Surmeier, D. J., Honda, C. N., and Willis, W. D. 1988. Natural grouping of primate spinothalamic neurons based on cutaneous stimulation. Physiological and anatomical features. J. Neurophysiol. 59, 833–860. Svensson, B. A., Rastad, J., Westman, J., and Wiberg, M. 1985. Somatotopic termination of spinal afferents to the feline lateral cervical nucleus. Exp. Brain Res. 57, 576–584. Swett, J. E., McMahon, S. B., and Wall, P. D. 1985. Long ascending projections to the midbrain from cells of lamina I and nucleus of the dorsolateral funiculus of the rat spinal cord. J. Comp. Neurol. 238, 401–416. Szucs, P., Odeh, F., Szokol, K., and Antal, M. 2003. Neurons with distinctive firing patterns, morphology and distribution in lamina V-VII of the neonatal rat lumbar spinal cord. Eur. J. Neurosci. 17, 537–544. Taub, A. and Bishop, P. O. 1965. The spinocervical tract: dorsal column linkage, conduction velocity, primary afferent spectrum. Exp. Neurol. 13, 1–21. Tavares, I., Almeida, A., Albino-Teixeira, A., and Lima, D. 1997. Lesions of the caudal ventrolateral medulla block the hypertension-induced inhibition of noxious-evoked c-fos expression in the rat spinal cord. Eur. J. Pain 1, 149–160. Tavares, I., Almeida, A., Esteves, F., Lima, D., and Coimbra, A. 1998. The caudal ventrolateral medullary reticular formation is reciprocally connected with the spinal cord. Society Neurosci Abst 24, 1132. Tavares, I. and Lima, D. 1994. Descending projections from the caudal medulla oblongata to the superficial or deep dorsal horn of the rat spinal cord. Exp. Brain Res. 99, 455–463. Tavares, I. and Lima, D. 2002. The caudal ventrolateral medulla as an important inhibitory modulator of pain transmission in the spinal cord. J. Pain. 3, 337–346. Tavares, I., Lima, D., and Coimbra, A. 1993. Neurons in the superficial dorsal horn of the rat spinal cord projecting to the medullary ventrolateral reticular formation express c-fos after noxious stimulation of the skin. Brain Res. 623, 278–286. Tavares, I., Lima, D., and Coimbra, A. 1996a. Catecholaminergic and serotonergic input to spinal dorsal horn neurons projecting to the caudal ventrolateral medulla of the rat. Abst 8th World Congress on Pain 448. Tavares, I., Lima, D., and Coimbra, A. 1996b. The ventrolateral medulla of the rat is connected with the spinal cord dorsal horn by an indirect descending pathway relayed in the A5 noradrenergic cell group. J. Comp. Neurol. 374, 84–95. Thiele, F. H. and Horsley, V. 1901. A study of the degenerations observed in the central nervous system in a case of fracture dislocation of the spine. Brain 24, 519–531. Thies, R. 1985. Activation of lumbar spinoreticular neurons by stimulation of muscle, cutaneous and sympathetic afferents. Brain Res. 333, 151–155. Thies, R. and Foreman, R. D. 1983. Inhibition and excitation of thoracic spinoreticular neurons by electrical stimulation of vagal afferent nerves. Exp. Neurol. 82, 1–16. Thompson, R. H., Canteras, N. S., and Swanson, L. W. 1996. Organization of projections from the dorsomedial nucleus of the hypothalamus: A PHA-L study in the rat. J. Comp. Neurol. 376, 143–173. Todd, A. J., McGill, M. M., and Shehad, S. A. S. 2000. Neurokinin 1 receptor expression by neurons in laminae I, III and IV of the rat spinal dorsal horn that project to the brainstem. Eur. J. Neurosci. 12, 689–700. Todd, A. J., Puskar, Z., Spike, R. C., Hughes, C., Watt, C., and Forrest, L. 2002. Projection neurons in lamina I of rat spinal cord with the neurokinin 1 receptor are selectively innervated by substance p-containing afferents and respond to noxious stimulation. J. Neurosci. 22, 4103–4113. Todd, A. J. and Spike, R. C. 1993. Localization of classical neurotransmitters and neuropeptides within neurons in

526 Ascending Pathways: Anatomy and Physiology lamina I-III of the mammalian spinal dorsal horn. Prog. Neurobiol. 41, 609–645. Traub, R. J. and Murphy, A. 2002. Colonic inflammation induces fos expression in the thoracolumbar spinal cord increasing activity in the spinoparabrachial pathway. Pain 95, 93–102. Trevino, D. L. 1976. The Origin and Pojections of a Spinal Nociceptive and Thermoreceptive Pathway. In: Sensory Functions of the Skin in Primates, with Special Reference to Man (ed. Y. Zotterman), pp. 367–376. Pergamon Press. Trevino, D. L. and Carstens, E. 1975. Confirmation of the location of spinothalamic neurons in the cat and monkey by the retrograde transport of horseradish peroxidase. Brain Res. 98, 177–182. VanderHorst, V. G. J. M., Mouton, L. J., Blok, B. F. M., and Holstege, G. 1996. Distinct cell groups in the lumbosacral cord of the cat project to different areas in the periaqueductal gray. J. Comp. Neurol. 376, 361–385. Vierck, C. J. and Luck, M. M. 1979. Loss and recovery of reactivity to noxious stimulation in monkeys with primary spinothalamic cordotomies, followed by secundary and tertiary lesions of other cord sectors. Brain 102, 233–248. Villanueva, L., Bernard, J. F., and Le Bars, D. 1995. Distribution of spinal cord projections from the medullary subnucleus reticularis dorsalis and the adjacent cuneate nucleus: a Phaseolus vulgaris-leucoagglutinin study in the rat. J. Comp. Neurol. 352, 11–32. Villanueva, L., Bouhassira, D., Bing, Z., and Le Bars, D. 1988. Convergence of heterotopic nociceptive information onto subnucleus reticularis dorsalis (SRD) neurons in the rat medulla. J. Neurophysiol. 60, 980–1009. Villanueva, L., Bouhassira, D., Bing, Z., and Le Bars, D. 1991. Spinal afferent projections to subnucleus reticularis dorsalis in the rat. J. Neurophysiol. 60, 980–1009. Villanueva, L., Desbois, C., Le Bars, D., and Bernard, J. F. 1998. Organization of diencephalic projections from the medullary subnucleus reticularis dorsalis and the adjacent cuneate nucleus: a retrograde and anterograde tracer study in the rat. J. Comp. Neurol. 390, 133–160. Walker, A. E. 1940. The spinothalamic tract in man. Arch. Neurol. Psychiat. 43, 284–298. Walker, A. E. 1942a. Relief of pain by mesencephalic tractotomy. Arch. Neurol. Psychiat. 48, 865–880. Walker, A. E. 1942b. Somatotopic localization of spino thalamic and sensory trigeminal tracts in mesencephalon. Arch. Neurol. Psychiat. 48, 884–889. Wang, C. C. and Shyu, B. C. 2004. Differential projections from the mediodorsal and centrolateral thalamic nuclei to the frontal cortex in rats. Brain Res. 995, 226–235. Westlund, K. N. and Craig, A. D. 1996. Association of spinal lamina I projections with brainstem catecholamine neurons in the monkey. Exp. Brain Res. 110, 151–162. Westlund, K. N., Bowker, R. M., Ziegler, M. G., and Coulter, J. D. 1983. Noradrenergic projections to the spinal cord of the rat. Brain Res. 263, 15–31. Westlund, K. N., Bowker, R. M., Ziegler, M. G., and Dan, J. 1981. Origins of spinal noradrenergic pathways demonstrated by retrograde transport of antibody to dopamine-aˆ-hydroxylase. Neurosci. Lett. 25, 243–249. Whitsel, B. L., Rustioni, A., Dreyer, D. A., Loe, P. R., Allen, E. E., and Metz, C. B. 1978. Thalamic projections to S-1 in macaque monkey. J. Comp. Neurol. 178, 385–409. Wiberg, M. and Blomqvist, A. 1984. The spinomesencephalic tract in the cat: its cells of origin and termination pattern as demonstrated by the intraaxonal transport method. Brain Res. 291, 1–18. Wiberg, M., Westman, J., and Blomqvist, A. 1987. Somatosensory projection to the mesencephalon: an anatomical study in the monkey. J. Comp. Neurol. 264, 92–117.

Willis, W. D. 1988. Nociceptive neurons in the primate ventral posterior lateral (VPL) nucleus. In: Cellular Thalamic Mechanisms (eds. M. Bentivoglio and R. Spreafico), pp. 77–92. Elsevier. Willis, W. D., Kenshalo, D. R., Jr., and Leonard, R. B. 1979. The cells of origin of the primate spinothalamic tract. J. Comp. Neurol. 188, 543–574. Willis, W. D., Trevino, D. L., Coulter, J. D., and Maunz, R. A. 1974. Responses of primate spinothalamic tract neurons to natural stimulation of hindlimb. J. Neurophysiol. 37, 358–372. Willis, W. D., Zhang, X., Honda, C. N., and Giesler, G. J. 2001. Projections from the marginal zone and deep dorsal horn to the ventrobasal nuclei of the primate thalamus. Pain 92, 267–276. Yezierski, R. P. 1988. Spinomesencephalic tract: projections from the lumbosacral spinal cord of the rat, cat, and monkey. J. Comp. Neurol. 267, 131–146. Yezierski, R. P. 1990. The effects of midbrain and medullary stimulation on spinomesencephalic tract cells in the cat. J. Neurophysiol. 63, 240–255. Yezierski, R. P. and Broton, J. G. 1991. Functional properties of spinomesencephalic tract (SMT) cells in the upper cervical spinal cord of the cat. Pain 45, 187–196. Yezierski, R. P. and Mendez, C. M. 1991. Spinal distribution and collateral projections of rat spinomesencephalic tract cells. Neuroscience 44, 113–130. Yezierski, R. P. and Schwartz, R. H. 1986. Response and receptive-field properties of spinomesencephalic tract cells in the cat. J. Neurophysiol. 55, 76–96. Yezierski, R. P., Sorkin, L. S., and Willis, W. D. 1987. Response properties of spinal neurons projecting to midbrain or midbrain-thalamus in the monkey. Brain Res. 437, 165–170. Yoshida, A., Dostrovsky, J. O., and Chiang, C. Y. 1992. The afferent and efferent connections of the nucleus submedius in the rat. J. Comp. Neurol. 324, 115–133. Yu, X. H., et al. 1999. NK-1 receptor immunoreactivity in distinct morphological types of lamina I neurons of the primate spinal cord. J. Neurosci. 19, 3545–3555. Zardettosmith, A. M. and Gray, T. S. 1995. Catecholamine and NPY efferents from the ventrolateral medulla to the amygdala in the rat. Brain Res. Bull. 38, 253–260. Zemlan, F. P., Leonard, C. M., Kow, L. M., and Plaff, D. W. 1978. Ascending tracts of the lateral columns of the rat spinal cord: a study using the silver impregnation and horseradish peroxidase techniques. Exp. Neurol. 62, 298–334. Zhang, D., Carlton, S. M., Sorkin, L. S., and Willis, W. D. 1990. Collaterals of primate spinothalamic tract neurons to the periaqueductal gray. J. Comp. Neurol. 296, 277–290. Zhang, E. T. and Craig, A. D. 1997. Morphology and distribution of spinothalamic lamina I neurons in the monkey. J. Neurosci. 17, 3274–3284. Zhang, E. T., Han, Z. S., and Craig, A. D. 1996. Morphological classes of spinothalamic lamina I neurons in the cat. J. Comp. Neurol. 367, 537–549. Zhang, X. J., Gokin, A. P., and Giesler, G. J. 2002. Responses of spinohypothalamic tract neurons in the thoracic spinal cord of rats to somatic stimuli and to graded distention of the bile duct. Somatosens. Mot. Res. 19, 5–17. Zhang, X. J., Wenk, H. N., Honda, C. N., and Giesler, G. J. 2000. Locations of spinothalamic tract axons in cervical and thoracic spinal cord white matter in monkeys. J. Neurophysiol. 83, 2869–2880. Zou, X. Y., Lin, Q., and Willis, W. D. 2000. Enhanced phosphorylation of NMDA receptor 1 subunits in spinal cord dorsal horn and spinothalamic tract neurons after intradermal injection of capsaicin in rats. J. Neurosci. 20, 6989–6997.

36 Dorsal Columns and Visceral Pain W D Willis Jr. and K N Westlund, University of Texas Medical Branch, Galveston, TX, USA ª 2009 Elsevier Inc. All rights reserved.

36.1 36.1.1 36.1.1.1 36.1.1.2 36.1.2 36.1.2.1 36.1.2.2 36.2 36.2.1 36.2.2 36.2.3 36.2.3.1 36.2.3.2 36.2.3.3 36.2.3.4 36.2.3.5 36.2.3.6 36.2.3.7 36.2.3.8 36.3 References

Clinical Evidence Concerning Spinal Cord Pathways That Signal Visceral Pain Spinothalamic Tract Anterolateral cordotomy Commissural myelotomy Posterior Column Hitchcock procedure (stereotactic C1 central myelotomy) Limited midline myelotomy Basic Science Evidence Concerning Spinal Cord Pathways That Signal Visceral Pain Spinothalamic Tract Spinoreticular, Spinoparabrachial, Spinoamygdalar, and Spinohypothalamic Tracts Postsynaptic Dorsal Column Path Historical evidence for a visceral projection in the dorsal column Effects of interruption of the dorsal column or a lesion of dorsal column nuclei on responses of brainstem and thalamic neurons to noxious visceral stimuli Effects of a dorsal column lesion on behavioral responses Effects of a dorsal column lesion on the regional cerebral blood flow changes that result from colorectal distention in monkeys Blockade of synaptic relay in sacral cord by morphine or 6-cyano-7-nitroquinoxaline2,3-dione Projections of the postsynaptic dorsal column pathway Upregulation of NK1 receptors in PSDC neurons after colon inflammation Fos expression in PSDC neurons after noxious visceral stimulation Descending Facilitation

527 527 527 529 529 529 529 530 530 531 531 531 531 533 534 534 534 536 537 537 539

Glossary activity box Apparatus used to determine the amount and time course of exploratory activity of an animal, such as a rat. central neuropathic pain pain that develops following injury to the central nervous system. CNQX 6-cyano-7-nitroquinoxaline-2,3-dione, a non-N-methyl-D-aspartic acid receptor antagonist. kainic acid lesion damage produced by injection of kainic acid, a substance that produces excitotoxicity.

NMDA N-methyl-D-aspartic acid. pain referral Projection of the source of pain to an area of the body distant to the actual area of injury. paresthesias Unusual sensations, such as tingling or burning. rhizotomy Transaction of one or more spinal roots. viscerospecific responses Neuronal activity evoked by sensory input from a particular visceral organ.

527

528 Dorsal Columns and Visceral Pain

36.1 Clinical Evidence Concerning Spinal Cord Pathways That Signal Visceral Pain 36.1.1

(a)

(b)

Spinothalamic Tract

36.1.1.1

Anterolateral cordotomy It is well known that n is relieved (at least temporarily) and thermal sense is lost over the appropriate part of the contralateral body following an anterolateral cordotomy (Spiller, W. G., 1905; Spiller, W. G. and Martin, E., 1912; Foerster, O. and Gagel, G., 1932; reviewed in Gybels, J. M. and Sweet, W. H., 1989). The signals are transmitted from one side of the body to the contralateral thalamus (Kenshalo, D. R. et al., 1980; Chung, J. M. et al., 1986; Bushnell, M. C. et al., 1993; Lee, J. I. et al., 1999; 2005) and from there to the appropriate regions of the cerebral cortex (see Casey, K. L. and Bushnell, M. C., 2000). It has been presumed that the pain signals are conveyed chiefly by the spinothalamic tract, which decussates at the spinal cord level (Mehler, W. R., 1962), although other pathways that accompany the spinothalamic tract are also likely to contribute. These include the spinoreticular, spinoparabrachial, spinohypothalamic, and other tracts (Willis, W. D. and Westlund, K. N.,1997; Willis, W. D. and Coggeshall, R. E., 2004). Innocuous thermal signals are attributed just to the spinothalamic tract. Anterolateral cordotomy can relieve superficial and deep somatic pain, as well as visceral pain (and can block thermal sense), provided that the lesion is extensive enough (Gybels, J. M. and Sweet, W. H., 1989; Nathan, P. W. et al., 2001). For complete pain relief on the contralateral side of the body, a cordotomy at an upper cervical level needs to extend from just posterior to the denticulate ligament, across the remainder of the lateral funiculus and well into the anterior funiculus (Figure 1(a); Nathan, P. W. et al., 2001). However, even after an initially successful cordotomy, pain relief may not persist more than a few months to a year or so, although in some cases the pain relief is of very long duration (Gybels, J. M. and Sweet, W. H., 1989). It is unclear why the pain can recur. Some suggestions are that other pathways now convey the pain signals, the disease advances (e.g., metastatic cancer may activate spinothalamic neurons whose axons were not interrupted by the cordotomy), or central neuropathic pain develops. Because of the recurrence of pain after a large proportion of cordotomies, neurosurgeons have

(c)

Figure 1 (a) Drawing of a cross section of the human spinal cord at the third cervical level. The dotted area shows the region that needs to be sectioned by a cordotomy in order to relieve contralateral pain completely. Note that the lesion must extend to a level that is posterior to the expected location of the denticulate ligament and anteromedially across the lateral funicuclus and into the anterior funiculus. (b) Drawing of a cross section of the human spinal cord at a mid-thoracic level showing the location of a limited midline myelotomy that was used to relieve completely the pain of colon cancer for the duration of the 3-month survival period. No opioid analgesics were required after a tapering-off period. (c) Photomicrograph of a cross section of the human spinal cord at the level of a limited midline myelotomy that was placed at a mid-thoracic level in a patient with a painful presacral sarcoma. The lesion (shown by the area of demyelination near the midline of the dorsal columns) eliminated the pain and the need for narcotics for the duration of the patient’s survival time, which was 3 years postsurgery. (a) From Nathan, P. W., Smith, M., and Deacon, P. 2001. The crossing of the spinothalamic tract. Brain 124, 793–803. (b) From Hirshberg, R. M., Al-Chaer, E. D., Lawand, N. B., Westlund, K. N., and Willis, W. D. 1996. Is there a pathway in the posterior funiculus that signals visceral pain? Pain 47, 291–305.

tended to limit the use of this procedure to patients with pain from a terminal disease, usually cancer, or to abandon the procedure altogether in favor of pharmacotherapy. Visceral pain can be relieved by cordotomy, provided that the lesion extends into the anterior funciculus medially to the spinal cord gray matter (Gybels, J. M. and Sweet, W. H., 1989). A unilateral cordotomy can be effective if the visceral pain is restricted to one side. However, if the pain is bilateral, a bilateral cordotomy may be needed. Unfortunately, this can lead to undesired side effects,

Dorsal Columns and Visceral Pain

such as incontinence because of interruption of descending pathways that control bowel and bladder function. If the cordotomy is done at a high cervical level for pain originating from the upper part of the body, there is danger that the respiratory control pathways may be interrupted, leading to severe (potentially lethal) difficulty with breathing. 36.1.1.2

Commissural myelotomy An alternative procedure called commissural myelotomy is directed at interrupting the axons of spinothalamic tract neurons of both sides as they cross the midline (Armour, D., 1927; Mansuy, L. et al., 1944; 1976; see Gybels, J. M. and Sweet, W. H., 1989). A lesion is made near the midline of the spinal cord and extending rostrocaudally for as many segments as needed to interrupt the appropriate projections. The lesion should be sufficiently deep to ensure that the crossing spinothalamic axons in the anterior white commissure are cut. Of course, the crossing axons of a number of tracts that accompany the spinothalamic tract, such as spinoreticular axons, are also interrupted, as are many axons in the posterior funciculi. According to the analysis of Dargent, M. et al. (1963), this procedure is apparently particularly effective for vaginal and visceral pain. Interestingly, commissural myelotomy often relieves clinical pain even if on testing there is no hypalgesia. Furthermore, pain and temperature sensation may be lost over a much greater extent of the body than could be predicted from the location and dimensions of the commissural myelotomy (Gybels, J. M. and Sweet, W. H., 1989). Based on evidence reviewed in the following, it now seems likely that the effect of a commissural myelotomy depends at least in part on the interruption of a visceral pain pathway that ascends in the posterior funiculi.

36.1.2

Posterior Column

36.1.2.1 Hitchcock procedure (stereotactic C1 central myelotomy)

Hitchcock developed a completely different approach to lesioning the spinal cord to relieve pain (Hitchcock, E., 1970; 1974; 1977; see also Papo, L. and Luongo, A., 1976; Eiras, J. et al., 1980; Schvarcz, J. R., 1977; 1978; Sourek, K., 1985). He placed a lesion in the central part of the upper cervical spinal cord using a stereotactic approach. The location of the lesion was sometimes determined by recordings of evoked potentials but more often by the sensory effects of electrical stimulation through the electrode

529

and by the changes in the sensory examination produced by a lesion. Stimulation in the central cord at C1 at 50 Hz typically resulted in a burning sensation in the chest or abdomen (Hitchcock, E., 1970; see Gybels, J. M. and Sweet, W. H., 1989). A lesion in the same location produced a change in pinprick sensation, either a loss of the ability to distinguish sharp from blunt or loss of a sensation of pain in response to pinprick. The analgesia was bilateral. Cancer pain was relieved in most cases, and the relief persisted until death or for over 5 years. Some patients (20%) failed to have a sensory loss and also did not experience pain relief. In the surgical series done by Schvarcz J. R. (1977; 1978), lesions were made at a depth of 5 mm from the posterior surface of the spinal cord, reaching the base of the posterior column. Electrical stimulation produced paresthesias in the feet, legs, or trunk (and also in the trigeminal distribution). Relief of cancer pain persisted in 78% of cases for at least 0.5–2 years (most of the patients died by this time). Other types of pain, including peripheral and central neuropathic pain, were relieved for 0.5–4 years. No neurological deficits were seen. Several other clinical studies reported similar results (Papo, L. and Luongo, A., 1976; Eiras, J. et al., 1980; Sourek, K., 1985). 36.1.2.2

Limited midline myelotomy Instead of a lesion at an upper cervical level, Gildenberg P. L. and Hirshberg R. M. (1984) made a midline lesion at T10 in patients with pelvic cancer pain. The location was chosen to be just above the level of entrance of primary afferent fibers from the pelvic viscera into the spinal cord. The procedure was termed a limited midline myelotomy. Eight cases done by Hirshberg, using a mechanical probe, were described further and a postmortem specimen showing the spinal cord lesion in one patient was illustrated (Figure 1(b)) in Hirshberg R. M. et al. (1996). The lesion interrupted the medial parts of the posterior funiculi but did not appear to intrude into the central gray matter or anterior white commissure. The results of the lesions in the eight cases were generally quite favorable, with pain relief that lasted as long as the patients survived and with little or no need for strong analgesic drugs. The chief of neurosurgery at our institution, Dr. H. J. W. Nauta, made lesions using a technique similar to that described by Hirshberg in a series of patients who had pain from pelvic or other cancers. The results in each case were again generally favorable and the need for strong analgesics greatly

530 Dorsal Columns and Visceral Pain

reduced. In one case, a midline myelotomy was done in a patient with inflammatory bowel disease secondary to irradiation that had successfully eradicated a cervical cancer (Nauta, H. J. W. et al., 1997; 2000). The patient had severe ongoing pain, and the pain intensified during bowel movements. As a consequence of the pain, the patient had lost a substantial fraction of her body weight, and it was judged that she would not survive much more weight loss. After midline myelotomy, this patient lived for almost 5 years with no further pelvic pain (although she did experience subdiaphragmatic pain because of peritonitis). She died from complications of diabetes. In another of the cases reported by Nauta H. J. W. et al. (1997; 2000), pain was reduced from 10 to 2–3 on the visual analog scale, and narcotic medication was tapered from 30 mg of intravenously administered morphine per hour preoperatively to 5 mg per hour within 5 days postoperatively. Another patient had unbearable pain from a presacral sarcoma, despite several efforts to resect the tumor. A midline myelotomy was done in the area shown in Figure 1(c). The lesion resulted in dramatic pain relief for the remainder of the patient’s life. He survived the surgery by 36 months, and for most of this time he did not require narcotic medication. In general, only in some cases were even minor and transient sensory side effects observed. Pelvic cancer pain was consistently reduced following midline myelotomy, and narcotic usage could be decreased on average by 83%. Several other groups around the world have had similar experiences with midline myelotomies (Becker, R. et al., 1999; Kim, Y. S. and Kwon, S. J., 2000; Filho, O. V. et al., 2001; Hu, J. S. and Li, Y. J., 2002; Hwang, S. L. et al., 2004), and the results have been reviewed by Becker, R. et al., (2002).

36.2 Basic Science Evidence Concerning Spinal Cord Pathways That Signal Visceral Pain 36.2.1

Spinothalamic Tract

The spinothalamic tract conveys somatic but also some visceral nociceptive information to the thalamus (Figure 2(a)). Studies in which recordings were made from antidromically activated spinothalamic tract neurons have demonstrated that many of these cells can be activated (or in some instances inhibited) following stimulation of viscera. For example, Foreman and his group have shown that feline and

Spinothalamic tract

(a)

Skin

Viscus

(b)

Anterolateral tract axon

Visceral PSDC pathway Gr Cu

C1

Midthoracic

L6-S1 Figure 2 (a) Convergence of visceral and somatic afferent inputs on an anterolateral tract neuron. Such viscerosomatic convergence is thought to be responsible for referral of visceral pain to somatic structures. (b) Course followed by the axonal projections of postsynaptic dorsal column neurons found in the central region of the spinal cord gray matter at sacral and mid-thoracic levels. The anterograde tracer, phaseolus vulgaris leucoagglutinin (PHA-L), was injected and then several days later traced in axons of the dorsal column to the brainstem. The projection from the sacral cord ascended at the midline, whereas that from the mid-thoracic cord ascended more laterally, just ventral to the dorsal intermediate sulcus. Information about visceral nociception most likely travels with other sensory input to the thalamus in the medial lemniscus. Data from Wang, C. C., Willis, W. D., and Westlund, K. N. 1999. Ascending projections from the central, visceral processing region of the spinal cord: a PHA-L study in rats. J. Comp. Neurol. 415, 341–367; illustration from Willis, W. D., AlChaer, E. D., Quast M. J., and Westlund, K. N. 1999. A visceral pain pathway in the dorsal column of the spinal cord. Proc. Natl. Acad. Sci. U. S. A 96, 7675–7679.

Dorsal Columns and Visceral Pain

primate spinothalamic tract cells can be excited by electrical stimulation of cardiopulmonary visceral afferent fibers, occlusion of a coronary artery, or injection of bradykinin into the coronary circulation (see review by Foreman, R. D., 1989). Similarly, spinothalamic tract cells have been shown to respond to electrical stimulation of the greater splanchnic nerve (Hancock, M. B. et al., 1975; Foreman, R. D. et al., 1981), distension of any of several hollow viscera, including the gall bladder (Ammons, W. S. et al., 1984), kidney (Ammons, W. S., 1987), ureter (Ammons, W. S., 1989), urinary bladder (Milne, R. J. et al., 1981), and colon (Al-Chaer, E. D. et al., 1999) or noxious stimulation of the testicle (Milne, R. J. et al., 1981). In general, spinothalamic tract and other neurons that are activated by visceral stimulation also respond to stimulation of somatic tissue. This convergence of visceral and somatic input onto spinal cord neurons, including nociceptive neurons that project to the brain, is thought to help account for the referral of visceral pain to the body wall in many clinical conditions (Figure 2(a); Head, H., 1893). Examples of the somatic receptive fields of viscerosensitive spinothalamic cells that correspond to the distribution of pain referral are noted in Foreman (Foreman, R. D., 1989) and Milne (Milne, R. J. et al., 1981). Only rarely can a spinal neuron be found that seems to respond to just visceral stimuli and not to somatic ones. However, when the search stimulus is colon distension, rather than antidromic activation from the lateral thalamus, viscerospecific responses can be recorded from cells located rostrally in the central lateral nucleus of the intralaminar complex of the thalamus (Ren, Y. et al., 2006). This region has been shown to receive direct spinal innervation from lamina X neurons (Wang, C. C. et al., 1999) and is rich in opiates (Sar, M. et al., 1978). The spinothalamic projection from lamina X is situated at the medialmost edge of the spinothalamic tract and shifts laterally as it ascends with the spinothalamic tract. 36.2.2 Spinoreticular, Spinoparabrachial, Spinoamygdalar, and Spinohypothalamic Tracts Several studies have demonstrated the effectiveness of visceral stimulation in exciting (or inhibiting) spinoreticular tract neurons (Blair, R. W. et al. 1984; Hobbs, S. F. et al., 1990), spinoparabrachial and spinoamygdalar neurons (Menetrey, D. and De Pommery, J., 1991; Bernard, J. F. et al., 1994), and spinohypothalamic tract neurons (Katter, J. T. et al.,

531

1996; Zhang, X. et al., 2002). A cordotomy or a commissural myelotomy is likely to interrupt these pathways, and thus the relief of visceral pain by such lesions is likely to be at least partially explained by this, as well as by interruption of the spinothalamic tract.

36.2.3

Postsynaptic Dorsal Column Path

36.2.3.1 Historical evidence for a visceral projection in the dorsal column

Recordings from the human posterior funiculus have revealed the presence of visceral afferents that respond to distention of the urinary bladder (Puletti, F. and Blomqvist, A. J., 1967). Responses at various levels of the dorsal column-medial lemniscus pathway have also been reported in animal experiments following electrical stimulation of visceral nerves (Amassian, V. E., 1951; Aidar, O. et al., 1952; Rigamonti, D. D. and Hancock, M. B., 1974; 1978). 36.2.3.2 Effects of interruption of the dorsal column or a lesion of dorsal column nuclei on responses of brainstem and thalamic neurons to noxious visceral stimuli

To determine if there is a visceral nociceptive pathway in the dorsal columns of experimental animals, recordings were made from viscero-responsive neurons in the ventral posterior lateral nucleus of the thalamus in rats before and after surgical interruption of either the dorsal columns bilaterally or the ipsilateral ventrolateral column, which contains the spinothalamic and associated nociceptive pathways (Al-Chaer, E. D. et al., 1996a). The dorsal column lesion reduced the responses of the thalamic neurons to colorectal distension on average by about 80% (Figure 3(Ae), cf. upper and middle rows of records). The remaining response was eliminated by the lesion of the ventrolateral quadrant of the spinal cord (Figure 3(Ae), lower row of records). Responses to weak mechanical stimuli applied to the skin were abolished by the dorsal column lesion, whereas the responses to the strongest mechanical stimuli were affected only by the ventrolateral quadrant lesion (Figure 3(Ad)). Similar effects were seen when the noxious visceral stimulus was inflammation of the colon by intraluminal injection of mustard oil (not illustrated). The mustard oil produced a progressive increase in the background activity of the viscerosensitive thalamic neurons. A dorsal column lesion

532 Dorsal Columns and Visceral Pain

was more effective in reducing the background activity than was a ventrolateral quadrant lesion. Neurons in the rat ventral posterior lateral thalamic nucleus could also be found that responded to distention of the duodenum (Figure 3(Ba); Feng, Y. et al., 1998). In these experiments, a lesion of the dorsal

(A)

(a)

Rate (spikes s–1)

(d) 500

(b)

BR PR PI

(c)

Control

(e)

(f)

200

0

0

500

200

0

0

500

200

0

0

DC lesion

DC + VLC lesions

10 s (B) (a) 30

Rate (spikes s–1)

column placed at the midline failed to reduce the responses (Figure 3(Bb)). However, bilateral lesions just ventral to the dorsal intermediate sulcus at an upper cervical level were effective (Figure 3(Bc)). This shift in the location of the dorsal column lesion needed to interrupt nociceptive responses in the

20

0.2 ml

40

0.3 ml

80 mm Hg

60 0.4 ml

0.5 ml

0 (b) 30

0 (c) 30

0 0

100 (d)

0

100 (e)

0 Time (s)

100

100

0

(f)

VPM VPL

Dorsal Columns and Visceral Pain

thalamus relates to the fact that the visceral input originated from an abdominal, rather than a pelvic organ (see Figure 2(b), discussion below, and Wang, C. C. et al., 1999). The off-midline part of the dorsal column pathway that carries visceral input from the thoracic level of the spinal cord was investigated in behavioral (see Figure 2(b) and discussion below) and electrophysiological studies after noxious chemical irritation of the pancreas (Houghton, A. K. et al., 1997; 2001). Noxious stimulation of the pancreas by applications of bradykinin to its exposed surface in anesthetized rats resulted in excitation of neurons in the ventral posterior nucleus of the thalamus (Houghton, A. K. et al., 2001). The mean firing rate of thalamic neurons was increased 412 120% above baseline during the first 40 s after bradykinin application to the pancreas and was sustained for 3–6 min. Large dorsal column lesions effectively eliminated the increased responses of thalamic neurons to applications of bradykinin on the pancreas and baseline activity remained constant. Enhanced responses to skin pinch after pancreatic application of bradykinin dropped after a dorsal column lesion from 242% over baseline back to 100%. The effects of noxious stimulation of the pancreas with bradykinin involved a spinal synaptic relay rather than a vagal relay since thalamic activation was prevented by intrathecal administration of morphine. This action of morphine could be antagonized by naloxone. Visceral responses can also be recorded from neurons in the ventral posterior lateral nucleus in monkeys

533

(cf., Chandler, M. J. et al., 1992; Bru¨ggemann, J. et al., 1994), as in rats. The effects of a dorsal column lesion on such responses in monkeys are consistent with those obtained in rats (Al-Chaer, E. D. et al., 1998). The thalamic responses to visceral input are relayed through the dorsal column nuclei. Visceral responses of neurons in the rat ventral posterior lateral thalamic nucleus could be reduced by small electrolytic or kainic acid lesions of the nucleus gracilis (Al-Chaer, E. D. et al., 1997). Responses of cells in the nucleus gracilis have been recorded after noxious stimulation of either the colon or the pancreas (Al-Chaer, E. D. et al., 1996b; 1997; Houghton, A. K. et al., 2001).

36.2.3.3 Effects of a dorsal column lesion on behavioral responses

Changes observed in behavioral experiments were consistent with the electrophysiological findings. For example, when a rat is put into an unfamiliar plastic activity box, it moves freely around in the box until it adapts to this new environment. The movements can be tracked automatically by computer. Beams of ultraviolet light cross the plastic box, and whenever a beam is blocked by the animal, this is counted as a movement. Under normal conditions, the exploratory activity gradually decreases over about 45 min. However, if the animal experiences pain, for example, because of the presence of allodynia or hyperalgesia, the exploratory activity decreases more rapidly.

Figure 3 (A) shows the effects of sequential lesions of the dorsal columns (DC) and of the ventrolateral column (VLC) on one side on the responses of a neuron in the rat ventral posterior thalamic nucleus to a graded series of mechanical and visceral stimuli. The filled circle in (a) shows the recording site; the hatched area in (b) the somatic receptive field, and the black areas on a drawing of a transverse section of the spinal cord in (c) the extent of the lesions. Responses to brushing the skin (BR), application of pressure to a fold of skin with an arterial clip (PR) and pinching the skin with a stronger arterial clip (PI) are seen in (d), before and after the lesions. The responses to colorectal distentions of 20, 40, 60, and 80 mmHg are shown in (e), before and after the lesions. The action potential of the thalamic neuron at different times during the experiment is illustrated in (f) to indicate the stability of the recording. (B) Shows the effects of lesions of the dorsal columns placed in the upper cervical spinal cord at the midline or bilaterally just ventral to the dorsal intermediate sulci on the responses of a neuron in the rat ventral posterior lateral nucleus. In (a), upper row of records, are shown the responses of the neuron to graded distensions of the duodenum. The volumes of fluid injected into a balloon at the end of a catheter inserted into the duodenum are indicated in ml. The middle row of records (b) was taken after a midline lesion was made in the dorsal columns. The lesion had no clear effect. The lower row of records (c) shows that bilateral lesions of the dorsal columns ventral to the dorsal intermediate sulci substantially reduced the responses. The action potential of the thalamic neuron at different times during the experiment is shown in (b) to indicate the stability of the recording. The midline lesion is indicated by the hatched area and the more laterally placed lesions by the black area in (d). The receptive field of the neuron is shown in (e) and the recording site in (f) (A) From AlChaer, E. D., Lawand, N. B., Westlund, K. N., and Willis, W. D. 1996a. Visceral nociceptive input into the ventral posterolateral nucleus of the thalamus: a new function for the dorsal column pathway. J. Neurophysiol. 76, 2661–2674. (B) From Feng, Y., Cui, M., Al-Chaer, E. D., and Willis, W. D. 1998. Epigastric antinociception by cervical dorsal column lesions in rats. Anesthesiology 89, 411–420.

534 Dorsal Columns and Visceral Pain

Exploratory activity is also reduced in rats with pancreatitis (Houghton, A. K. et al., 1997), and this reduction is counteracted following a lesion of the dorsal columns. Similarly, infusion of bradykinin into the common bile and pancreatic duct in rats results in a reduction in rearing behavior, and this vertical exploratory behavior is increased after a dorsal column lesion (Houghton, A. K. et al., 2001). Since the pancreas is an intra-abdominal organ, rather than a pelvic organ, the dorsal column had to be interrupted bilaterally and it included the areas ventral to the dorsal intermediate sulci (see below and Wang, C. C. et al., 1999). Feng Y. et al. (1998) inserted a balloon into the duodenum through a catheter. Distention of the balloon resulted in contractions of the abdominal muscles that were graded in force depending on the amount of balloon distention. Interruption of the dorsal columns resulted in a reduction in these abdominal muscle contractions. The role of the dorsal column versus that of the spinothalamic tract and associated pathways was tested by Palecek J. et al. (2002). Exploratory activity of rats was shown to be reduced following either an intradermal injection of capsaicin (Figure 4(a)) or by inflammation of the colon with mustard oil, coupled with a mild degree of colorectal distention (Figure 4(c)). The effects of a capsaicin injection on exploratory activity could be reversed by dorsal rhizotomies on the side of the injection or by a lesion of the ventrolateral column of the spinal cord on the side opposite to the injection, but not by a bilateral lesion of the dorsal column (Figure 4(b)). By contrast, the effects of colon inflammation and distention on exploratory activity were eliminated by a bilateral lesion of the dorsal columns, and this change persisted for at least 90 days (Figure 4(d)). 36.2.3.4 Effects of a dorsal column lesion on the regional cerebral blood flow changes that result from colorectal distention in monkeys

In each of four monkeys anesthetized with isoflurane, it was possible to survey the changes in regional cerebral blood flow that were produced by colorectal distention, using a 4.7 T magnet for functional magnetic resonance imaging (Willis, W. D. et al., 1999). The images were averaged over a standard period of time with or without visceral distention. The intensity of the colorectal distention was to 80 mm of Hg, well into the noxious range. Images through a coronal section of the brain at the level

of the posterior thalamus were compared, before and after surgery (Figure 5). In one animal, sham surgery was done over the dorsal column, but no lesion was made (Figure 5, left-most images). In the other three animals, the dorsal columns were interrupted at a mid-thoracic level. At various times after recovery from the surgery, the animals were re-anesthetized and fMRIs repeated at several intervals up to 4 months after the surgery. The sham surgery had no obvious effect on the regional cerebral blood flow produced by noxious colorectal distention. However, the lesion of the dorsal columns completely eliminated the blood flow changes in all three animals, and this effect of the lesion persisted for as long as the animals were followed (Figure 5). 36.2.3.5 Blockade of synaptic relay in sacral cord by morphine or 6-cyano-7nitroquinoxaline-2,3-dione

The experiments described above indicate that the dorsal columns contain axons that signal visceral pain. However, a lesion of the dorsal columns interrupts not only the ascending branches of dorsal root ganglion cells that project to the dorsal column nuclei but also axons belonging to the postsynaptic dorsal column pathway (reviewed in Willis, W. D. and Coggeshall, R. E, 2004). An experiment was therefore designed to determine if noxious visceral signals are conveyed by the direct dorsal column projection or by postsynaptic dorsal column neurons (Al-Chaer, E. D. et al., 1996b). The experimental arrangement is shown in Figure 6. Recordings were made from the nucleus gracilis, rather than from the thalamus, to avoid the complication of visceral signals conveyed by the spinothalamic and accompanying pathways, as well as by the dorsal columns. The visceral stimulus was graded colorectal distention. The location of the part of the spinal cord that relayed the information to the medulla was restricted to the sacral segments by transecting the hypogastric nerves bilaterally. A microdialysis fiber was inserted across the sacral cord in order to introduce drugs into the dorsal horn that could block synaptic transmission but that would not interfere with direct nerve impulse transmission. The drugs included morphine and the non-N-methylD-aspartic acid (NMDA) glutamate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). The prediction was that these drugs would prevent the responses of neurons of the gracile nucleus to colorectal distention if postsynaptic dorsal column neurons were responsible for the responses, but not

Dorsal Columns and Visceral Pain

(a) 400

CAP

Entries

200

(b) 600

RHIZ-I

Entries

400

535

200 0 600

0 Distance traveled

1000

Entries

400

RHIZ-C

200

500

0

0

600

3000

400

2000

Entries

STT-C

Entries

STT-I

200

1000

Resting

0

10

20

0 40 50 600 Time (min.) 400

30

200 0 600

CONTROL SURG. CONTROL CAP 0.5h CAP 24h

Entries

400 200 0 0

(c)

10

20

(d) 600

600 Entries

400

DC

COLON

200

30

50 40 Time (min.) DC

Entries

400 200

0

0 600

2000

Distance traveled

Entries

DC 90

Entries

DC 180

400

1000

200

0 3000

0 600

2000

400 200

1000

Resting

0 0

10 CONTROL

20

30

40 50 Time (min.)

SURG. CON.

0

0

10

20

COLON 0.5h

30

50 40 Time (min.) COLON 24h

Figure 4 Time course of exploratory activity as monitored by a computer after introduction of rats into an activity box. The level of exploratory activity is determined by the number of interruptions of infrared light beams over a period of 45 min after the rat was placed in the activity box. The parameters included number of entries into a different zone, total distance traveled, and resting time. In (a) and (b), an intradermal injection of capsaicin was given, whereas in (c) and (d) mustard oil was injected into the colon and a latex balloon inserted and inflated to a pressure of 30 mmHg. At 30 min following either stimulus, exploratory activity was tested. Note that in (a), the capsaicin (CAP) injection resulted in a significant reduction in exploratory activity (and increased resting time). In (b), this was prevented by a prior extensive dorsal rhizotomy on the side ipsilateral to the injection (RHIZ-I), but was unaffected by a contralateral dorsal rhizotomy (RHIZ-C). A lesion that interrupted the spinothalamic tract contralateral to the injection (STT-C) also eliminated the reduction in exploratory activity following CAP, whereas an ipsilateral cordotomy (STT-I) had no effect; nor did a bilateral dorsal column (DC) lesion. In (c), colon inflammation and distention reduced the exploratory activity, and in (d) this change was eliminated by a dorsal column (DC) lesion. The effect lasted for 90 (DC 90) and 180 (DC 180) days. From Palecek, J., Paleckova, V., and Willis, W. D. 2002. The roles of pathways in the spinal cord lateral and dorsal funiculi in signaling nociceptive somatic and visceral stimuli in rats. Pain 96, 297–307.

536 Dorsal Columns and Visceral Pain

Figure 5 Functional magnetic resonance imaging showing the changes in regional cerebral blood flow in the brains of four different monkeys in coronal slices made at the level of the posterior thalamus. The blood flow changes were evoked by repeated colorectal distention to 80 mmHg under isoflurane anesthesia. The images in the upper row were made prior to surgery. Those in the lower row were from the same animals but after surgery. The animal whose images are shown at the left was subjected to sham surgery: the dorsal column was exposed at a mid-thoracic level, but no lesion was made. In the other three animals, the dorsal columns were interrupted at a mid-thoracic level. There was no obvious difference in regional blood flow changes in the animal with sham surgery, but the blood flow changes in the other animals were completely eliminated (previously unpublished data.).

if the direct dorsal column pathway were involved. This was important, since it was conceivable that noxious visceral signals could be transmitted to the dorsal column nuclei by unmyelinated, peptidergic branches of dorsal root ganglion neurons. Such fibers have been demonstrated, although the functions of these axons are still unknown (see Willis, W. D. and Coggeshall, R. E., 2004). The results of this experiment indicated that the postsynaptic dorsal column pathway is responsible for the visceral pain signals that ascend in the dorsal columns. Both morphine and CNQX blocked visceral nociceptive transmission from the colon to the gracile nucleus, and the effects of morphine were reversed by naloxone, indicating that the morphine acted on opiate receptors (Figure 7). The CNQX must have exerted its effect by blocking a critical synaptic relay that involves non-NMDA glutamate receptors. 36.2.3.6 Projections of the postsynaptic dorsal column pathway

The course of the ascending axons of postsynaptic dorsal column neurons in the sacral spinal cord was traced using the Phaseolus vulgaris leukoagglutinin (PHA-L) anterograde tracing technique and compared with the projections from postsynaptic dorsal column neurons in the mid-thoracic spinal cord (Wang, C. C. et al., 1999). Injections of PHA-L were made into the central region of the spinal cord for several reasons. This area is known to receive visceral afferent input (Honda, C. N., 1985; Sugiura, Y. et al., 1989), and recordings had been

made in this region from a number of postsynaptic dorsal column neurons that responded to noxious visceral stimuli (Al Chaer, E. D. et al., 1996a; 1996b). Many cells around the central canal have ascending projections in the dorsal columns that are labeled following injections of retrograde tracer into the dorsal column nuclei or the dorsal column itself (Hirshberg, R. M. et al., 1996). The nociceptive visceral information is likely to be relayed from the dorsal column nuclei to the lateral thalamus by way of the medial lemnsicus. However, recent observations indicate that many postsynaptic dorsal column neurons that are activated by noxious visceral stimuli are also located in the nucleus proprius of the spinal cord dorsal horn (Palecek, J. et al., 2003b), presumably adjacent to postsynaptic dorsal column neurons that lack visceral input (Figure 8). Postsynaptic dorsal column neurons in lamina X of the sacral cord were found to project their axons through the medial part of the fasciculi gracilis to the nuclei gracilis (Figure 2(b); Wang, C. C. et al., 1999). Thus, the projections of these postsynaptic dorsal column cells are in exactly the position in the medial posterior columns that was targeted by the Hitchcock procedure (Hitchcock, E. 1970; 1974; 1977) and by limited midline myelotomy (see Hirshberg, R. M. et al., 1996; Nauta, H. J. W. et al., 1997; 2000). These axons would also be interrupted by a commissural myelotomy. However, axons that ascend from postsynaptic dorsal column neurons in the mid-thoracic cord to the lateral part of the gracilis

Dorsal Columns and Visceral Pain

537

NG

DC–T10

h.n.

S1

Microdialysis fiber

p.n.

Figure 6 Drawing of the experimental arrangement. Recordings were made of the responses of neurons in the nucleus gracilis (NG, upper right) in response to colorectal distension. This avoided the problem that would have been encountered with thalamic recordings, since neurons of the ventral posterior lateral nucleus could be affected by either the dorsal column pathway or the spinothalamic tract. The input from the colon to the spinal cord was limited to just that traversing the pelvic nerve and ending in the sacral spinal cord. This was done by sectioning the hypogastric nerves prior to the experiment. A microdialysis fiber was placed across the spinal cord at S1 so that drugs that are likely to block synaptic transmission in the dorsal horn could be administered locally. Access to the dorsal column (DC) at T10 permitted a test of the effect of a dorsal column lesion. From Al-Chaer, E. D., Lawand, N. B., Westlund, K. N., and Willis, W. D. 1996a. Visceral nociceptive input into the ventral posterolateral nucleus of the thalamus: a new function for the dorsal column pathway. J. Neurophysiol. 76, 2661–2674.

nucleus and the medial part of the cuneate nucleus do so near the dorsal intermediate septum (Figure 2(b); Wang, C. C. et al., 1999). Thus, there appears to be a viscerotopic organization of this visceral pathway similar to that of the somatosensory part of the postsynaptic dorsal column pathway (see Willis, W. D. and Coggeshall, R. E., 2004). The results of the studies of stimulation of internal organs of the abdomen described above by Houghton A. K. et al. (1997; 2001) and Feng Y. et al.(1998) are consistent with this observation. In these studies, distention or chemical irritation of abdominal viscera was used to activate neurons in the rat ventral posterior lateral nucleus. Lesions placed in the dorsal column at the midline

failed to influence the responses. However, lesions lateral to the midline in the area of the dorsal intermediate septum were effective. Clinical studies from a group in Korea (Kim, Y. S. and Kwon, S. J., 2000) report favorable results in patients experiencing stomach cancer pain when lesions were made near the incoming thoracic dorsal root fibers rather than at the midline. This indicates that the viscerotopic organization is similar in humans and animals and that offmidline myelotomies will offer better relief of thoracic or upper abdominal visceral pain than do midline myelotomies.

538 Dorsal Columns and Visceral Pain

(a)

(b)

(c) Control BR

100 75 50 25 0

PR

PI

(d)

(e)

Rate (spikes s–1)

Morphine 100 75 50 25 0 Naloxone 100 75 50 25 0 CNQX 100 75 50 25 0 0 10 20 30 40 50 60 70 Time (s)

0

20

40

60

20

0

20

40

40

60 0 Time (s)

20

40

60

60

0

20

40

60

80 mm Hg

Figure 7 Effects of morphine and CNQX administered into the sacral cord by microdialysis on the responses of a neuron in the gracile nucleus to graded somatic and visceral stimuli. (a) Shows the recording site in the gracile nucleus. (b) Indicates the receptive field of the gracile neuron. In (c) are the responses of the gracile neuron to BR, PR, and PI stimuli applied to the cutaneous receptive field. (d) Shows the responses to graded colorectal distention to 20, 40, 60, and 80 mmHg. The upper row of recordings in (c) and (d) are the control responses taken before administration of drugs. The second row of recordings shows the effects of morphine given by microdialysis. There was little, if any, change in the responses to the somatic stimuli, but the responses to colorectal distention were eliminated. The third row of recordings shows that systemically administered naloxone counteracted the effects of morphine. The lowest row of recordings shows the effect of CNQX in blocking the responses to colorectal distention. In (e) are action potentials recorded at different times during the experiment to show the stability of the recordings. From Al-Chaer, E. D., Lawand, N. B., Westlund, K. N., and Willis, W. D. 1996b. Pelvic visceral input into the nucleus gracilis is largely mediated by the postsynaptic dorsal column pathway. J. Neurophysiol. 76, 2675–2690.

36.2.3.7 Upregulation of NK1 receptors in PSDC neurons after colon inflammation

The cells of origin of several nociceptive pathways that ascend from the spinal cord to the brain are known to contain neurokinin-1 (NK-1) receptors (Todd, A. J. et al., 2000). These pathways include the spinothalamic and spinoreticular tracts. However, postsynaptic dorsal horn neurons do not contain NK-1 receptors under normal conditions, although an up-regulation of these receptors does occur in some of these neurons following visceral inflammation (Palecek, J.et al., 2003a). 36.2.3.8 Fos expression in PSDC neurons after noxious visceral stimulation

A comparison was made of the numbers and locations of neurons belonging to the spinothalamic tract and to the

postsynaptic dorsal column pathway that express Fos, the product of the immediate/early gene, c-fos, following either an intradermal injection of capsaicin or distention of the ureter (see Figure 8; Palecek, J. et al., 2003b). The spinothalamic neurons were retrogradely labeled from the contralateral thalamus and the postsynaptic dorsal column neurons from the ipsilateral nucleus gracilis. Ureter distention was accomplished by tightening a ligature that had previously been placed around the ureter. The ureter was distended proximal to the site where the ligature blocked the flow of urine. Fos-labeled neurons were distributed over a considerable length of the spinal cord, from T11 to L6. This study confirmed that spinothalamic tract cells can be activated by a noxious visceral stimulus and that postsynaptic dorsal column neurons are also activated by such stimuli.

Dorsal Columns and Visceral Pain

Th4

A Fos–

PSDC

B Fos+

Ureter

C Fos+

STT

539

D Fos–

Th11 Th12 Th13 L1 L2 L3 L4

L5

L6

Figure 8 Effect of distention of the ureter in evoking expression of Fos protein in identified projection neurons in rats. Postsynaptic dorsal column neurons were labeled retrogradely following injection of a tracer into the nucleus gracilis (leftmost column), and spinothalamic neurons were identified following injection of a different retrograde tracer into the ventral posterior lateral nucleus of the thalamus (right-most column). The middle columns show neurons identified by retrograde labeling that were also labeled for Fos protein following distention of the ureter. From Palecek, J., Paleckova, V., and Willis, W. D. 2003b. Fos expression in spinothalamic and postsynaptic dorsal column neurons following noxious visceral and cutaneous stimuli. Pain 104, 249–257.

36.3 Descending Facilitation It has been shown that the responses of spinal cord neurons to visceral stimulation depend in large part on a spino-bulbo-spinal circuit (Cervero, F. and Wolstencroft, J. H., 1984; Tattersall, J. E. et al., 1986; Zhuo, M. and Gebhart, G. F., 2002) that when activated facilitates visceral responses at the spinal cord level. Our anterograde tract tracing studies of the projections from lamina X demonstrate an ascending component that joins the medial edge of the spinothalamic tract (Wang, C. C. et al., 1999). This ascending pathway has terminations in the nucleus raphe magnus, rostral ventromedial medulla, and medial reticular formation. This pathway is the only reported direct input to the nucleus raphe magnus from the spinal cord and is likely to be important for the activation of brainstem facilitatory neurons with axons that descend into the spinal cord to

enhance the responses of spinal cord neurons to noxious visceral stimuli. Palecek J. and Willis W. D. (2003) confirmed that a dorsal column lesion did not affect visceromotor reflex responses under normal conditions (cf., Ness, T. J. and Gebhart, G. F., 1988). However, the enhanced visceromotor responses to graded colorectal distention that followed colon inflammation with mustard oil were reduced or prevented by bilateral lesions of the dorsal columns. This suggests that the visceral reflex is enhanced because of activity induced by the colon inflammation and conveyed to the brainstem by way of the dorsal column. A lesion of the ventrolateral spinal cord eliminated the visceromotor reflex, presumably by interrupting a facilitatory pathway that descends from the brainstem and/or the ascending spinothalamic projection from lamina X. It is our working hypothesis that interruption of the postsynaptic dorsal column pathway by a lesion placed

540 Dorsal Columns and Visceral Pain

in the dorsal columns reduces visceral pain not only because such a lesion prevents visceral pain signals from reaching the thalamus by way of the dorsal column nuclei and medial lemniscus, but also because of a reduction of descending facilitation affecting visceral nociceptive neurons in the spinal cord, including postsynaptic dorsal column and spinothalamic tract neurons.

References Aidar, O., Geohegan, W. A., and Ungewitter, L. H. 1952. Splanchnic afferent pathways in the central nervous system. J. Neurophysiol. 15, 131–138. Al-Chaer, E. D., Feng, Y., and Willis, W. D. 1998. A role for the dorsal column in nociceptive visceral input into the thalamus of primates. J. Neurophysiol. 79, 3143–3150. Al-Chaer, E. D., Feng, Y., and Willis, W. D. 1999. Comparative study of viscerosomatic input onto postsynaptic dorsal column and spinothalamic tract neurons in the primate. J. Neurophysiol. 82, 1876–1882. Al-Chaer, E. D., Lawand, N. B., Westlund, K. N., and Willis, W. D. 1996a. Visceral nociceptive input into the ventral posterolateral nucleus of the thalamus: a new function for the dorsal column pathway. J. Neurophysiol. 76, 2661–2674. Al-Chaer, E. D., Lawand, N. B., Westlund, K. N., and Willis, W. D. 1996b. Pelvic visceral input into the nucleus gracilis is largely mediated by the postsynaptic dorsal column pathway. J. Neurophysiol. 76, 2675–2690. Al-Chaer, E. D., Westlund, K. N., and Willis, W. D. 1997. Nucleus gracilis: an integrator for visceral and somatic information. J. Neurophysiol. 78, 521–527. Amassian, V. E. 1951. Fiber groups and spinal pathways of cortically represented visceral afferents. J. Neurophysiol. 14, 445–460. Ammons, W. S. 1987. Characteristics of spinoreticular and spinothalamic neurons with renal input. J. Neurophysiol. 50, 480–495. Ammons, W. S. 1989. Primate spinothalamic cell responses to ureteral occlusion. Brain Res. 496, 124–130. Ammons, W. S., Blair, R. W., and Foreman, R. D. 1984. Responses of primate T1-T5 spinothalamic neurons to gallbladder distension. Am. J. Physiol. 247, R995–R1002. Armour, D. 1927. Surgery of the spinal cord and its membranes. Lancet i, 691–697. Becker, R., Gatscher, S., Sure, U., and Bertalanffy, H. 2002. The punctuate midline myelotomy concept for visceral cancer pain control- case report and review of the literature. Acta Neurochir. Suppl. 79, 77–78. Becker, R., Sure, U., and Bertalanffy, H. 1999. Punctate midline myelotomy. A new approach in the management of visceral pain. Acta Neurochir. (Wien) 141, 881–883. Bernard, J. F., Huang, G. F., and Besson, J. M. 1994. The parabrachial area: electrophysiological evidence for an involvement in visceral nociceptive processes. J. Neurophysiol. 71, 1646–1660. Blair, R. W., Ammons, W. S., and Foreman, R. D. 1984. Responses of thoracic spinothalamic and spinoreticular cells to coronary artery occlusion. J. Neurophysiol. 51, 636–648. Bru¨ggemann, J., Shi, T., and Apkarian, A. V. 1994. Squirrel monkey lateral thalamus. II. Viscero-somatic convergent representation of urinary bladder, colon and esophagus. J. Neurosci. 14, 6796–6814. Bushnell, M. C., Duncan, G. H., and Tremblay, N. 1993. Thalamic VPM nucleus in the behaving monkey. I.

Multimodal and discriminative properties of thermosensitive neurons. J. Neurophysiol. 69, 739–752. Casey, K. L. and Bushnell, M.C. (eds.) (2000) Pain Imaging. IASP Press. Cervero, F. and Wolstencroft, J. H. 1984. A positive feedback loop between spinal cord nociceptive pathways and antinociceptive areas of the cat’s brain stem. Pain 20, 125–138. Chandler, M. J., Hobbs, S. F., Qing-Gong, Fu., Kenshalo, D. R., Blair, R. W., and Foreman, R. D. 1992. Responses of neurons in ventroposterolateral nucleus of primate thalamus to urinary bladder distension. Brain Res. 571, 26–34. Chung, J. M., Lee, K. H., Surmeier, D. J., Sorkin, L. S., Kim, J., and Willis, W. D. 1986. Response characteristics of neurons in the ventral posterior lateral nucleus of the monkey thalamus. J. Neurophysiol. 56, 370–390. Dargent, M., Mansuy, L., Cohen, J., and De Rougemont, J. 1963. Les problems poses par la douleur dans l’evolution des cancers gyne´cologiques. Lyon chirurg. 59, 62–83. Eiras, J., Garcia, J., Gomez, J., Carvavilla, L. I., and Ucar, S. 1980. First results with extralemniscal myelotomy. Acta Neurochir. Suppl. 30, 377–381. Feng, Y., Cui, M., Al-Chaer, E. D., and Willis, W. D. 1998. Epigastric antinociception by cervical dorsal column lesions in rats. Anesthesiology 89, 411–420. Filho, O. V., Araujo, M. R., Florencio, R. S., Silva, M. A. C., and Silveira, M. T. 2001. CT-guided percutaneous punctuate midline myelotomy for the treatment of intractable visceral pain: a technical note. Stereotact. Funct. Neurosurg. 77, 177–182. Foerster, O. and Gagel, G. 1932. Die Vorderseitenstrangdurchschneidung beim Menschen: Eine klinisch-pathophysioligisch-anatomische Studie. Z. Ges. Neurol. Psychiat. 138, 1–92. Foreman, R. D. 1989. Organization of the spinothalamic tract as a relay for cardiopulmonary sympathetic afferent fiber activity. In: Progress in Sensory Physiology (ed. D. Ottoson), Vol. 9, pp. 1–51. Springer. Foreman, R. D., Hancock, M. B., and Willis, W. D. 1981. Responses of spinothalamic tract cells in the thoracic spinal cord of the monkey to cutaneous and visceral inputs. Pain 11, 149–162. Gildenberg, P. L. and Hirshberg, R. M. 1984. Limited myelotomy for the treatment of intractable cancer pain. J. Neurol. Neurosurg. Psychiat. 47, 94–96. Gybels, J. M. and Sweet, W. H. 1989. Neurosurgical Treatment of Persistent Pain. Karger. Hancock, M. B., Foreman, R. D., and Willis, W. D. 1975. Convergence of visceral and cutaneous input onto spinothalamic tract cells in the thoracic spinal cord of the cat. Exp. Neurol. 47, 240–248. Head, H. 1893. On disturbances of sensation with especial reference to the pain of visceral disease. Brain 16, 1–132. Hirshberg, R. M., Al-Chaer, E. D., Lawand, N. B., Westlund, K. N., and Willis, W. D. 1996. Is there a pathway in the posterior funiculus that signals visceral pain? Pain 47, 291–305. Hitchcock, E. 1970. Stereotactic cervical myelotomy. J. Neurol. Neurosurg. Psychiat. 33, 224–230. Hitchcock, E. 1974. Stereotactic myelotomy. Proc. R. Soc. Med. 67, 771–772. Hitchcock, E. 1977. Stereotactic spinal surgery. Neurol. Surg. 433, 271–280. Hobbs, S. F., Oh, U. T., Brennan, T. J., Chandler, M. J., Kim, K. S., and Foreman, R. D. 1990. Urinary bladder and hindlimb stimuli inhibit T1–T6 spinothalamic and spinoreticular cells. Am. J. Physiol. 258, R10–R20. Honda, C. N. 1985. Visceral and somatic afferent convergence onto neurons near the central canal in the sacral spinal cord of the cat. J. Neurophysiol. 53, 1059–1078.

Dorsal Columns and Visceral Pain Houghton, A. K., Kadura, S., and Westlund, K. N. 1997. Dorsal column lesions reverse the reduction in homecage activity in rats with pancreatitis. NeuroReport 8, 3795–3800. Houghton, A. K., Wang, C. C., and Westlund, K. N. 2001. Do nociceptive signals from the pancreas travel in the dorsal column? Pain 89, 207–220. Hu, J. S. and Li, Y. J. 2002. Clinical application of midline myelotomy to treat visceral cancer pain. Natl. Med. J. China 82, 856–867 (in Chinese). Hwang, S. L., Lin, C. L., Lieu, A. S., Kuo, T. H., Yu, K. L. K., OuYang, F., Wang, S. N., Lee, K. T., and Howng, S. L. 2004. Punctate midline myelotomy for intractable visceral pain caused by hepatobiliary or pancreatic cancer. J. Pain Symptom Management 27, 79–84. Katter, J. T., Dado, R. J., Kostarczyk, E., and Giesler, G. J. 1996. Spinothalamic and spinohypothalamic tract neurons in the sacral spinal cord of rats. II. Responses to cutaneous and visceral stimuli. J. Neurophysiol. 75, 2606–2628. Kenshalo, D. R., Giesler, G. J., Leonard, R. B., and Willis, W. D. 1980. Responses of neurons in primate ventral posterior lateral nucleus to noxious stimuli. J. Neurophysiol. 43, 1594–1614. Kim, Y. S. and Kwon, S. J. 2000. High thoracic midline dorsal column myelotomy for severe visceral pain due to advanced stomach cancer. Neurosurgery 46, 85–92. Lee, J. I., Antezanna, D., Dougherty, P. M., and Lenz, F. A. 1999. Responses of neurons in the region of the thalamic somatosensory nucleus to mechanical and thermal stimuli graded into the painful range. J. Comp. Neurol. 410, 541–555. Lee, J. I., Ohara, S., Dougherty, P. M., and Lenz, F. A. 2005. Pain and temperature encoding in the human thalamic somatic sensory nucleus (ventral caudal): inhibition-related bursting evoked by somatic stimuli. J. Neurophysiol. 94, 1676–1687. Mansuy, L., Lecuire, J., and Acassat, L. 1944. Technique de la mye´lotomie commissurale poste´rieure. J. Chir. 60, 206–213. Mansuy, L., Sindou, M., Fischer, G., and Brunon, J. 1976. La cortotomie spino-thalamique dans les douleurs cance´reuses. Re´sultats d’une se´rie de 124 malades operas par abord direct poste´rieur. Neuro-chirurgie 22, 437–444. Mehler, W. R. 1962. The anatomy of the so-called ‘‘pain tract’’ in man: analysis of the course and distribution of the ascending fibers of the fasciculus anterolateralis. In: Basic Research in Paraplegia (eds. J. D. French and R. W. Porter), pp. 26–55. Thomas. Menetrey, D. and De Pommery, J. 1991. Origins of spinal ascending pathways that rech central areas involved in visceroception and visceronociception in the rat. Eur. J. Neurosci. 3, 249–259. Milne, R. J., Foreman, R. D., Giesler, G. J., and Willis, W. D. 1981. Convergence of cutaneous and pelvic visceral nociceptive input onto primate spinothalamic neurons. Pain 11, 163–183. Nathan, P. W., Smith, M., and Deacon, P. 2001. The crossing of the spinothalamic tract. Brain 124, 793–803. Nauta, H. J. W., Hewitt, E., Westlund, K. N., and Willis, W. D. 1997. Surgical interruption of a midline dorsal column visceral pain pathway: case report and review of the literature. J. Neurosurg. 86, 538–542. Nauta, H. J. W., Soukup, V. M., Fabian, R. H., Lin, J. H. T., Grady, J. J., Williams, C. G. A., Campbell, G. A., Westlund, K. N., and Willis, W. D. 2000. Punctate mid-line myelotomy for the relief of visceral cancer pain. J. Neurosurg. (Spine 1) 92, 125–130. Ness, T. J. and Gebhart, G. F. 1988. Colorectal distention as a noxious visceral stimulus: physiologic and pharmacologic characterization of pseudoaffective reflexes in the rat. Brain Res. 450, 153–169. Palecek, J. and Willis, W. D. 2003. The dorsal column pathway facilitates visceromotor responses to colorectal distention after colon inflammation in rats. Pain 104, 501–507.

541

Palecek, J., Paleckova, V., and Willis, W. D. 2002. The roles of pathways in the spinal cord lateral and dorsal funiculi in signaling nociceptive somatic and visceral stimuli in rats. Pain 96, 297–307. Palecek, J., Paleckova, V., and Willis, W. D. 2003a. Postsynaptic dorsal column neurons express NK1 receptors following colon inflammation. Neuroscience 116, 565–572. Palecek, J., Paleckova, V., and Willis, W. D. 2003b. Fos expression in spinothalamic and postsynaptic dorsal column neurons following noxious visceral and cutaneous stimuli. Pain 104, 249–257. Papo, L. and Luongo, A. 1976. High cervical commissural myelotomy in the treatment of pain. J. Neurol. Neurosurg. Psychiat. 39, 705–710. Puletti, F. and Blomqvist, A. J. 1967. Single neuron activity in posterior columns of the human spinal cord. J. Neurosurg. 27, 255–259. Ren, Y., Lu, Y., Yang, H., and Westlund, K. N. Responses of neurons in central lateral thalamic nucleus to mechanical and chemical visceral stimulation in rats. APS Abstracts, American Pain Society, 2006. Rigamonti, D. D. and Hancock, M. B. 1974. Analysis of field potentials elicited in the dorsal column nuclei by splanchnic nerve A-beta afferents. Brain Res. 77, 326–329. Rigamonti, D. D. and Hancock, M. B. 1978. Viscerosomatic convergence in the dorsal column nuclei of the cat. Exp. Neurol. 61, 337–348. Sar, M., Stumpf, W. E., Miller, R. J., Chang, K.-J., and Cuatrecasas, P. 1978. Immunohistochemical localization of enkephalin in rat brain and spinal cord. J Comp. Neurol. 182, 17–38. Schvarcz, J. R. 1977. Functional exploration of the spinomedullary junction. Acta Neurochir. Suppl. 24, 179–185. Schvarcz, J. R. 1978. Spinal cord stereotactic techniques re trigeminal nucleotomy and extralemniscal myelotomy. Appl. Neurophysiol. 41, 99–112. Sourek, K. 1985. Central thermromyelo-coagulation for intractable chronic pain and opioid peptides. In: 8th International Congress of Neurological Surgery, Toronto, 1985, Abstract 221. Spiller, W. G. 1905. The occasional clinical resemblance between caries of the vertebrae and lumbothoracic syringomyelia and the location within the spinal cord of the fibres for the sensations of pain and temperature. Univ. Pennsylvania Med. Bull. 18, 147–154. Spiller, W. G. and Martin, E. 1912. The treatment of persistent pain of organic origin in the lower part of the body by division of the anterolateral column of the spinal cord. JAMA 58, 1489–1490. Sugiura, Y., Terui, N., and Hossoya, Y. 1989. Difference in distribution of central terminals between visceral and somatic unmyelinated (C) primary afferent fibers. J. Neurophysiol. 62, 834–840. Tattersall, J. E., Cervero, F., and Lumb, B. M. 1986. Effects of reversible spinalization on the visceral input to viscerosomatic neurons in the lower thoracic spinal cord of the cat. J. Neurophysiol. 56, 785–796. Todd, A. J., McGill, M. M., and Shehab, S. A. 2000. Neurokinin 1 receptor expression by neurons in laminae I, III and IV of the rat spinal dorsal horn that project to the brainstem. Eur. J. Neurosci. 12, 689–700. Wang, C. C., Willis, W. D., and Westlund, K. N. 1999. Ascending projections from the central, visceral processing region of the spinal cord: a PHHA-L study in rats. J. Comp. Neurol. 415, 341–367. Willis, W. D. and Coggeshall, R. E. 2004. Sensory Mechanisms of the Spinal Cord, 3rd edn. Kluwer Academic/Plenum. Willis, W. D. and Westlund, K. N. 1997. Neuroanatomy of the pain system and of the pathways that modulate pain. J. Clin. Neurophysiol. 14, 2–31.

542 Dorsal Columns and Visceral Pain Willis, W. D., Al-Chaer, E. D., Quast, M. J., and Westlund, K. N. 1999. A visceral pain pathway in the dorsal column of the spinal cord. Proc. Natl. Acad. Sci. U. S. A. 96, 7675–7679. Zhang, X., Gokin, A. P., and Giesler, G. J. 2002. Responses of spinohypothalamic tract neurons in the thoracic spinal cord

of rats to somatic stimuli and to graded distention of the bile duct. Somatosens. Mot. Res. 19, 5–17. Zhuo, M. and Gebhart, G. F. 2002. Facilitation and attenuation of a visceral nociceptive reflex from the rostroventral medulla in the rat. Gastroenterology 122, 1007–1019.

37 Visceral Pain G F Gebhart and K Bielefeldt, University of Pittsburgh, Pittsburgh, PA, USA ª 2009 Elsevier Inc. All rights reserved.

37.1 37.2 37.2.1 37.2.2 37.2.3 37.2.4 37.2.4.1 37.2.4.2 37.2.4.3 37.3 37.3.1 37.3.1.1 37.3.1.2 37.3.1.3 37.3.2 37.3.3 37.4 37.4.1 37.4.2 37.4.3 37.5 References

Introduction Visceral Sensation Organization of Visceral Sensory Innervation Visceral Nociceptors and Sensory Endings Chemical Character of Visceral Sensory Neurons Central Organization of Visceral Pain Vagus nerves Spinal nerves Spinal pathways and supraspinal terminations Functional Basis of Visceral Pain Visceral Mechanoreceptors and Mechano-Nociceptors Afferent fiber recordings Information acquired in vitro Gene deletions, visceral pain, and mechanosensation Sleeping (Silent) Nociceptors Visceral Chemo-Nociception Visceral Hypersensitivity Sensitization and Excitability of Visceral Nociceptors Central Sensitization Central Modulation of Visceral Pain Summary

Glossary referred visceral pain Visceral pain is not generally felt at the source, but rather is perceived as arising from other tissues (skin and/or muscle) innervated by non-visceral nerves having input onto second-order spinal neurons that converges with input from visceral organs onto the same spinal neurons. Accordingly, visceral pain is commonly referred (or transferred, an older terminology) to non-visceral tissues. nociceptor sensitization Sensitization of nociceptors reflects a change in their excitability expressed as an increase in response magnitude to a noxious intensity of stimulation accompanied by a reduction in threshold stimulus intensity required to activate the nociceptor. visceral nociceptors Sensory endings in viscera which, when activated by an adequate stimulus

544 544 545 545 547 549 549 549 550 551 552 552 553 556 557 558 559 560 561 563 564 565

(stretch/tension, ischemia, inflammatory mediators), commonly give rise to sensations of discomfort and pain. visceral hypersensitivity Increased sensitivity or response to a visceral stimulus, which can arise from sensitization of visceral sensory endings (e.g., visceral mechanoreceptors), sensitization of central nervous system neurons receiving increased input from sensitized visceral sensory endings, or a combination of both. Clinically, visceral hypersensitivity is associated with discomfort or pain produced by normally non-painproducing stimuli (e.g., ingestion of food, normal bladder fillling) and commonly includes increased sensitivity to probing in the areas of referred visceral sensation, which moreover are increased in size (area).

543

544 Visceral Pain

37.1 Introduction Of all possible sources of pain within the body, pain arising from internal organs commonly generates the greatest autonomic and emotional responses. This is linked to several characteristics of visceral pain, the most apparent being that the source of pain is neither visible nor typically felt at the source. Visceral pain also is commonly diffuse in character and poorly localized. In addition, it is also referred (or transferred) to nonvisceral, somatic structures (like skin and muscle), and there is considerable overlap in areas of referred pain from adjacent organs. For example, sites of referral from thoracic and abdominal organs (esophagus, gallbladder, and heart) overlap, making it difficult for both physicians and patients to determine the source of pain. That diffuse substernal chest pain has high emotional valence is readily appreciated, given the potential significance of such pain. Similarly, pelvic genitourinary organs have overlapping patterns of referral with the distal colon. It is also characteristic of visceral pain that the areas of referred sensation increase in size and sensitivity in organ inflammation and disease. For example, repetitive episodes of angina lead to increased tenderness (hyperalgesia) of chest and shoulder skin and abdominal tenderness spreads and increases in area in interstitial cystitis and irritable bowel syndrome (IBS). Distinct from cutaneous, muscle, or joint pain, tissue-damaging stimuli do not commonly produce pain when applied to the viscera. Tissue crushing, cutting, or burning stimuli applied to visceral tissue generally produce little conscious sensation and rarely produce pain. Instead, stretch of the smooth muscle layers of hollow organs (e.g., by distension), traction on the mesentery, ischemia, and inflammation are more reliably uncomfortable or pain-producing in viscera. The bases of the above attributes of visceral pain and unique features that distinguish visceral from nonvisceral pain are the focus of this chapter.

37.2 Visceral Sensation The viscera are invested with a wide range of sensory receptors, although when activated in healthy organs they do not generally give rise to conscious sensation. This raises the issue of whether these neurons are afferent or sensory, which is considered below in

Section 37.3. We are generally unaware of movement of air in and out of the lungs, blood flowing through vessels, beating of the heart, or food in the stomach despite the fact that sensory receptors in the bronchial tree, lungs, vessels, heart, esophagus, and stomach are activated by these events. Information from activation of visceral sensory neurons is faithfully transmitted to the central nervous system, but rarely is perceived. Rather, activation of most visceral sensory receptors plays important roles in the regulation and maintenance of many essential functions (e.g., respiration, blood flow, food digestion), which requires rapid feedback to adjust to changes in demand due to exertion, food intake or other activities. While autonomic functions associated with the visceral afferent innervation can influence affective and cognitive processes and are, in turn, influenced by affective and cognitive processes, most of the afferent input from the viscera never reaches consciousness. Visceral events, of course, do lead to conscious sensations. Under physiological conditions, humans perceive a sense of fullness related to organs involved in food intake (i.e., stomach) or waste elimination (rectum and bladder). Aside from these sensations related to functions that trigger intentional changes in behavior, most consciously perceived input from the viscera carries negative connotations, such as nausea, palpitation, dyspnea, discomfort (e.g., overfilling, gas, bloating), and pain. Normally, visceral pain is infrequent, but in cases of functional gastrointestinal disorders (e.g., nonulcer dyspepsia, IBS (see Chapter Irritable Bowel Syndrome), noncardiac chest pain, functional abdominal pain syndrome), interstitial cystitis/painful bladder syndrome, inflammatory visceral disorders (e.g., pancreatitis, inflammatory bowel disease), neoplasias, etc., discomfort and pain are common, persistent, and typically difficult to treat. The so-called functional visceral disorders are characterized by pain and discomfort and enhanced sensitivity to stimuli in the absence of a demonstrable organic cause (i.e., there are no apparent structural, biochemical, or inflammatory conditions to explain the symptoms). Such functional disorders constitute a significant socioeconomic burden worldwide; the estimated prevalence of abdominal pain syndromes can range widely for different specific syndromes, but prevalence rates typically range between 22% and 28% of the adult population (Halder, S. L. and Locke, G. R., 2007). Characteristically, these and other visceral disorders are characterized by hypersensitivity, meaning

Visceral Pain

that normally non-pain-producing visceral events are perceived as uncomfortable or painful, which is likely contributed to by both peripheral and central nervous system mechanisms. 37.2.1 Organization of Visceral Sensory Innervation The viscera are unique among all tissues in the body. Each internal organ is innervated by two nerves, which share some functions, but are not physiologically redundant and include important functional distinctions. Anatomically, the visceral sensory innervation is physically associated with the sympathetic and parasympathetic divisions of the autonomic nervous system. Correspondingly, Langley J. N. (1921) termed visceral afferent fibers associated with sympathetic nerves afferent sympathetic fibers. This sometimes confusing nomenclature has been replaced by use of the name of the nerve (e.g., inferior cardiac, lumbar splanchnic, pelvic), which in addition avoids assigning putative function(s) to the visceral innervation. Given the physical association of the visceral innervation with the autonomic nervous system, visceral afferent fibers are thus contained in nerves that terminate in the spinal cord (spinal nerves) or in the brainstem (vagus nerves). The bilateral vagus nerves are perhaps the most widely distributed nerves in the body. They innervate most internal organs, including all of the thoracic viscera (proximal esophagus, heart, bronchopulmonary system), most of the abdominal viscera (distal esophagus, stomach, small and proximal large intestines, liver, pancreas, etc.), and some of the pelvic viscera. The vagus nerves are mixed and contain both efferent and afferent axons, but most axons in the vagus nerves (80%) are sensory (afferent) fibers and the remainder parasympathetic efferents. The nodose (primarily) and smaller, rostrally located jugular ganglia contain the cell bodies of vagal afferent fibers, most of which terminate bilaterally with some viscerotopic organization in the medullary brainstem nuclei of the solitary tract (NTS). Some vagal afferents, at least in nonhuman primates and rats, project to the upper cervical spinal cord (C1–2), where they may contribute to referred sensations and modulate nociceptive processing within the spinal cord (Foreman, R., 1999). The cell bodies of spinal afferents innervating the viscera are located bilaterally in dorsal root ganglia (DRG) from the cervical to sacral spinal cord. As mentioned above, their axons travel with sympathetic efferent fibers (except for the pelvic nerves)

545

and, thus, traverse pre- and paravertebral ganglia en route to the spinal cord (Figure 1). In prevertebral ganglia, some afferent axons give rise to collateral branches that synapse on intraganglionic neurons and influence organ function (e.g., motility, secretion). 37.2.2 Visceral Nociceptors and Sensory Endings Because tissue-damaging crushing, cutting, or burning stimuli that generate pain from skin do not commonly produce pain when applied to the viscera, it was long argued that the viscera were not innervated, and when visceral innervation was established, it was argued that the viscera were insensate. It is now well established that stimuli adequate for activation of visceral nociceptors differ from those adequate for activation of cutaneous nociceptors. They include distension of hollow organs, traction on the mesentery, ischemia, and inflammation. For example, experimental hollow organ distension reproduces in patients the localization, intensity, and quality of sensations associated with their visceral disorder. Because distension of hollow organs, as well as traction on the mesentery, are mechanical events (stretch), it is assumed that many visceral nociceptors are mechanoreceptors with receptive endings in visceral smooth muscle layers or serosa where they transduce the mechanical energy of tension/stretch into electrical activity (nerve membrane depolarization, action potentials). There are chemo-nociceptors in epithelial and subepithelial layers of visceral organs, but they have not been studied as extensively as have mechanoreceptors and their receptive endings have not been identified as they have for some mechanoreceptors. Virtually all visceral sensory neuron axons are slowly conducting, thinly myelinated A- or unmyelinated C-fibers. Because mechanical events are common in most organs, visceral mechanosensation and endings in muscle layers of hollow organs that respond to tension/stretch have been the focus of most studies. Unfortunately, the morphology of spinal nerve peripheral terminals in organs is virtually unknown; they are assumed to be free without structural specialization. However, two morphologically distinct endings associated principally with vagal afferent endings have been described. Intraganglionic laminar endings (IGLEs), which have been shown to be mechanosensitive, and intramuscular arrays (IMAs) are located in the upper gastrointestinal tract (Zagorodnyuk, V. P. and

546 Visceral Pain

Nodose ganglion

NTS Paravertebral ganglia

Vagus nerve

SCG MCG

Cervical

StG Prevertebral ganglia Thoracic

CG SMG IMG

Lumbar HgN Sacral

MPG

Pelvic nerve

Figure 1 Cartoon illustrating innervation of the viscera. The vagus nerve innervates organs in the thoracic and abdominal cavities. Visceral afferent nerves that terminate in the spinal cord also innervate organs in the thoracic and abdominal cavities as well as those in the pelvic floor, including the genitalia (not shown). The cell bodies of vagal sensory neurons are contained in the nodose and jugular (not shown) ganglia with central terminations bilaterally in the nucleus tractus solitarii (NTS). The cell bodies of spinal visceral sensory neurons are contained in dorsal root ganglia interposed between the paravertebral ganglia (the sympathetic chain) and the spinal cord and are not illustrated in this cartoon. CG, coeliac ganglion; HgN, hypogastric nerve; IMG and SMG, inferior and superior mesenteric ganglia, respectively; MPG, major pelvic ganglion. SCG, superior cervical ganglia; MCG, middle cervical ganglia; StG, stellate cervical ganglia.

Brookes, S. J. H., 2000; Zagorodnyuk, V. P. et al., 2003). As their name indicates, vagal IGLEs appear as branching endings surrounding neurons within a ganglion of the myenteric plexus (Phillips, R. J. and Powley, T. L., 2000; Powley, T. L. and Phillips, R. J., 2002). IGLEs associated with vagal afferent terminals are present throughout much of the gastrointestinal tract, but are most densely distributed in the esophagus, stomach, and duodenum (Wang, F. B. and Powley, T. L., 2000). Like IGLEs, IMAs are also thought to be mechanosensitive, but differ in morphology and distribution from IGLEs. IMAs are long arrays of terminals, typically running parallel with each other and parallel to the orientation of smooth muscle cells. They bridge between the parallel terminals within one of the muscle layers of an organ and form a lattice-like network. IMA distribution within the gastrointestinal tract is more restricted than that of IGLEs; IMAs associated with vagal afferent terminals are present in the stomach (cardia) and sphincters of the upper gastrointestinal tract and are uncommon in the intestines. Although terminal end organs have not

been described for visceral spinal nerves, an IGLE-like low threshold, slowly adapting mechanoreceptor has been reported in the colonic and rectal innervation of the guinea-pig (Lynn, P. A. et al., 2003). Whether activation of either IGLEs or IMAs give rise to visceral pain is uncertain because it would appear, based on their essentially proximal and distal distribution within the gastrointestinal tract and low response threshold, that neither are particularly well suited to that function. Powley T. L. and Phillips R. J. (2002) have speculated that IGLEs detect rhythmic motor activity, which requires response to muscle/ organ tension; IMAs also respond to muscle/organ stretch. However, the association of IMAs with sphincters, and because IGLEs and IMAs have heretofore been best described and characterized in association with vagal afferent endings, suggests a role for these mechanosensors in normal physiological processes (e.g., food intake, defecation) rather than nociception. Recent studies suggest that varicose branch points of spinal afferents within the serosa or deeper layers of the gastrointestinal tract

Visceral Pain

may correspond to fibers activated by high-intensity, noxious mechanical stimuli (Blackshaw, L. A. et al., 2007). 37.2.3 Chemical Character of Visceral Sensory Neurons During ontogeny, sensory neurons develop different phenotypes dependent on their differential sensitivity and exposure to growth factors. As mentioned above, essentially all visceral sensory neurons have unmyelinated or thinly myelinated axons. In DRG, this population of sensory neurons can be separated into two largely distinct groups based on the expression of growth factor receptors or other neurochemical markers (Molliver, D. C. et al., 1997). Small-diameter peptide-containing DRG neurons express the high-affinity receptor for nerve growth factor trkA, the temperature-, proton-, and capsaicinsensitive transient receptor potential vanilloid ion channel (TRPV)1 and the neuropeptides substance P and/or calcitonin gene-related peptide (CGRP). The second group of small-diameter DRG cells depends on glial cell line-derived neurotrophic factor (GDNF) during embryonic development, binds the plant lectin isolectin B4 (IB4) and releases neurotransmitters such as adenosine triphosphate (ATP) rather than peptides as transmitters. Immuno- histochemical studies have consistently shown that about 80% of visceral sensory neurons within the DRG are peptidergic and contain CGRP or substance P. Visceral sensory neurons in the placode-derived nodose ganglia, however, depend on different growth factors during development and show a different distribution of neurochemical markers. While the expression of neuropeptides CGRP and/or substance P is closely associated with the presence of TRPV1 channels in DRG neurons, this does not hold for nodose ganglion neurons; less than 10% express neuropeptides CGRP or substance P, whereas about 50% of nodose neurons exhibit TRPV1-like immunoreactivity. In studies of cutaneous or muscle sensory neurons, expression of TRPV1, CGRP, or the presence of IB4 binding are often used as surrogate markers to classify neurons as nociceptive. As discussed below, 70–80% of mechanosensitive spinal afferents innervating abdominal or pelvic viscera are activated by innocuous intensities of stimulation (i.e., are low-threshold mechanosensors). Most studies of mechanosensitive vagal afferents, however, reveal an even more homogeneous response profile; high-

547

threshold mechanosensitive fibers are rarely found. Thus, peptide expression is a poor predictor of physiological properties of visceral sensory neurons, arguing against the use of neurochemical content as a surrogate indicator of function. Subsequent studies have established by immunohistochemistry, in situ hybridization, and/or current or voltage response to ligands applied directly to cell soma that some visceral sensory neurons also contain other peptides (e.g., vasoactive intestinal polypeptide, cholecystokinin) and express ligand-gated channels and receptors (e.g., different members of the family of transient receptor potential channels, including TRPV1, acid-sensing ion channels (ASICs), both ionotropic and metabotropic glutamate, purinergic, serotoninergic, -aminobutyric acid (GABA)-ergic, and opioid receptors). As information continues to accumulate, it is apparent that there is no marker at present that distinguishes visceral sensory neurons from nonvisceral sensory neurons or visceral nociceptors from nonnociceptors. It could be argued that visceral sensory neuron terminals are generally exposed to a richer chemical milieu than other sensory neurons (and thus express a wider array of receptors and channels, although this has not been quantified). The environments in which visceral sensory endings reside include exposure to acids, digestive enzymes, hormones, nutrients, toxins (ingested or secreted by gut flora, for example), metabolites of xenobiotics, and bioactive chemicals released from nearby enteric nervous system neurons, sympathetic nerve terminals, epithelial cells like enterochromaffin cells in the gut, and urothelial cells in the urinary bladder and mast cells. Visceral sensory neurons have been shown to respond to products released in these environments, including protons, norepinephrine, serotonin, histamine, tryptase, ghrelin, cholecystokinin, and other gastric and duodenal secretions that initiate digestion and motility. In the gastrointestinal tract, serotonin plays an especially important role as a signaling molecule. More than 90% of the body’s serotonin is found within the intestine with most stored in secretory granules on the basolateral side of enteroendocrine cells. These enteroendocrine cells are specialized epithelial cells that can release into the lamina propria a variety of mediators, including serotonin, upon mechanical or chemical stimulation, which secondarily activate extrinsic and intrinsic sensory neurons. Interestingly, the number of enteroendocrine cells increases after intestinal inflammation and remains

548 Visceral Pain

elevated in patients with continuing complaints despite resolution of the inciting infection (Spiller, R. C. et al., 2000), suggesting that serotonin release from enteroendocrine cells is important in the pathogenesis of functional bowel disorders. An example illustrating the importance of luminal factors within the gastrointestinal tract is the interaction between the PAR2 receptor and the pancreatic enzyme trypsin, which is especially relevant under pathologic conditions. The PAR2 receptor is a member of the proteinase-activated receptor (PAR) family, a group of G-protein-coupled receptors characterized by a tethered peptide–ligand that is part of the molecule and can activate the receptor once cleaved from the molecule by specific proteases. The pancreatic protease trypsin is one of the endogenous proteases that cleaves the ligand and thus activates the receptor. Pancreatic acinar cells secrete precursor forms of proteolytic enzymes, such as trypsin, that require activation within the lumen of the small intestine. During pancreatitis, however, activated trypsin is also present in the pancreatic duct and parenchyma. Experimental infusion of trypsin into the pancreatic duct activates pancreatic sensory neurons, most of which express PAR2 immunoreactivity, and triggers aversive behavior in animals. Selective experimental activation of PAR2 receptors mimics this effect, suggesting an important role of PAR2 in pain during acute pancreatitis (Hoogerwerf, W. A. et al., 2001; 2004). Similarly, mouse colon sensory neurons contain immunoreactivity for the PAR2 receptor and PAR2 agonists depolarize those neurons and cause a sustained hyperexcitability (Ahmed, K. et al., 2007). Relevant to IBS, biopsy samples from IBS patients release greater amounts of proteases than do samples from controls (Cenac, N. et al., 2007). Supernatants from colonic biopsies of IBS patients produce visceral hypersensitivity when given intracolonically in control, but not PAR2 knockout mice. Mast cells, which are closely associated with nerves in the human gastrointestinal mucosa (Stead, R. H. et al., 1989), are also a source of tryptase as well as other potential mediators and modulators of visceral sensation (Bueno, L. et al., 1997; Barbara, G. et al., 2006). Mucosal biopsies from IBS patients contained mediators that increased activity in rat mesenteric afferents, an effect inhibited by histamine H1 receptor blockade and serine protease inactivation (Barbara, G. et al., 2007). In the airway system, similarly specialized cells have been identified within the epithelium of the intrapulmonary bronchial tree. Based on their

ultrastructural and neurochemical characteristics with large, dense core vesicles and neuropeptide expression, they are referred to as neuroendocrine cells or neuroendocrine bodies when clustered in small groups (Cutz, E., 1982). Histological studies combining immunohistochemistry, retrograde labeling, and/or vagotomy reveal a complex innervation with vagal and spinal afferents projecting to these cells or cell clusters, where nerve terminals branch with formation of varicosities at branch points (Adriaensen, D. I. et al., 2003). Neuroepithelial bodies likely function as oxygen sensors within the airways as hypoxia inhibits potassium currents (Fu, X. W. et al., 2000). However, acute allergic inflammation triggers depletion of peptides from airway neuroepithelial cells, suggesting a role in broader signaling under physiologic and pathophysiologic conditions (Dakhama, A. et al., 2002). While the expression of one or another receptor or ligand-gated channel of a particular subunit composition may be determined at some future time to identify all or a subset of visceral sensory neurons, one feature of visceral sensory neurons may distinguish them from nonvisceral counterparts, and that is cell size. Cutaneous nociceptors are on the whole associated with thinly myelinated and unmyelinated axons and it is generally the case that these nociceptors have small-diameter cell bodies (e.g., 15– 20 mm). Virtually all visceral sensory neurons have thinly myelinated or unmyelinated axons, yet their cell bodies tend to be medium in size (e.g., 25 mm in diameter), at least those associated with the gastrointestinal tract and urinary bladder. This is of importance when nociceptors are studied and identified principally on the basis of cell diameter because visceral nociceptors are not generally contained in the population of small-diameter sensory neurons assumed to be nociceptors solely because of small diameter. The foregoing addresses, at least indirectly, identification of and assignment of function of sensory neurons, including visceral sensory neurons, based on different properties of the cells: size (diameter), cell content (e.g., peptides), expression of one or another channel or receptor, dependence on exposure during development to different growth factors. Assignment of function based upon one or more of these properties is unfortunately relatively common in the literature, and is both confusing to nondiscriminating readers and misleading. It is not possible at present to assign function (e.g., nociceptor) to a sensory neuron based on any of the above properties. As discussed

Visceral Pain

below, nociceptors, including visceral nociceptors, are defined by response to an adequate stimulus, and even then assignment of function can be difficult, if not contentious, if the quality of the stimulus is uncertain, unknown or of limited physiologic relevance, such as punctate stimulation of viscera.

37.2.4 Pain

Central Organization of Visceral

37.2.4.1

Vagus nerves Although they extensively innervate the viscera, the vagus nerves are generally considered not to play a role in nociception. However, they may contribute to the complex sensory experience of visceral pain, which includes strong autonomic reactions, including nausea or dyspnea. Vagal afferents project to the bilaterally located nuclei of the solitary tract in the dorsal medulla, an important relay station for visceral input. Vagal input reaches more rostral brain structures involved in autonomic regulation, such as the hypothalamus, supraoptic nucleus, and – via the parabrachial nucleus and ventro-medial thalamus – the insular cortex, anterior cingulate cortex, and amygdala, regions that play a role the regulation of affective responses to different stimuli including pain. 37.2.4.2

Spinal nerves Because vagotomy was found to be generally ineffective in relieving visceral pain, whereas spinal nerve transaction or destruction of sympathetic

549

prevertebral ganglia often provided pain relief (at least for a limited period of time), the spinal visceral nerves (sympathetic afferents) were inferred to be the conveyors of nociceptive information from the organs to the spinal cord. Their termination in the spinal cord is noteworthy on several counts. Firstly, spinal visceral afferent fibers terminate in a pattern that largely overlaps with terminations of cutaneous nociceptors: superficial layers of the spinal dorsal horn, deeper in lamina V and dorsal to the central canal, an area often referred to as lamina X. Visceral afferent fibers also terminate within the interomediolateral cell column/sacral parasympathetic nucleus where afferent input influences efferent output back to the same as well as to other organs (Figure 2). Secondly, spinal visceral afferents represent less than 10%, and probably closer to 5%, of the total afferent input into the spinal cord from all tissues. In compensation for this relatively sparse input, the central projection of a single visceral afferent fiber bifurcates at its spinal segment of entry in the dorsal root into caudally and rostrally directed main branches that can extend in either the dorsal funiculus or Lissauer’s tract for two or three spinal segments before penetrating the spinal dorsal horn. In addition, during their longitudinal journey these main branches give off multiple collateral branches into the spinal dorsal horn (superficial laminae and laminae V and X, including contralateral laminae V and X) where, moreover, their number of terminal swellings are greater than found on cutaneous C-fiber

Figure 2 Distribution of visceral afferent terminals in the thoracic and sacral spinal cord. Photomicrographs illustrate internalization of the substance P receptor (yellow) in the superficial dorsal horn and area dorsal to the central canal in rat T13 and S1 spinal cord sections. Internalization of the substance P receptor was produced by distension of the colon in the rat (Honore´, P., Kamp, E. H., Rogers, S. D., Gebhart, G. F., and Mantyh, P. W. 2002. Activation of lamina I spinal cord neurons that express the substance p receptor in visceral nociception and hyperalgesia. J. Pain 3, 3–11). SPN, sacral parasympathetic nucleus.

550 Visceral Pain

Brain DRG

Figure 3 Illustration of viscerosomatic and viscerovisceral convergence of inputs onto a second-order spinal neuron. Illustrated is input from the abdominal skin, urinary bladder, and distal colon onto the same spinal neuron. Activation of the second-order neuron is illustrated here as being conveyed to the brain via the anterolateral ascending pathway; not illustrated is a postsynaptic dorsal column pathway, which also conveys visceral sensory information to the brain. DRG, dorsal root ganglion.

terminations within the spinal dorsal horn (which are typically limited to the spinal segment of entry). These anatomic characteristics of visceral afferent spinal terminations surely contribute to the diffuse nature of visceral pain and difficulty in localizing its source. A final notable and defining characteristic of spinal visceral input that also contributes to poor localization is convergence. It is a feature of virtually all second-order spinal neurons upon which visceral afferent fibers terminate that convergent inputs from somatic and/or other visceral organs are also received. Typically, a single dorsal horn neuron that receives a visceral input (e.g., from colon) has a convergent cutaneous receptive field and also receives input from another viscus (e.g., urinary bladder, uterus) (Figure 3). Thus, viscerosomatic and viscerovisceral convergence upon second-order spinal neurons is the general rule (rather than the exception), and further compromises localization of visceral inputs. 37.2.4.3 Spinal pathways and supraspinal terminations

Spinal visceral afferent input is further transmitted rostrally and distributed widely in the brainstem (largely associated with reflex functions; e.g., micturition), hypothalamus, and thalamus and then to areas of the cerebral cortex where discriminative and affective components of visceral information assumes

consciousness and triggers responses/behavior. Interestingly, thalamic and cortical neurons that receive a visceral input also exhibit viscerosomatic and viscerovisceral convergence (e.g., Apkarian, A. et al., 1995) (Figure 4). The ascending pathways in spinal cord white matter that convey visceral information to the brain are contained principally in the anterolateral quadrants of the spinal cord and in the dorsal columns. Thus, there are spinomedullary, spinopontine, spinomesencephalic, spinohypothalamic, and spinothalamic tracts that ascend in the anterolateral quadrant of the spinal cord, predominantly contralateral to the side of input. The postsynaptic dorsal column paths are ipsilateral to the side of input and ascend to the nuclei gracilis and cuneatus in the medulla, where they cross and ascend to the contralateral ventrobasal thalamus (e.g., Palecek, J. et al., 2002). In addition to these principal pathways that convey information to supraspinal sites, there are intraspinal propriospinal pathways that are less well understood and presumably have modulatory functions and another pathway from lamina I neurons to pontine parabrachial nuclei and thence to the amygdala, principally the central nucleus. This latter pathway is believed to specifically convey visceral information of a noxious character to the amygdala, which importantly is associated with anxiety and affective dimensions of pain (Phelps, E. A. and LeDoux, J, E., 2005). Functional imaging studies have complemented and expanded our appreciation of the central representation of visceral inputs. Although the current spatial resolution of imaging methods has limited ability to study the initial processing of visceral input in the brainstem, reports to date suggest that cutaneous and visceral stimuli activate similar brain regions. Pain-induced anxiety, which tends to be more significant during visceral stimulation, is associated with stronger activation of the midbrain periaqueductal gray (PAG) (Dunckley, P. et al., 2005). Similarly, activation of cortical structures does not show a pattern during visceral pain distinct from somatic pain, with the anterior cingulate cortex (ACC), the anterior insular cortex and – less consistently – the primary and secondary sensory cortices activated by both visceral and somatic pain (Hobson, A. R. and Aziz, Q., 2004). Despite the overall similarity between brain patterns of activation produced by cutaneous and visceral stimuli, subtle differences have emerged. Compared to noxious cutaneous stimulation, visceral pain tends to cause a stronger activation of the ACC and typically activates the

Visceral Pain

Response to visceral stimulation

551

Cutaneous receptive fields

+CRD, oED +CRD, –ED

WDR 3V WDR

+CRD, oED +CRD, +ED LT

VL +CRD, oED VM VPL + Excitation – Inhibition o No response

WDR

VPM 1 mm

LT

Figure 4 Illustration of viscerosomatic and viscerovisceral convergence onto neurons recorded in the rat thalamus. The vertical tract recording electrode through the ventral posteriolateral (VPL) thalamus illustrates, from top to bottom, cutaneous receptive fields on the right for five sequential thalamic neurons and responses of the same neurons to colorectal distension (CRD) and esophageal distension (ED) on the left. All neurons studied responded to both CRD and either innocuous cutaneous stimulation (identified as low threshold, LT) or both innocuous and noxious cutaneous stimulation (identified as wide dynamic range, WDR). Some neurons were also inhibited, excited or did not respond to ED. From Danzebrink R. M. and Gebhart G. F. (unpublished).

perigenual portion of the ACC, which has been linked to the generally stronger emotional reactions associated with visceral pain (Strigo, I. A. et al., 2003). Interestingly, only the intensity and not the pattern of activation differs between perceived and unperceived (subliminal) visceral stimulus intensities (Sidhu, H. et al., 2004).

37.3 Functional Basis of Visceral Pain Nociceptors are defined by response to a noxious stimulus and their ability to encode suprathreshold stimulus intensities. Sherrington C. S. (1906) defined noxious stimuli as those that damage or threaten damage to skin, and this definition, which has been applied widely to all tissues, is problematic with respect to the viscera because tissue-damaging visceral insult is not reliably pain-producing. Instead, visceral

stimuli that reliably generate sensations of discomfort or pain include, as stated previously, hollow organ overdistension, traction on the mesentery, organ ischemia, and organ inflammation, the latter two perhaps acting indirectly to alter the chemical milieu at an afferent receptive ending to increase neuron excitability to other stimuli. Accordingly, tension/stretch (produced by muscle contraction or organ distension, respectively) is an adequate acute noxious visceral stimulus at intensities (e.g., balloon pressures) above threshold for activation of visceral mechano-nociceptors. In experimental studies with humans, verbal reports or various scaling procedures identify distending pressures that are uncomfortable or painful. Concomitant recording of contractile phenomena allows differentiation between stretch (activation of receptor in parallel with muscle cells) and tension (activation of receptors in series with muscle cells). In nonhuman animal experiments, whether the intensity of visceral stimulation is noxious has to be inferred

552 Visceral Pain

from autonomic responses, which generally are produced at intensities of stimulation below the noxious threshold, or animal behavior. It is also noteworthy that innervation of the viscera, relative to skin, is sparse and thus spatial summation is important to activation of visceral mechanoreceptors and the production of discomfort or pain. Thus, in nonhuman animals it is necessary to use a distending balloon of sufficient length to produce a change in behavior that can be interpreted as aversive or painful. In the absence of behavioral evidence, the quality of mechanical stimulation is unknown and often difficult to establish as relevant to activation of mechano-nociceptors and visceral pain. 37.3.1 Visceral Mechanoreceptors and Mechano-Nociceptors 37.3.1.1

Afferent fiber recordings Obviously, the stomach and temporary storage organs like the urinary bladder and distal colon/rectum experience periodic filling (and emptying), which distends these organs, commonly without generating either discomfort or pain. Mechanosensors in these organs are sensitive to and respond to filling within the physiological range, eventually leading, for example, to an urge to evacuate the bladder or bowel. Consistent with these sensations and functions produced by organ filling, most mechanosensitive afferent fibers contained in the nerves innervating these organs have low thresholds for response. The proportion of low-threshold mechanosensitive endings in spinal nerves innervating the stomach, esophagus, and gallbladder (splanchnic nerves) and the urinary bladder, uterus, and distal colon (pelvic nerves) is 70–80%, and this has been a generally consistent finding across species (cat, chicken, ferret, guinea-pig, mouse, opossum, and rat). The remaining 20–30% of afferent fibers have high thresholds for response, typically 30 mm Hg distending pressure, which corresponds very well to colon distending pressures in rats that produce behavior leading to avoidance of the stimulus. Because high-threshold mechanoreceptors in the viscera respond only to intensities of stimulation in the noxious range and encode the intensity of suprathreshold stimuli, they fulfill requirements as nociceptors and are considered to be mechano-nociceptors that signal acute visceral pain. Unlike low-threshold cutaneous mechanoreceptors, which when activated give rise to sensation (e.g., movement of a hair follicle, movement of a cotton wisp across the skin), low-threshold visceral

mechanoreceptors when activated within the physiological range of intensities generally produce no conscious sensation, but rather contribute to autonomic regulation of organ function. It has been suggested consequently that these receptors and associated axons are not sensory, but rather afferent. However, low-threshold visceral mechanoreceptors possess the uncommon attribute of continuing to respond, if not also to encode, stimulus intensity well into the noxious range. Thus, their activation at some (high) intensity of stimulation can lead to sensations perceived as uncomfortable or painful. The afferent–sensory function of visceral nerves was appreciated by Sherrington C. S. (1900), who commented that activation of visceral nerves rarely resulted in conscious sensations (i.e., an afferent function), but when sensation was produced it was typically pain (i.e., a sensory function). In all visceral nerves studied, including gastric vagal afferent fibers, low-threshold mechanosensitive afferents, when tested with high-intensity stimuli, respond vigorously and typically at a rate (frequency) greater than their high-threshold mechano-nociceptor counterparts (Figure 5). Clearly, as stimulus intensity increases, high-threshold mechano-nociceptors are also activated and it can be argued that uncomfortable or painful sensation arises from their activation. Their contribution is undeniable in acute visceral pain, but low-threshold mechanoreceptors (like their high-threshold counterparts) also possess the ability to be sensitized (see below and Figure 5), a quality commonly associated only with nociceptors. Accordingly, it is likely that both low- and highthreshold mechanoreceptors in hollow organs contribute to sensations of discomfort and pain in functional gastrointestinal (nonulcer dyspepsia, IBS) and urinary bladder (interstitial cystitis/painful bladder syndrome) disorders as well as in ischemia, inflammation, or neoplastic diseases associated with visceral pain. Consistent with this interpretation, psychophysical experiments in human volunteers have demonstrated that pharmacologic modulation of sensory function similarly shift thresholds for nonpainful and painful sensations (Vandenberghe, J. et al., 2005). There are two additional features of low- and highthreshold mechanosensitive endings in viscera that suggest their functions are not always or easily separable. First, both respond to either or both chemical and thermal stimuli in addition to mechanical stimulation (the usual experimental search stimulus). That is, they are polymodal and virtually all mechanosensitive endings when tested have been found to respond also to a

Visceral Pain

Total no. impulses 50

Pre Post

40 30

Response to organ distension

20 10 0 0

10

20

30

40

50

60

70

80

Total no. impulses 50 Pre Post

40

20 10 0 0

10

20 30 40 50 60 70 Distension pressure (mm Hg)

indirectly through enteroendocrine cells). Whether such chemosensitive endings, typically studied in the mucosal surfaces of the gastrointestinal tract, are also mechano- or thermosensitive has not been systematically examined, although when examined mechanosensitivity is commonly noted. If specific and selective visceral chemosensors without mechanosensitivity exist, which is very likely the case, the argument that both low- and high-threshold polymodal mechanosensors can contribute to discomfort and pain is strengthened. Secondly, low- and high-threshold mechanoreceptors cannot be distinguished on the basis of fiber type (A or C), size or content of cell soma, or pharmacologically (e.g., sensitivity to chemical or inflammatory mediators). 37.3.1.2

30

80

Figure 5 Stimulus–response functions for low-threshold (top) and high-threshold (bottom) mechanosensitive pelvic nerve fibers innervating the urinary bladder of the rat. Before bladder irritation, high-threshold fibers first responded at 30 mm Hg bladder distension and then encoded distending pressure throughout the range of pressures tested. In contrast, low-threshold fibers begin to respond at physiologic distending pressures, but also encoded distending pressures throughout the ranges of pressures tested. Note that response magnitude of low-threshold fibers is greater than for high-threshold fibers at all intensities of bladder distension. Note also that response magnitude increases significantly for both low- and high-threshold fibers after bladder irritation and response threshold for highthreshold fibers decreases significantly into the physiologic range (i.e., both low- and high-threshold mechanosensitive fibers sensitize). Reproduced from Su, X., Sengupta, J. N., and Gebhart, G. F. 1997. Effects of opioids on mechanosensitive pelvic nerve afferent fibers innervating the urinary bladder of the rat. J. Neurophysiol. 77, 1566–1580, used with permission from the American Physiological Society.

chemical and/or to a thermal stimulus. A considerable literature has established the sensitivity of visceral afferents in both the vagal and spinal innervations to chemical stimuli (principally hormones and putative mediators as well as nutrients that may act directly or

553

Information acquired in vitro In addition to mechanoreceptor characteristics described above, in which afferent fibers were studied while distending intact hollow organs or occluding vessels, in vitro studies of visceral organs, typically opened and pinned flat in a dish with nerves attached, provide different information (Figure 6). For example, receptive endings in the organ can be readily localized by response to applied mechanical stimuli and the endings can be further isolated experimentally and subjected directly to chemical and thermal stimuli. Esophagus, stomach, small bowel, urinary bladder, uterus, ureter, testes, and colon–rectum all have been studied in this fashion. As above, mechanical search stimuli typically have been used and include brushing/stoking the mucosal surface of the organ to locate receptive endings functionally identified as mucosal, punctuate pressure to identify serosal receptors, and circumferential stretch of the organ to identify muscular stretch receptors. Single-fiber studies in all organs examined to date reveal typical patterns of activation, allowing inferential assignment of mucosal, muscular, and serosal receptive endings. Mucosal receptors respond only to stroking of the mucosal surface and not to stretch/ tension, whereas muscular receptors respond to stretch/tension and not stroking the mucosal surface. Finally, only intense punctate stimuli activate serosal receptors. In some organs (e.g., stomach, urinary bladder, and colon) receptive endings that respond to both mucosal stroking and stretch/tension have been found (termed muscular–mucosal endings; Figure 6). It should be noted that these descriptors of receptive endings have not been histologically confirmed and are based solely on responses to mechanical stimuli. Nonetheless, use of in vitro

554 Visceral Pain

Mesenteric Serosal Muscular Mucosal Mucosal stroking (10 g) Muscular/mucosal

Circumferential stretch (4 g)

Muscular 5s 10 s Mucosal

Muscular mucosal

Lumbar splanchnic nerve

Pelvic nerve

IMA

IMG LSN PN MPG

Figure 6 Responses of different types of the mechanosensitive endings innervating the mouse colon. Muscular receptors are illustrated topmost as responding to circumferential stretch of the colon but not stroking of the mucosal surface. Mucosal endings respond to mucosal stroking, but not to stretch, and muscle–mucosal fibers respond to both stroking of the mucosa and circumferential stretch. The application of strokes across the mucosal receptive ending and the duration of stretch are illustrated beneath the recordings. The distribution of receptive endings for the lumbar splanchnic nerve and pelvic nerve innervations of the mouse colon are illustrated bottommost, showing receptive endings located in the mesentery and serosa as well as those associated with muscle, mucosa and muscle-mucosa. IMA, inferior mesenteric artery; IMG, inferior mesenteric ganglion; LSN, lumbar splanchnic nerve; MPG, major pelvic ganglion; PN, pelvic nerve. Adapted from Brierley, S. M., Jones, R. C. W., III, Gebhart, G. F., and Blackshaw, L. A. 2004. Splanchnic and pelvic mechanosensory afferents signal different qualities of colonic stimuli in mice. Gastroenterology 127, 166–178.

organ–nerve preparations has confirmed many of the findings of earlier work and, importantly, has notably expanded our understanding of the contributions of mechanosensitive endings in viscera to presumed functions. For example, in addition to increasing recognition

that the vagus nerves are involved in chemo-nociception (see below), there is also evidence for a role of vagal afferents in esophageal mechano-nociception (Yu, S. et al., 2005). Nonnociceptive esophageal tension receptors exhibited saturable responses to esophageal distension, whereas nociceptive A- and C-fiber esophageal vagal afferents discriminated noxious intensities of esophageal distension (and also responded to activators of TRPV1). Significantly, studies of the two nerves innervating the same organ have been carried out for both the mouse colon and mouse urinary bladder. Although is has long been appreciated that the two nerves innervating an organ execute different functions, comparison of the properties of the two innervations provides new information that could, for example, inform development of therapeutic strategies. In a comparison between the lumbar splanchnic nerve and pelvic nerve innervations of the mouse colon (Brierley, S. M. et al., 2004), most of the colonic receptive endings in the lumbar splanchnic nerve responded to blunt probing and were located along the mesenteric attachment and the serosa (Figure 6). In contrast, no pelvic nerve receptive endings were found in the mesenteric attachment and significantly more receptive endings responded to stretch than in the lumbar splanchnic nerve, including muscular– mucosal endings (which were not found in the lumbar splanchnic innervation). Analysis of response properties of the same receptive endings in the different innervations revealed further differences. Responses to the same intensities of stroking and stretch stimuli were significantly greater in pelvic nerve endings than in lumbar splanchnic counterparts. Overall, the pelvic nerve innervation of the mouse colon contained greater proportions of stretch/tension and mucosal receptors, which moreover generated greater magnitude responses, than the lumbar splanchnic innervation. Similarly, comparison of the lumbar splanchnic nerve and pelvic nerve innervations of the mouse urinary bladder reveals significant differences between the proportions and distribution of types of mechanosensitive receptive endings. As found for the colon, the distribution of lumbar splanchnic receptive endings in urinary bladder was more circumscribed than the distribution of pelvic nerve receptive endings, which again contained an ending (muscular–urothelial) not found in the lumbar splanchnic innervation. A final means of study of visceral sensory neurons is to study cell soma using patch clamp methodology. These studies do not, of course, permit the type of

Visceral Pain

functional evaluation derived from single-fiber studies, and instead address aspects of mechanisms and changes in visceral neuron excitability, specifically the differential roles of voltage- or ligand-gated ion channels. Such studies have been carried out in rat stomach (vagal and splanchnic innervations), mouse intestine, mouse colon, rat colon, and rat urinary bladder (lumbar splanchnic and pelvic innervations). Because of low innervation density, the study of visceral sensory neurons requires the injection of retrograde labels into muscle layers of the organ of interest. The uptake and retrograde transport of the label into the soma allows identification of neurons projecting to the organ of interest. Consistent with results obtained in vivo, isolated visceral sensory neurons do not generate spontaneous activity. However, cells obtained from animals with experimentally induced inflammation show significant oscillation of the resting membrane potential, resulting in spontaneous action potential discharge, demonstrating an increase in excitability. This increase in excitability is associated with an increase in voltage-sensitive sodium currents, primarily a tetrodotoxin (TTX)-resistant sodium current, and a decrease in voltage-sensitive potassium currents, primarily the transient or A-type current (Yoshimura, N. and deGroat, W. C., 1999; Stewart, T. M. et al., 2003; Dang, K. et al., 2004; Beyak, M. J. and Vanner, S., 2005; Xu, G. et al., 2006). In addition to voltage-sensitive ion channels, the expression and properties of ligand-gated channels also changes in animal models of visceral pain. Ischemia is the most common cause of cardiac pain, experienced by millions of Americans suffering from coronary artery disease. Tissue acidosis due to accumulation of lactate can activate cardiac afferents and likely triggers ischemic pain. Perhaps consistent with the importance of ischemia as a trigger of visceral pain, a comparison between cardiac sensory neurons and randomly chosen neurons in the same DRG showed that a higher fraction of visceral sensory neurons express ASICs (Benson, C. J. et al., 1999). Experimental injury, such as gastric ulceration, increases the current density of these acid-sensitive currents in visceral sensory neurons (Sugiura, T. et al., 2005), demonstrating that sensitization does not only affect excitability (i.e., the generation of action potentials in response to a given stimulus), but also the signal transduction process (i.e., the depolarization triggered by a mechanical, chemical, or thermal stimulus). Based on the properties of proton-evoked currents, most visceral sensory neurons

555

express different members of the ASIC family of ion channels as well as the vanilloid receptor TRPV1. The preferential expression of TRPV1 in small-diameter, presumably nociceptive neurons raised the question whether it may play a role in visceral pain. A high percentage (60–80%) of mouse and rat colon sensory neurons express TRPV1 (Robinson, D. R. et al., 2004; Christianson, J. A. et al., 2006) and TRPV1 is the principal detector in mouse colon of extracellular acidosis (Sugiura, T. et al., 2007). Serotonin acutely alters TRPV1 function in colon sensory neurons, shifting the temperature-activation curve of this ion channel to normal body temperatures (Sugiura, T. et al., 2004). About 90% of the body’s serotonin is found within the gastrointestinal tract, primarily in enterochromaffin cells, and serotonin is released in high concentrations during mucosa stimulation. Studies of patients with functional bowel diseases, such as IBS, suggest changes in serotonin release and/or reuptake within the intestinal mucosa, raising the question whether modulation of TRPV1 function may contribute to the enhanced responses to physiologic stimuli seen in these patients. In addition to modulation by G-protein-coupled receptors, changes in TRPV1 expression have been examined under experimental and clinical conditions. Animal models of visceral inflammation as well as distinct human disorders from gastroesophageal reflux disease, painful bladder syndrome to rectal urgency are associated with increases in TRPV1 expression (e.g., Chan, C. L. H. et al., 2003; Bhat, Y. and Bielefeldt, K., 2006; Mukerji, G. et al., 2006). Purines, which include ATP and its breakdown products, are released during cell injury and may thus play a role in nociception. Among the families of purinergic receptors, the ligand-gated P2X receptors have attracted special attention because of their role in visceral sensation. As described Chapter Urothelium as a Pain Organ, the bladder epithelium (urothelium) releases ATP during physiologic stimulation, such as stretch. Bladder sensory neurons express P2X receptors and respond to purinergic agonists (Yoshimura, N. et al., 2003; Dang, K. et al., 2005). Cystitis significantly increases the peak current triggered by purinergic agonists, consistent with a potential role of this signaling pathway in causing discomfort and increased micturition frequency, associated with bladder inflammation. Similarly, colon distension in the rat releases ATP in a stimulus-dependent manner, and the release of ATP is increased further after experimental induction of colon inflammation (Wynn, G. et al., 2003; 2004).

556 Visceral Pain

Responses to colon distension in the colitis model were attenuated by a purinergic receptor antagonist, suggesting a role for ATP in colon mechanosensory transduction. 37.3.1.3 Gene deletions, visceral pain, and mechanosensation

The availability of mice with selected gene deletions (knockout mice) has provided the opportunity to examine the potential role of several molecules in visceral pain. To date, voltage-gated sodium channel (NaV1.8), TRPV1, purinergic receptor (P2X), and ASIC knockout mice have been studied and each molecule has been found to contribute at least in part to responses to noxious visceral stimuli or of visceral mechanoreceptors. As mentioned above, the TTX-resistant sodium current is increased in neurons obtained from animals with gastrointestinal or bladder inflammation. In sensory neurons, TTXresistant current is largely due to activation of the voltage-gated sodium channel NaV1.8. Genetic deletion of this ion channel in mice is associated with a decrease in aversive behavior in response to intraperitoneal injection of acetic acid (Laird, J. M. et al., 2002), supporting a potential role of NaV1.8 in visceral pain. The pain behavior in this model is also likely contributed to by activation of nonvisceral afferents within the parietal peritoneum. More direct evidence was provided by other studies, one employing transient suppression of TTX-resistant sodium currents in bladder sensory neurons with antisense oligonucleotides, which abolished the increase in micturition frequency seen after acute bladder irritation (Yoshimura, N. et al., 2001), and the other employing NaV1.8 and NaV1.9 knockout mice, which reported that neuron hyperexcitability produced by jejunitis was absent in NaV1.8, but not NaV1.9 knockout mice (Hillsley, K. et al., 2006). Genetic deletion of functional TRPV1 receptors also leads to changes in visceral function, suggesting a role of TRPV1 in visceral mechanosensation. TRPV1 knockout mice have a higher frequency of nonvoiding bladder contractions (Birder, A. L. et al., 2001). Nerve recordings from mesenteric nerve bundles innervating the small bowel and colonic afferents within the pelvic nerve revealed blunted mechanosensation in TRPV1 knockout mice compared with wild-type controls (Rong, W. et al., 2004; Jones, R. C. W. et al., 2005). Deletion of TRPV1 also altered responses to inflammatory mediators, consistent with a potential role of this ion channel in peripheral sensitization (Jones, R. C. W. et al., 2005). However,

biophysical studies have not demonstrated a direct activation of TRPV1 by stretch. Thus, the channel likely alters cellular excitability and enhances responses to different stimulus modalities, including stretch. As discussed separately in more detail (Chapter Urothelium as a Pain Organ), purinergic receptors play an important role in bladder function. Bladder filling triggers ATP release from urothelial cells, which activates bladder sensory neurons and may trigger reflex micturition. Consistent with this model, P2X3 knockout mice exhibit bladder hyporeflexia (Cockayne, D. A. et al., 2000). A more complex picture emerges from studies examining the role of different members of the ASIC family in visceral sensation. Genetic deletion of ASIC3 blunts responses to colorectal distension and mechanical stimulation of gastroesophageal afferents in mice, suggesting a role in visceral mechanosensation (Jones, R. C. W. et al., 2005; Page, A. J. et al., 2005). In contrast, deletion of ASIC1a increased mechanosensitivity of gastroesophageal and colonic afferents without affecting cutaneous afferents and deletion of ASIC2 blunted responses of gastroesophageal, but enhanced those of mesenteric afferents in the distal colon (Page, A. J. et al., 2005). ASICs form heteromultimeric channels, leading to speculation that the subunit composition has significant effects on the mechanosensitive properties of visceral sensory neurons (Wemmie, J. et al., 2006). Thus, genetic studies showed that – as is true for cutaneous pain – no single molecule explains the complex phenomenon of pain. Yet, some differences between cutaneous and visceral sensation has emerged, most notably the potential role of TRPV1 and P2X receptors in mechanosensation. The foregoing studies focused on the initial events triggered by noxious visceral stimulation, namely signal transduction and cellular excitability in primary afferent neurons. Consistent with a role of substance P and neurokinin receptors in synaptic transmission of visceral afferent input within the spinal cord, genetic deletion of neurokinin receptor 1 blunted responses to intraperitoneal injection of acetic acid in mice (Laird, J. M. A. et al., 2000). Despite these findings and preclinical studies with different neurokinin receptor blockers in rodent models of visceral pain, neurokinin antagonists do not appear to be effective when used to treat visceral pain in humans. The genetic basis for visceral pain has also been addressed in humans. Considering the high

Visceral Pain

prevalence of functional gastrointestinal disorders in the general population and the expression of pain and discomfort as the primary symptoms, most studies have focused on IBS or nonulcer dyspepsia. As mentioned above, serotonin plays an important role in afferent signaling within the gastrointestinal tract. Mechanical or chemical stimuli can trigger serotonin release from enteroendocrine cells into the lamina propria, where high tissue concentrations activate terminals of both intrinsic and extrinsic primary afferent neurons within the vicinity. Reuptake of serotonin by the high-affinity transporter serotonin transporter (SERT) expressed by epithelial cells terminates this signal. This led to the hypothesis that differences in the properties of SERT may contribute to the pathogenesis of functional gastrointestinal disorders. Consistent with this assumption, deletion of SERT in mice triggers changes in bowel habits with alternating diarrhea and constipation, a common clinical manifestation in patients with IBS (Gershon, M. D. and Tack, J., 2007). Two allelic variants of the serotonin transporter have been identified in humans. These alleles have different kinetics of serotonin uptake, leading to the hypothesis that they may contribute to the pathogenesis of functional bowel disorders. While initially supported, several studies have failed to show a linkage between one of the alleles and IBS (Camilleri, M., 2004). Holtmann G. et al. (2004) examined the link between a G-protein  subunit and functional dyspepsia. Prior studies had shown that the expression of the two allelic forms of this molecule affected intracellular signaling in neurons and was linked to affective disorders. As was true for SERT, a subsequent study did not confirm the linkage reported in this initial observation (Andresen, V. et al., 2006). These conflicting results likely reflect the fact that a complex trait, such as enhanced sensitivity to visceral stimulation, can typically not be explained by a single gene defect, but rather a complex interaction between multiple genetic and environmental factors. Thus, contributions of any single candidate gene to the variance of phenotypic expression will be limited, requiring very large studies to more conclusively address their role in the development of visceral pain syndromes. 37.3.2

Sleeping (Silent) Nociceptors

In the mid-1980s Schmidt and coworkers (Schmidt, R. F., 1996) characterized a novel nociceptor in the knee joint of the cat they dubbed silent or sleeping. These nociceptors could be activated by electrical

557

stimulation, but not by the usual high-intensity mechanical stimuli tested. During the minutes and hours after experimental inflammation of the knee joint, however, these nociceptors became progressively sensitive to mechanical stimuli, including to nonnoxious movement of the joint, and developed spontaneous activity. It has subsequently been established that sleeping nociceptors do respond to mechanical stimulation in the absence of inflammation, but only at intensities that are potentially damaging to tissue, and hence they are not truly silent. Microneurographic studies suggest that between 15% and 20% of C-fiber nociceptors in human skin are of the sleeping variety (Torebjo¨rk, H. E. et al., 1996), and sleeping nociceptors also have been documented in the visceral innervation (Figure 7), although estimates of their number vary widely from 30% to >80%. Studies of sleeping visceral nociceptors have focused principally on the pelvic nerve innervation of the rat or cat urinary bladder and colon. Whether the afferents studied were actually sleeping is uncertain, and it has to be appreciated that assignment to this category is typically based on the absence of a response to organ distension in the noxious range. Given the filling, storage, and emptying functions of the bladder and colon, which are supported by the high proportion (70%) of pelvic nerve afferents with low thresholds for mechanical activation, that a similar large 10 Hz] Preinflammation

30 min after inflammation

1 h after inflammation

5

10

20

30

40

60

80

100

Pressure (mm Hg) Figure 7 Illustration of a mechanically insensitive, silent (sleeping) visceral nociceptor. Responses to balloon distension of the colon (5–100 mm Hg, 20 s) are shown before experimental organ inflammation (the fiber did not respond to colon distension or bladder distension, not shown), 30 and 60 min after intracolonic instillation of zymosan. Spontaneous activity is apparent after colon inflammation as are responses to colon distension. Adapted from Coutinho, S., Su, X., Sengupta, J. N., and Gebhart, G. F. 2000. Role of Sensitized Pelvic Nerve Afferents from the Inflamed Rat Colon in The Maintenance of Visceral Hyperalgesia. In: Nervous System Plasticity and Chronic Pain, Progress in Brain Research (eds. J. Sandku¨her, B. Bromm, and G. F. Gebhart), Vol. 129, pp. 375–387. Elsevier.

558 Visceral Pain

proportion of pelvic nerve afferents are of the sleeping variety seems disproportionate. It is clear, however, that the proportion of sleeping nociceptors in the visceral innervation is greater than has been reported in skin, but the proportion and contributions of sleeping nociceptors to visceral pain states remains to be established. Some of these mechanically insensitive afferents may have been chemosensitive and would have responded to a chemical stimulus not tested. A potential role of chemical signaling is supported by recruitment of silent vagal gastric afferents after exposure to bile acids (Page, A. J. et al., 2002). 37.3.3

Visceral Chemo-Nociception

Most studies of visceral afferents focus on mechanosensation, as mechanical stimuli can trigger reproducible responses without inducing tissue damage. However, visceral afferents are also exposed to potentially noxious chemical signals, such as acidity in the proximal gastrointestinal tract, and products that may accumulate during ischemia, such as lactate, protons, and bradykinin, and thus contribute to visceral discomfort and pain. Gastro-esophageal reflux disease (GERD, gastric acid reflux into the lower esophagus), myocardial ischemia, and lower airway irritation are all associated with discomfort and/or pain. Although experimental evidence obtained in animal studies is limited, both spinal and vagal afferents are involved in chemo-nociception. Using the expression of the immediate early gene c-fos as a surrogate marker for neuronal activation after acid exposure of the stomach, noxious chemical stimuli activated vagal but not spinal pathways (Schuligoi, R. et al., 1998). This is consistent with behavioral responses to intragastric acid administration, which were blunted after vagotomy (Lamb, K. et al., 2003). In studies of mouse vagal gastro-esophageal afferent fibers, more than 50% of fibers that responded to circular tension also responded to bile acid (a component of gastric acid reflux into the esophagus); significantly, a population of mechanically insensitive (sleeping) afferents was activated by bile acid, suggesting the presence of specific chemosensors (which did to respond to other chemicals studied) (Page, A. J. et al., 2002). Additional support for vagal involvement in chemo-nociception is provided by results showing that independent of the acute response to protons (glycocholic acid and hydrochloric acid), acid exposure enhanced subsequent responses of gastric vagal afferents to mechanical stimulation, suggesting a sensitizing

interaction between different stimulus modalities (Kang, Y. et al., 2004) (Figure 8). Coronary artery occlusion in animals or myocardial ischemia in humans leads to the release and accumulation of a variety of substances in sinus blood (e.g., bradykinin, adenosine, serotonin, prostaglandins; see Meller, S. T. and Gebhart, G. F., 1992 for a review) that have been shown to activate cardiac afferent fibers in the spinal innervation. Experimental coronary artery occlusion also triggers a rapid decrease in myocardial pH, and both protons and lactic acid (which accumulates during tissue hypoxia) have been shown to activate ischemia-sensitive cardiac afferent fibers in the spinal splanchnic innervation (Pan, H. L. et al., 1999). Many ischemiasensitive cardiac (Pan, H. and Chen, S. R., 2002) and abdominal splanchnic afferents are also responsive to bradykinin, serotonin, and prostaglandins (see Longhurst, J. C., 1995 for review) as well as mechanical probing. As in other organs, myocardial ischemia has been reported to recruit mechanically insensitive (sleeping) cardiac splanchnic afferent fibers (Pan, H. and Chen, S. R., 2002). In healthy subjects, the afferent innervation of the lower airways does not normally contribute to conscious sensations. However, dyspnea, chronic cough, and chronic obstructive pulmonary disease, in addition to inhalation of irritant chemicals, are associated with discomfort and/or pain, and it appears that the vagal afferent innervation plays a dominant role. As indicated previously, the cell bodies of vagal sensory fibers are contained in the nodose and smaller jugular ganglia, which are derived from placode and neural crest cells, respectively. Undem, B. J. and coworkers have provided evidence that the vagal ganglionic source of axons supplying the airways is associated with the neurochemical and physiological phenotype of the afferent fiber (Riccio, M. M. et al., 1996). Nodose ganglion A-fibers have low thresholds for mechanical activation, adapt rapidly to mechanical stimulation, and are not activated by capsaicin. In contrast, jugular ganglion A-fibers have higher thresholds for mechanical activation, adapt slowly to mechanical stimulation, and are typically responsive to capsaicin. C-fibers associated with somata in both the nodose and jugular ganglia are also mechanically sensitive and also respond to capsaicin and bradykinin (Undem, B. J. et al., 2004); in addition, C-fibers innervating the lung from the nodose ganglion express P2X receptors and respond to purinergic agonists (jugular C-fibers do not). Because proportions of these mechanically sensitive nodose and

Visceral Pain

Distension

20 mV

Baseline

559

pH 7

1s

Spike frequency (Hz)

pH 4

2.5

Baseline pH 4

2.0

cm H2O 30

1.5 1.0 0.5

0

0.0 0

10 20 30 Pressure (cm H2O)

40

Figure 8 Intracellular recordings from a nodose ganglion neuron innervating the mouse stomach show low baseline activity (top left) and an increase (response) in activity (top right) during luminal distension (0–30 cm H2O, 10 s, shown bottom right). When the luminal proton concentration was raised to pH 4, baseline activity and the response to distension increased. The stimulus response function for this neuron is summarized on the bottom left and demonstrates a significant shift to the left in the presence of an increase in luminal pH to 4. From Bielefeldt K. (unpublished).

jugular ganglia afferents are sensitive to acidic solutions and other algogenic chemical stimuli, they are considered to function as airway and lung nociceptors. In support, airway inflammation increases the mechanical sensitivity of the rapidly adapting population of vagal afferents and triggers an increase in the synthesis of neuropeptides substance P and CGRP (Undem, B. J. et al., 2002).

37.4 Visceral Hypersensitivity Like other tissues in the body, an increase in the excitability of sensory neurons innervating an organ can lead to exaggerated responses to applied stimuli, including intensities of stimulation in the physiologic range that normally do not lead to conscious sensation. Inflammation of visceral tissues, like inflammation of skin, muscle, or joints, typically increases visceral neuron excitability and raises

normally unattended afferent input from the viscera to the level of consciousness in the form of discomfort and pain. By far, however, most persistent visceral pain conditions are characterized by hypersensitivity in the absence of inflammation or other cause. Accordingly, visceral hypersensitivity has been suggested to represent a biomarker for functional gastrointestinal and bladder disorders, which in the case of IBS can be experimentally established by balloon distension of the rectum. These functional disorders are relatively common, persistent, and generally inexplicable clinically. The characteristic discomfort and pain is often precipitated by ingestion of food, but also can be disassociated from events that logically would be expected to exacerbate symptoms. Typically, nonnoxious intensities of visceral stimulation (e.g., ingestion of food or beverage, low pressures of gastric or rectal distension, bladder filling) trigger painful sensations, which some have inappropriately and inaccurately termed visceral allodynia.

560 Visceral Pain

There is an association (30%) between IBS and previous (and resolved) gastrointestinal infection, but antecedent or contemporaneous events that lead to development of functional disorders are otherwise unknown. Abuse in childhood, including sexual abuse, has been advanced as a contributing factor in development of functional disorders as have stress and anxiety, which are commonly reported by patients and can clearly exacerbate symptoms. Given that the cause of such disorders is unknown, there has been considerable attention paid to peripheral versus central nervous system contributions to initiation and maintenance of discomfort and pain in functional disorders. Both visceral sensory neuron excitability and sensitization and central nervous system dysregulation are considered below. 37.4.1 Sensitization and Excitability of Visceral Nociceptors Sensitization is a defining characteristic of nociceptors first described by Perl for cutaneous nociceptors (see Perl, E., 1996 for an overview) and which has since been established for nociceptors innervating other tissues. Sensitization is an increase in response magnitude to suprathreshold stimuli and/or a decrease in response threshold; not uncommonly, both response magnitude increases and response threshold decreases (and spontaneous activity can develop) (see Figure 5 for examples of sensitization of responses of low- and high-threshold mechanosensitive pelvic nerve afferent fibers to bladder distension). Experimentally, sensitization is commonly produced following tissue inflammation or insult, and an extensive literature has identified mediators and mechanisms of inflammation-produced sensitization, principally in nonvisceral tissues (e.g., McMahon, S. B. et al., 2006). Clinically, in functional disorders, sensitization of visceral sensory neurons is present in the absence of gross inflammation or tissue insult, but visceral sensory neurons can sensitize after exposure to noninjurious stimuli. For example, gastric vagal mechanosensitive afferents uniformly have low thresholds for response to balloon distension of the stomach, but also encode stimulus intensity into the noxious range. Response magnitude to gastric distension can be affected not only by intragastric instillation of acids or by gastric ulceration, but also by transient intragastric exposure to stimuli that do not injure the tissue (e.g., see Kang, Y. et al., 2004). The significance of these findings is twofold. First,

gastric vagal mechanoreceptors, which are generally considered not to contribute to visceral pain, do sensitize and significantly increase input into the central nervous system (nucleus of the solitary tract) which must have consequences, if not to interpretation or awareness of gastric sensation, then at least (or in addition) to efferent outflow to the stomach via the dorsal vagal motor nucleus. Second, that innocuous gastric stimuli can produce a time-limited sensitization of responses of gastric vagal mechanoreceptors reveals considerable neural plasticity, suggesting that normal visceral events can modulate visceral sensory neuron excitability even in healthy persons. Because sensitization reveals an underlying change in neuron excitability, changes in neuron ion channels must be responsible for increases in response magnitude and decreases in response threshold, at least during the initial period of sensitization (see above and Gold, M. S., 2006). Experimental models of visceral hypersensitivity are associated with an increase in neuron input resistance and decrease in resting membrane potential. While the exact mechanisms have not been studied in visceral sensory neurons, changes in the expression and/or function of two pore domain potassium channels and hyperpolarization-activated IH likely also contribute. In addition, both voltagegated sodium (NaV) and voltage-gated potassium (KV) channels have been documented to change in visceral sensory neurons as predicted based on understanding of general biophysical principles. In experimental models of gastric ulceration, gastritis, ileitis, colitis, and cystitis, peak inward sodium currents significantly increase after visceral insult, and the increase is largely contributed to by the TTX-resistant component of the current (e.g., NaV1.8), although precisely which sodium channel has not been established. In addition to changes in threshold, the sensitization is characterized by an increase in action potentially frequency during stimulation. Again voltage-sensitive sodium channels play an important role in this context. As already mentioned, current density increases, the voltage dependence of channel activation shifts and recovery from inactivation is accelerated, and all of these factors clearly facilitate repetitive firing. Conversely, the outward potassium current (the A type current) is reduced and the voltage dependence of activation shifts to more positive potentials in visceral sensory neurons after visceral insult, which is also consistent with an increase in neuron excitability.

Visceral Pain

Central Sensitization

In addition to increased responses and decreased response thresholds, sensitization of visceral nociceptors importantly leads to changes in excitability of central nervous system neurons upon which they terminate, a consequence termed central sensitization. Nociceptor sensitization and central sensitization are considered to underlie, respectively, the expression of primary and secondary hypersensitivity. The most readily apparent reflection of central sensitization in the clinical setting is expansion of the area of referred sensation, which is accompanied by tenderness to palpation (a reflection of peripheral sensitization). The spinal cord has been the principal focus of study with respect to central sensitization, but neurons in supraspinal sites also undergo changes in excitability and, as discussed below, supraspinal sites can contribute significantly to the maintenance of central sensitization and may play a critical role in the maintenance of chronic pain disorders, including functional visceral disorders. The sensitization of central neurons, which has been studied extensively in the spinal cord, results from increased release of neuroactive substances (e.g., glutamate, neurokinins like substance P) from visceral sensory nerve terminals in the spinal cord and from second-order spinal interneurons upon which they may terminate. Because supraspinal sites are also engaged by persistent nociceptive input, another source of neuroactive substances (e.g., serotonin, norepinephrine, and GABA) is derived from projections to the spinal cord from the brainstem. Finally, nonneuronal glia become activated in persistent pain conditions, which has been widely documented in nonhuman animal somatic inflammatory models, and can contribute additional neuroactive substances (e.g., cytokines, chemokines) and modulators to the complex chemical milieu in spinal cord. Contributions from the latter sources (supraspinal sites and glia) likely become more important over time, and their influence may persist and contribute to altered sensations from the viscera in the absence of sustained visceral nociceptor sensitization (see below). Changes within the spinal cord and brain stem areas of visceral input following experimental organ inflammation or noxious stimulation have been assessed by following expression of the immediate early gene, c-fos, upregulation of the neuronal isoform of nitric oxide synthase, and internalization of the receptor for substance P, the neurokinin 1 receptor. These experimental approaches show that organ

insult causes an increase in the indicator studied as well as an anatomical expansion of indicator beyond the normal, resting range of visceral input to the spinal cord. Figure 9 illustrates this point for the

100

% internalized sP receptors

37.4.2

561

Control Inflamed

75 50 25 0 T12–L1 L2–5 L6–S1

Inflamed

Control

Lumbar splanchnic nerve IMG

Pelvic nerve MPG

Colon Figure 9 Internalization of substance P (sP) receptors by colon distension in the absence (control) and 3 h following intracolonic instillation of zymosan (inflamed). In the absence of colon insult (control), noxious colon distension (80 mm Hg, 20 s) leads to internalization of the sP receptor in superficial spinal laminae in an anatomically appropriate distribution (i.e., T12–L1 and L6–S1 spinal segments via the lumbar splanchnic nerve and pelvic nerve innervations of the rat colon – there is no receptor internalization in lumbar spinal segments 2–5). Three hours after intracolonic instillation of an inflamogen, zymosan (inflamed), a time at which responses to colon distension are significantly increased (i.e., colon hypersensitivity is present behaviorally), the amount of sP receptor internalized (quantified at top) is significantly increased and now includes L2–5. IMG, inferior mesenteric ganglia; MPG, major pelvic ganglion. Adapted from Honore´ , P., Kamp, E. H., Rogers, S. D., Gebhart, G. F., and Mantyh, P. W. 2002. Activation of lamina I spinal cord neurons that express the substance p receptor in visceral nociception and hyperalgesia. J. Pain 3, 3–11.

562 Visceral Pain

spinal cord, showing that internalization of the substance P receptor produced by colon distension increases significantly after colon insult and, moreover, now includes an area of the spinal cord that showed no receptor internalization after colon distension in the absence of insult (Honore´, P. et al., 2002). This representation of central sensitization occurred within hours after colonic insult, revealing that mechanosensitive colon afferents sensitize, sleeping afferents awaken, and the visceral innervation and second-order neurons upon which the afferents terminate are rapidly and easily modified (i.e., are highly plastic). Other studies in rats show rapid changes in supraspinal sites as well, suggesting their involvement in states of increased central excitability (e.g., Coutinho, S. et al., 1998). Central sensitization also affects somatic and visceral inputs that converge on spinal neurons, as shown by reduced thresholds for hindpaw withdrawal after bladder or colon insult (Jaggar, S. I. et al., 1999; Miranda, A. et al., 2004; Lamb, K. et al., 2006). Such data obtained in animals are consistent with results from human studies. For example, repetitive colorectal distension increases pain perception and the area of cutaneous pain referral in normals (Ness, T. J. et al., 1990) as well as patients with functional bowel disease (Munakata, J. et al., 1997). Similarly, infusion of 0.15 M hydrochloric acid into the distal esophagus not only reduces stimulus threshold in the distal esophagus, but also in the nonacid-exposed esophagus as well as on the chest wall area of referral within an hour after acid exposure (Sarkar, S. et al., 2000; 2001), again revealing that central sensitization produced by a visceral input is also apparent in the area of somatic referral. Another expression of central sensitization, which can reflect either spinal or supraspinal involvement, is sensitization that develops between organs with inputs onto spinal dorsal horn neurons within the same spinal segments, an expression of viscero-visceral convergence (e.g., urinary bladder and colon), or between organs that do not share patterns of spinal segmental overlap. The former are easy to understand anatomically, and while not rigorously studied in the human population, patients with functional bowel disorders often also complain about pelvic pain or symptoms consistent with interstitial cystitis (Whitehead, W. et al., 2002). Conversely, many patients with interstitial cystitis also suffer from functional bowel disorders (Alagiri, M. et al., 1997). In nonhuman animals, it has been established that colon inflammation triggers bladder hyperactivity

(Pezzone, M. A. et al., 2005) and, conversely, that cystitis produces colon hypersensitivity (Lamb, K. et al., 2006; Winnard, K. P. et al., 2006). Animal and human studies have clearly established the contribution of supraspinal sites to sensitization to visceral input. In susceptible rodent strains, stress enhances behavioral responses to visceral distension (Coutinho, S. V. et al., 2002; Bradesi, S. et al., 2005). While multiple mechanisms may contribute to this modulation of visceral input, descending inhibitory or facilitatory pathways likely play a role (see below), as shown by the effects of electrical stimulation within the rostral ventromedial medulla on responses to noxious colorectal distension (Zhuo, M. and Gebhart, G. F., 2002) and of selective abolition of descending facilitatory influences in a model of rodent pancreatitis (Vera-Portocarrero, L. P. et al., 2007). These reports are consistent with data obtained in human volunteers. Activation of descending inhibitory mechanisms through heterotopic stimulation blunted perception of rectal distension in healthy volunteers (Song, G. H. et al., 2006). Conversely, uncomfortable visceral input triggered by acid infusion into the duodenum lowered the pain threshold to proximal esophageal stimulation (Hobson, A. R. et al., 2004). These experiments also support a rapid involvement (minutes to hours) of supraspinal sites in central sensitization. Longer-term evidence of supraspinal contributions to central sensitization is provided by both clinical reports of esophageal or gastric hypersensitivity in patients with IBS (or somatic disorders like fibromyalgia) (Price, D. D. et al., 2007a; 2007b; Sharma, A. and Aziz, Q., 2007) and by various manipulations limited to the neonatal period that lead either to visceral hypersensitivity or increased susceptibility to organ insult in adult animals. In rats, neonatal colon irritation (intracolonic mustard oil) or colon distension (Al Chaer, E. D. et al., 2000), urinary bladder inflammation (intravesical zymosan, Randich, A. et al., 2006), maternal separation (a stressor, Coutinho, S. V. et al., 2002), or neonatal immune challenge with the bacterial endotoxin lipopolysaccharide (Spencer, S. J. et al., 2007) are all associated with increased organ sensitivity in the adult animal. Because these experimental neonatal manipulations are not associated with adult organ inflammation, the adult visceral hypersensitivity in these models is considered to be maintained by central nervous system mechanisms, including dysregulation or reorganization (discussed in Section 37.4.3).

Visceral Pain

Mechanistically, both human and nonhuman animal studies have established an important role for peripheral, spinal (and supraspinal) N-methyl-Daspartate (NMDA) receptors in central sensitization following visceral insult (e.g., McRoberts, J. A. et al., 2001; Willert, R. P. et al., 2004; see Woolf, C. J. and Thompson, S. W., 1991 for a general overview), although the relevant spinal neurons and signal transduction pathways in visceral sensory pathways are not revealed by these findings. The process of central sensitization is linked to long-term potentiation, which has been extensively studied in the hippocampus in relation to learning and memory, and in spinal cord exhibits similar characteristics that involve transcriptional and other events that lead to changes in excitability that can outlast the peripheral input. Although not focused on visceral inputs, these studies are based on features common to visceral nociceptive input: recordings from lamina I spinal dorsal horn neurons that project to the pontine parabrachial area and coactivation of substance P and NMDA receptors (Ikeda, H. et al., 2003; 2006). Study of this population of spinal neurons, upon which visceral afferents likely terminate (along with nonvisceral nociceptive afferents), reveals synaptic plasticity dependent upon neuroactive substances contained and released from visceral afferent terminals in the spinal cord and a cellular process that likely contributes to induction of central sensitization. 37.4.3

Central Modulation of Visceral Pain

One consequence of peripheral events that lead to central sensitization is activation of endogenous pain modulatory systems and there is growing appreciation that visceral disorders characterized by persistent discomfort and pain reveal, at least in part, a dysregulated central nervous system. The concept that there exist endogenous mechanisms that modulate pain arose from studies showing that electrical stimulation or chemical activation (e.g., glutamate to activate cells or drugs like opioids acting at their cognate receptors) in the brainstem PAG produced powerful descending inhibitory effects on spinal nociceptive inputs. The initial focus of such studies was on inhibitory inputs descending from the brainstem and on modulation of noxious inputs. Presently, it is appreciated that descending influences require a relay in the rostral ventromedial medulla between the PAG and spinal cord, are not restricted to modulation of only noxious inputs, and importantly not limited to only inhibitory influences.

563

Normally, descending modulation represents a balance between inhibitory and facilitatory influences, with inhibition typically dominant. Facilitatory influences, however, have been shown to predominate in some experimental conditions and have been hypothesized to contribute to maintenance of persistent pain states (Porreca, F. et al., 2002; Gebhart, G. F., 2004). With respect to functional visceral disorders that persist in the absence of a defined pathobiology, and many of which are comorbidly expressed with other generalized disorders (e.g., fibromyalgia), the concept of a dysregulated modulatory system has gained both currency and experimental support. Most nonhuman animal studies have examined nonvisceral pain, but several studies have confirmed for visceral inputs what has been more widely documented for nonvisceral inputs. Activation of brainstem sites (PAG and rostral ventromedial medulla) has been shown to facilitate visceromotor reflexes (Zhuo, M. and Gebhart, G. F., 2002) and spinal dorsal horn neuron responses (Zhuo, M. et al., 2002) to noxious colon distension in the rat. Similarly, an experimental pancreatitis in rats has been shown to be maintained by facilitatory influences descending from the rostral ventromedial medulla (Vera-Portocarrero, L. P. et al., 2007). These studies confirm that modulation of spinal nociceptive visceral transmission does not differ in character from modulation of nonvisceral inputs. Importantly, studies in humans suggest that facilitatory modulatory influences can contribute to persistent pain states, including visceral pain states. Such studies rely on interpretation of changes in patterns or intensity of brain imaging or on localization, wave form, and magnitude of event-related cortical potentials. For example, Dimcevski G. et al. (2007) recently reported functional brain reorganization in chronic pancreatitis patients. They electrically stimulated at different sites from above the gastro-esophageal junction to the horizontal part of the duodenum and recorded event-related brain potentials from surface electrodes on the scalp and also assessed sensation. They found that neuronal sources in the insula were most consistently changed in chronic pancreatitis patients relative to healthy controls and concluded that reorganization in this part of the brain is a contributing mechanism to pain in chronic pancreatitis. This and other reports (e.g., Price, D. D. et al., 2007a; 2007b) clearly reveal that central mechanisms are important to the maintenance of persistent visceral pain conditions. Mechanisms by which the

564 Visceral Pain

excitability of neurons in these or other brain areas might increase or decrease and be sustained are unknown. Stress and other external factors, as well as cognitive and emotional events, can contribute to activity in supraspinal sites and influence the interpretation of information arriving there from internal organs. The matrix of brain areas activated by painful visceral stimuli is similar to that seen during anticipation of such a painful stimulus, demonstrating the importance of cognitive influences (Ya´gu¨ez, L. et al., 2005). Stress activates the hypothalamic–pituitary– adrenal axis, resulting in the release of various neuroendocrine mediators. Studies in humans have demonstrated different neuroendocrine responses in patients with chronic visceral pain syndromes (Posserud, I. et al., 2004). These mediators may directly or indirectly affect visceral sensory function (e.g., Tache´, Y. et al., 2004) and may function as targets for pharmacologic interventions.

37.5 Summary (1) The principal conscious sensations that arise from the viscera are discomfort and pain. Typically, visceral pain is diffuse and difficult to localize, not distinctly felt at the source and instead referred to other tissues. (2) Most experimental work in humans and nonhuman animals has utilized hollow organ distension, an adequate (in the Sherringtonian context) noxious visceral stimulus. Visceral inflammation and ischemia are also considered to be adequate stimuli, but they are more difficult to control experimentally and thus have been less widely used. It is generally held that pain cannot be produced from all viscera (e.g., the parenchyma of solid organs like the liver) or from organs that have only an afferent innervation (and not a sensory innervation), but new knowledge has expanded our understanding of visceral sensations and suggest that these and other issues of visceral insensitivity should be reevaluated. (3) The innervation of the viscera is unique. Each organ is innervated by two nerves, either the vagus nerve and a spinal visceral nerve or a splanchnic nerve and the pelvic nerve, and the function(s) of each nerve differ. The route from the organ to the spinal cord of spinal visceral nerves involves transit of prevertebral ganglia, where axon collaterals of visceral nerves can

influence organ function, as well as paravertebral ganglia. Vagal afferent fibers terminate centrally in the brainstem nucleus of the solitary tract. (4) Cell bodies of the vagus nerves are contained in the nodose ganglia (primarily) and cell bodies of all other visceral nerves are contained in DRG. Generally, visceral sensory neuron cell bodies are larger in size than would be expected given that virtually all visceral sensory neurons have thinly myelinated or unmyelinated axons, which in the somatic realm are associated with smalldiameter cell bodies. (5) Spinal visceral nerves terminate in laminae I, II, V, and X, but importantly branch significantly within the spinal cord and extend both rostrally and caudally from the spinal segment of entry. Significantly, some terminations reach the contralateral side of the spinal cord. (6) Most mechanoreceptors in viscera have low thresholds for response to stretch/tension (e.g., balloon distension), but a significant proportion (20–30%) have high thresholds for response. The latter group fulfills criteria for nociceptors: their response threshold is in the noxious range (generally 30 mm Hg distending stimulus) and they encode stimulus intensity in the noxious range, but do not encode innocuous intensities of stimulation. (7) Low-threshold visceral mechanoreceptors respond in the physiologic range, but in addition possess properties that suggest involvement in visceral discomfort and pain. Unlike lowthreshold cutaneous mechanoreceptors, lowthreshold visceral mechanoreceptors respond vigorously to noxious intensities of stimulation, continue to encode stimulus intensity into the noxious range, and sensitize (a defining characteristic of nociceptors). These properties are not unlike some low-threshold sensory neurons that innervate another deep tissue, muscle. (8) Low-threshold visceral mechanoreceptors are normally and principally involved in afferent and reflex functions, but in conjunction with high-threshold visceral mechanoreceptors can contribute to intense acute visceral pain. In functional, inflammatory or ischemic visceral disorders, where sensitization develops and sleeping visceral nociceptors become active, we believe that all mechanosensitive visceral endings can contribute to uncomfortable and painful visceral sensation.

Visceral Pain

(9) Visceral sensory neurons sensitize and thereby contribute to central sensitization, a consequence of increased input to the central nervous system that is not limited only to the spinal cord. Tenderness to palpation and an increase in the area of referred sensation, respectively, mark peripheral and central sensitization. (10) Functionally, visceral sensory neurons in the different innervations of the same organ are affected differently by sensitizing events. This perhaps should not be surprising given that the proportions and distributions of mechanosensitive endings of the two innervations differ significantly for the organs studied to date. This is a developing area of investigation that has the potential to lead to therapeutic strategies targeting a selective innervation of a viscus. (11) Brainstem modulatory circuitry normally exerts an inhibitory influence on spinal pain transmission. Increased visceral input from sensitized receptors initiates processes of sensitization in both spinal and supraspinal sites, which can alter the balance between descending inhibitory and facilitatory influences on spinal pain transmission. In cases of long lasting visceral hypersensitivity (e.g., functional bowel disorders), the hypothesis that the hypersensitivity is maintained by supraspinal influences in the absence of sensitized visceral input is tenable.

References Adriaensen, D. I., Brouns, I., Van Genechten, J., and Timmermans, J-P. 2003. Functional morphology of pulmonary neuroepithelial bodies: extremely complex airway receptors. Anat. Rec. 270, 25–40. Ahmed, K., Amadesi, S., Bautista, F., Bunnett, N., and Vanner, S. J. 2007. Mechanisms of protease activated receptor 2 – evoked hyperexcitability of nociceptive neurons innervating the mouse colon. J. Physiol. 580, 977–991. Alagiri, M., Chottiner, S., Ratner, V., Slade, D., and Hanno, P. M. 1997. Interstitial cystitis: unexplained associations with other chronic disease and pain syndromes. Urology 49, 52–57. Al-Chaer, E. D., Kawasaki, M., and Pasricha, P. J. 2000. A new model of chronic visceral hypersensitivity in adult rats induced by colon irritation during postnatal development. Gastroenterology 119, 1276–1285. Andresen, V., Camilleri, M., Kim, H. J., Stephens, D. A., Carlson, P. J., Talley, N. J., Saito, Y. A., Urrutia, R., and Zinsmeister, A. R. 2006. Is there an association between GN[beta]3-C825T genotype and lower functional gastrointestinal disorders? Gastroenterology 130, 1985–1994. Apkarian, A., Bruggemann, J., Shi, T., and Airapetian, L. 1995. A Thalamic Model for True and Referred Visceral Pain. In: Visceral Pain, Progress in Pain Research and

565

Management (ed. G. F. Gebhart), Vol. 5, pp. 217–259. IASP Press. Barbara, G., Stanghellini, V., De Giorgio, R., and Corindaldesi, R. 2006. Functional gastrointestinal disorders and mast cells: implications for therapy. Neurogastroenterol. Motil. 18, 6–17. Barbara, G., Wang, B., Stanghellini, V., De Giorgio, R., Cremon, C., Di Nardo, G., Trevisani, M., Campi, B., Geppetti, P., Tonini, M., Bunnett, N., Grundy, D., and Corinaldesi, R. 2007. Mast cell-dependent excitation of visceral-nociceptive sensory neurons in irritable bowel syndrome. Gastroenterology 132, 26–27. Benson, C. J., Eckert, S. P., and McCleskey, E. W. 1999. Acidevoked currents in cardiac sensory neurons: a possible mediator of myocardial ischemic sensation. Circ. Res. 84, 921–928. Beyak, M. J. and Vanner, S. 2005. Inflammation-induced hyperexcitability of nociceptive gastrointestinal DRG neurones: the role of voltage-gated ion channels. Neurogastroenterol. Motil. 17, 175–186. Bhat, Y. and Bielefeldt, K. 2006. Capsaicin receptor (TRPV1) and non-erosive reflux disease. Eur. J. Gastroenterol. Hepatol. 18, 263–270. Birder, L. A., Kanai, A. J., de Groat, W. C., Kiss, S., Nealen, M. L., Burke, N. E., Dineley, K. E., Watkins, S., Reynolds, I. J., and Caterina, M. J. 2001. Vanilloid receptor expression suggests a sensory role for urinary bladder epithelial cells. Proc. Natl. Acad. Sci. U. S. A. 98, 13396–13401. Blackshaw, L. A., Brookes, S. J. H., Grundy, D., and Schemann, M. 2007. Sensory transmission in the gastrointestinal tract. Neurogastrol. Motil. 19(Supp 1), 1–19. Bradesi, S., Schwetz, I., and Ennes, H. S. 2005. Repeated exposure to water avoidance stress in rats: A new model for sustained visceral hyperalgesia. Am. J. Physiol. 289, G42–G53. Brierley, S. M., Jones, R. C. W., III, Gebhart, G. F., and Blackshaw, L. A. 2004. Splanchnic and pelvic mechanosensory afferents signal different qualities of colonic stimuli in mice. Gastroenterology 127, 166–178. Bueno, L., Floramonti, J., Delvaux, M., and Frexinos, J. 1997. Mediators and pharmacology of visceral sensitivity: from basic to clinical investigations. Gastroenterology 112, 1714–1743. Camilleri, M. 2004. Is there a SERT-ain association with IBS? Gut 53, 1396–1399. Cenac, N., Andrews, C. N., Holzhausen, M., Chapman, K., Cottrell, G., Andrade-Gordon, P., Steinhoff, M., Barbara, G., Beck, P., Bunnett, N. W., Sharkey, K., Ferraz, G. P., Shaffer, E., and Vergnolle, N. 2007. Role for protease activity in visceral pain in irritable bowel syndrome. J. Clin. Invest. 117, 636–647. doi:10.1172/JCI29255. Chan, C. L. H., Facer, P., Davis, J. B., Smith, G. D., Egerton, J., Bountra, C., Williams, N. S., and Anand, P. 2003. Sensory fibres expressing capsaicin receptor TRPV1 in patients with rectal hypersensitivity and faecal urgency. Lancet 361, 385–391. Christianson, J. A., Traub, R. J., and Davis, B. M. 2006. Differences in spinal distribution and neurochemical phenotype of colonic afferents in mouse and rat. J. Comp. Neurol. 494, 246–259. Cockayne, D. A., Hamilton, S. G., Zhu, Q. M., Dunn, P. M., Zhong, Y., Novakovic, S., Malmberg, A. B., Cain, G., Berson, A., Kassotakis, L., Hedley, L., Lachnit, W. G., Burnstock, G., McMahon, S. B., and Ford, A. P. 2000. Urinary bladder hyporeflexia and reduced pain-related behaviour in p2x3-deficient mice. Nature 407, 1011–1015.

566 Visceral Pain Coutinho, S. V., Plotsky, P. M., Sablad, M., Miller, J. C., Zhou, H., Bayati, A. I., McRoberts, J. A., and Mayer, E. A. 2002. Neonatal maternal separation alters stress-induced responses to viscerosomatic nociceptive stimuli in rat. Am. J. Physiol. 282, G307–G316. Coutinho, S., Su, X., Sengupta, J. N., and Gebhart, G. F. 2000. Role of Sensitized Pelvic Nerve Afferents from the Inflamed Rat Colon in The Maintenance of Visceral Hyperalgesia. In: Nervous System Plasticity and Chronic Pain, Progress in Brain Research (eds. J. Sandku¨her, B. Bromm, and G. F. Gebhart), Vol. 129, pp. 375–387. Elsevier. Coutinho, S., Urban, M. O., and Gebhart, G. F. 1998. Role of glutamate receptors and nitric oxide in the rostral ventromedial medulla in visceral hyperalgesia. Pain 78, 59–69. Cutz, E. 1982. Neuroendocrine cells of the lung. An overview of morphologic characteristics and development. Exp. Lung Res. 3, 185–208. Dakhama, A., Kanehiro, A., Makela, M. J., Loader, J. E., Larsen, G. L., and Gelfand, E. W. 2002. Regulation of airway hyperresponsiveness by calcitonin gene-related peptide in allergen sensitized and challenged mice. Am. J. Respir. Crit. Care Med. 165, 1137–1144. Dang, K., Bielefeldt, K., and Gebhart, G. F. 2004. Gastric ulcers reduce A-type potassium currents in rat gastric sensory ganglion neurons. Am. J. Physiol. 286, G573–G579. Dang, K., Bielefeldt, K., and Gebhart, G. F. 2005. Differential responses of bladder lumbosacral and thoracolumbar dorsal root ganglion neurons to purinergic agonists, protons, and capsaicin. J. Neurosci. 25, 3973–3984. Dimcevski, G., Saber, A. K., Funch-Jensen, P., Le Pera, D., Valeriani, M., Arendt-Nielsen, L., and Drewes, A. 2007. Pain in chronic pancreatitis: the role of reorganization in the central nervous system. Gastroenterology 132, 1546–1556. Dunckley, P., Wise, R. G., Fairhurst, M., Hobden, P., Aziz, Q., Chang, L., and Tracey, I. 2005. A comparison of visceral and somatic pain processing in the human brainstem using functional magnetic resonance imaging. J. Neurosci. 25, 7333–7341. Foreman, R. 1999. Mechanisms of cardiac pain. Annu. Rev. Physiol. 61, 143–167. Fu, X. W., Wang, D., Nurse, C. A., Dinauer, M. C., and Cutz, E. 2000. NADPH oxidase is an O2 sensor in airway chemoreceptors: evidence from Kþ current modulation in wild-type and oxidase-deficient mice. Proc. Natl. Acad. Sci. U. S. A. 97, 4374–4379. Gebhart, G. F. 2004. Descending modulation of pain. Neurosci. Biobehav. Rev. 27, 729–737. Gershon, M. D. and Tack, J. 2007. The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology 132, 397–414. Gold, M. S. 2006. Ion Channels: Recent Advances and Clinical Applications. In: Proceedings of the 11th World Congress on Pain (eds. H. Flor, E. Kalso, and J. O. Dostrovsky) pp. 73–92. IASP Press. Halder, S. L. and Locke, G. R., III. 2007. Epidemiology and Socioeconomic Impact of Visceral and Abdominal Pain Syndromes. In: Chronic Abdominal and Visceral Pain (eds. P. Pasricha, W. Willis, and G. F. Gebhart), pp. 11–16. Informa Healthcare. Hillsley, K., Lin, J.-H., Stnaisz, A., Grundy, D., Aerssens, J., Peeters, P. J., Moechars, D., Coulie, B., and Stead, R. H. 2006. Dissecting the role of sodium currents in visceral sensory neurons in a model of chronic hyperexcitability using NaV1.8 and NaV1.9 null mice. J. Physiol. 576, 257–267. Hobson, A. R. and Aziz, Q. 2004. Brain imaging and functional gastrointestinal disorders: has it helped our understanding. Gut 53, 1198–1206.

Hobson, A. R., Khan, R. W., Sarkar, S., Furlong, P. L., and Aziz, Q. 2004. Development of esophageal hypersensitivity following experimental duodenal acidification. Am. J. Gastroenterol. 99, 813–820. Holtmann, G., Siffert, W., Haag, S., Mueller, N., Langkafel, M., Senf, W., Zotz, R., and Talley, N. J. 2004. G-protein 3 subunit 825 CC genotype is associated with unexplained (functional) dyspepsia. Gastroenterology 126, 971–979. Honore´, P., Kamp, E. H., Rogers, S. D., Gebhart, G. F., and Mantyh, P. W. 2002. Activation of lamina I spinal cord neurons that express the substance p receptor in visceral nociception and hyperalgesia. J. Pain 3, 3–11. Hoogerwerf, W. A., Shenoy, M., Winston, J., Xiao, S. Y., He, Z., and Pasricha, P. J. 2004. Trypsin mediates nociception via the proteinase-activated receptor 2: a potentially novel role in pancreatic pain. Gastroenterology 127, 883–891. Hoogerwerf, W. A., Zou, L., Shenoy, M., Sun, D., Micci, M. A., Lee-Hellmich, H., Xiao, S. Y., Winston, J. H., and Pasricha, P. J. 2001. The proteinase-activated receptor 2 is involved in nociception. J. Neurosci. 21, 9036–9042. Ikeda, H., Heinke, B., Ruscheweyh, R., and Sandkuhler, J. 2003. Synaptic plasticity in spinal lamina i projection neurons that mediate hyperalgesia. Science 299, 1237–1240. Ikeda, H., Stark, J., Fischer, H., Wagner, M., Drdla, R., Jajer, T., and Sandkuhler, J. 2006. Synaptic amplifier of inflammatory pain in the spinal dorsal horn. Science 312, 1659–1662. Jaggar, S. I., Scott, H. C., and Rice, A. S. 1999. Inflammation of the rat urinary bladder is associated with a referred thermal hyperalgesia which is nerve growth factor dependent. Br. J. Anaesth. 83, 442–448. Jones, R. C. W., III, Xu, L., and Gebhart, G. F. 2005. The mechanosensitivity of mouse colon afferent fibers and their sensitization by inflammatory mediators require transient receptor potential vanilloid 1 and acid-sensing ion channel 3. J. Neurosci. 25, 10981–10989. Kang, Y., Bielefeldt, K., and Gebhart, G. F. 2004. Sensitization of mechanosensitive gastric vagal afferent fibers in the rat by thermal and chemical stimuli and gastric ulcers. J. Neurophysiol. 91, 1981–1989. Laird, J. M. A., Olivar, T., Roza, C., De Felipe, C., Hunt, S. P., and Cervero, F. 2000. Deficits in visceral pain and hyperalgesia of mice with a disruption of the tachykinin NK1 receptor gene. Neuroscience 98, 345–352. Laird, J. M., Souslova, V., Wood, J. N., and Cervero, F. 2002. Deficits in visceral pain and referred hyperalgesia in Nav1.8 (SNS/PN3)-null mice. J. Neurosci. 22, 8352–8356. Lamb, K., Kang, Y. M., Gebhart, G. F., and Bielefeldt, K. 2003. Gastric inflammation triggers hypersensitivity to acid in awake rats. Gastroenterology 125, 1410–1418. Lamb, K., Zhong, F., Gebhart, G. F., and Bielefeldt, K. 2006. Experimental colitis in mice and sensitization of converging visceral and somatic afferent pathways. Am. J. Physiol. 290, G451–G457. Langley, J. N. 1921. The Autonomic Nervous System. Heffer. Longhurst, J. C. 1995. Chemosensitive Abdominal Visceral Afferents. In: Visceral Pain Research and Management (ed. G. F. Gebhart), Vol. 5, pp. 99–132. IASP Press. Lynn, P. A., Olsson, C., Zagorodnyuk, V., Costa, M., and Brookes, S. J. H. 2003. Rectal intraganglionic laminar endings are transduction sites of extrinsic mechanoreceptors in the guinea pig rectum. Gastroenterology 125, 786–794. McMahon, S. B., Bennett, D. L. H., and Bevan, S. 2006. Inflammatory Mediators and Modulators of Pain. In: Wall and Melzack’s Textbook of Pain, 5th edn. (eds. S. B. McMahon and M. Koltzenburg), pp. 49–72. Elsevier. McRoberts, J. A., Coutinho, S. V., Marvizon, J. C., Grady, E. F., Tognetto, M., Sengupta, J. N., Ennes, H. S., Chaban, V. V.,

Visceral Pain Amadesi, S., Creminon, C., Lanthorn, T., Geppetti, P., Bunnett, N. W., and Mayer, E. A. 2001. Role of peripheral N-methyl-D-aspartate (NMDA) receptors in visceral nociception in rats. Gastroenterology 120, 1737–1748. Meller, S. T. and Gebhart, G. F. 1992. A critical review of the afferent pathways and the potential chemical mediators involved in cardiac pain. Neuroscience 48, 501–524. Miranda, A., Peles, S., Rudolph, C., Shaker, R., and Sengupta, J. N. 2004. Altered visceral sensation in response to somatic pain in the rat. Gastroenterology 126, 1082–1089. Molliver, D. C., Wright, D. E., Leitner, M. L., Parsadanian, A. S., Doster, K., Wen, D., Yan, O., and Snider, W. D. 1997. Ib4binding drg neurons switch from ngf to gdnf dependence in early postnatal life. Neuron 19, 849–861. Mukerji, G., Yiangou, Y., Agarwal, S. K., and Anand, P. 2006. Transient receptor potential vanilloid receptor subtype 1 in painful bladder syndrome and its correlation with pain. J. Urol. 176, 797–801. Munakata, J., Naliboff, B., Harraf, F., Kodner, A., Lembo, T., Chang, L., Silverman, D. H., and Mayer, E. A. 1997. Repetitive sigmoid stimulation induces rectal hyperalgesia in patients with irritable bowel syndrome. Gastroenterology 112, 55–63. Ness, T. J., Metcalf, A. M., and Gebhart, G. F. 1990. A psychophysiological study in humans using phasic colonic distension as a noxious visceral stimulus. Pain 43, 377–386. Page, A. J., Brierley, S. M., Martin, C. M., Price, M. P., Symonds, E., Butler, R., Wemmie, J. A., and Blackshaw, L. A. 2005. Different contributions of asic channels 1a, 2, and 3 in gastrointestinal mechanosensory function. Gut 54, 1408–1415. Page, A. J., Martin, C. M., and Blackshaw, L. A. 2002. Vagal mechanoreceptors and chemoreceptors in mouse stomach and esophagus. J. Neurophysiol. 87, 2095–2103. Palecek, J., Paleckova, V., and Willis, W. D. 2002. The roles of pathways in the spinal cord lateral and dorsal funiculi in signaling nociceptive somatic and visceral stimuli in rats. Pain 96, 297–307. Pan, H. and Chen, S. R. 2002. Myocardial ischemia recruits mechanically insensitive cardiac sympathetic afferents in cats. J. Neurophysiol. 87, 660–668. Pan, H. L., Longhurst, J. C., Eisenach, J. C., and Chen, S. R. 1999. Role of protons in activation of cardiac sympathetic C-fibre afferents during ischaemia in cats. J. Physiol. 518, 857–866. Perl, E. 1996. Pain and the Discovery of Nociceptors. In: Neurobiology of Nociceptors (eds. C. Belmonte and F. Cervero), pp. 5–36. Oxford University Press. Pezzone, M. A., Liang, R., and Fraser, M. O. 2005. A model of neural cross-talk and irritation in the pelvis: implications for the overlap of chronic pelvic pain disorders. Gastroenterology 128, 1953–1964. Phelps, E. A. and LeDoux, J. E. 2005. Contributions of the amygdala to emotion processing: from animal models to human behavior. Neuron 48, 175–187. Phillips, R. J. and Powley, T. L. 2000. Tension and stretch receptors in gastrointestinal smooth muscle: re-evaluating vagal mechanoreceptor electrophysiology. Brain Res. Rev. 34, 1–26. Porreca, F., Ossipov, M. H., and Gebhart, G. F. 2002. Tonic descending facilitation as a mechanism of chronic pain. Trends Neurosci. 25, 319–325. Posserud, I., Agerforz, P., Ekman, R., Bjornsson, E. S., Abrahamsson, H., and Simren, M. 2004. Altered visceral perceptual and neuroendocrine response in patients with irritable bowel syndrome during mental stress. Gut 53, 1102–1108. Powley, T. L. and Phillips, R. J. 2002. Musings on the wanderer: what’s new in our understanding of vago-vagal reflexes?: I.

567

Morphology and topography of vagal afferents innervating the GI tract. Am. J. Physiol. 283, G1217–G1225. Price, D. D., Craggs, J., Verne, N., Perlstein, W. M., and Robinson, M. E. 2007a. Placebo analgesia is accompanied by large reductions in pain-related brain activity in irritable bowel syndrome patients. Pain 127, 63–72. Price, D. D., Robinson, M. E., and Verne, G. N. 2007b. Measuring Pain and Hyperalgesia in Persistent Pain Conditions with a Special Emphasis on Irritable Bowel Syndrome. In: Chronic Abdominal and Visceral Pain (eds. P. Pasricha, W. Willis, and G. F. Gebhart), pp. 127–140. Informa Healthcare. Randich, A., Uzzell, T., DeBerry, J. J., and Ness, T. J. 2006. Neonatal urinary bladder inflammation produces adult bladder hypersensitivity. J. Pain 7, 469–479. Ricco, M. M., Kummer, W., Biglari, B., Myers, A. C., and Undem, B. J. 1996. Interganglionic segregation of distinct vagal afferent fibre phenotypes in guinea-pig airways. J. Physiol 496, 521–530. Robinson, D. R., McNaughton, P. A., Evans, M. L., and Hicks, G. A. 2004. Characterization of the primary spinal afferent innervation of the mouse colon using retrograde labelling. Neurogastroenterol. Motil. 16, 113–124. Rong, W., Hillsley, K., Davis, J. B., Hicks, G., Winchester, W. J., and Grundy, D. 2004. Jejunal afferent nerve sensitivity in wild-type and TRPV1 knockout mice. J. Physiol. 560, 867–881. Sarkar, S., Aziz, Q., Woolf, C. J., Hobson, A. R., and Thompson, D. G. 2000. Contribution of central sensitisation to the development of non-cardiac chest pain. Lancet 356, 1154–1159. Sarkar, S., Hobson, A. R., Furlong, P. L., Woolf, C. J., Thompson, D. G., and Aziz, Q. 2001. Central neural mechanisms mediating human visceral hypersensitivity. Am. J. Physiol. 281, G1196–G1202. Schmidt, R. F. 1996. The Articular Polymodal Nociceptor in Health and Disease. In: ThePolymodal Receptor: A Gateway to Pathological Pain, Progress in Brain Research (eds.T. Kumazawa, L. Kruger, and K. Mizumura), Vol. 113, pp. 53–81. Elsevier. Schuligoi, R., Joci, M., Heinemann, A., Schoninkle, E., Pabst, M. A., and Holzer, P. 1998. Gastric acid-evoked c-fos messenger RNA expression in rat brainstem is signaled by capsaicin-resistant vagal afferents. Gastroenterology 115, 649–660. Sharma, A. and Aziz, Q. 2007. Mechanisms of Visceral Sensitization in Humans. In: Chronic Abdominal and Visceral Pain (eds. P. Pasricha, W. Willis, and G. F. Gebhart), pp. 141–160. Informa Healthcare. Sherrington, C. S. 1900. Cutaneous Sensations. In: Textbook of Physiology (ed. E. A. Scha¨ffer), pp. 920–1001. Pentland. Sherrington, C. S. 1906. The Integrative Action of the Nervous System. Scribner. Sidhu, H., Kern, M., and Shaker, R. 2004. Absence of increasing cortical FMRI activity volume in response to increasing visceral stimulation in IBS patients. Am. J. Physiol. 287, G425–G435. Song, G. H., Venkatraman, V., Ho, K. Y., Chee, M. W., Yeoh, K. G., and Wilder-Smith, C. H. 2006. Cortical effects of anticipation and endogenous modulation of visceral pain assessed by functional brain MRI in irritable bowel syndrome patients and healthy controls. Pain 126, 79–90. Spencer, S. J., Hyland, N. P., Sharkey, K. A., and Pittman, Q. J. 2007. Neonatal immune challenge exacerbates experimental colitis in adult rats: potential role for TNF-. Am. J. Physiol. 292, R308–R315. Spiller, R. C., Jenkins, D., Thornley, J. P., Hebden, J. M., Wright, T., Skinner, M., and Neal, K. R. 2000. Increased rectal mucosal enteroendocrine cells, T lymphocytes and

568 Visceral Pain increased gut permeability following acute campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut 47, 804–811. Stead, R. H., Dixon, M. F., Bramwell, N. H., Riddell, R. H., and Bienenstock, J. 1989. Mast cells are closely apposed to nerves in the human gastrointestinal mucosa. Gastroenterology 97, 575–585. Stewart, T. M., Beyak, M. J., and Vanner, S. J. 2003. Ileitis modulates potassium and sodium currents in guinea pig dorsal root ganglia neurons. J. Physiol. 552, 797–807. Strigo, I. A., Duncan, G. H., Boivin, M., and Bushnell, M. C. 2003. Differentiation of visceral and cutaneous pain in the human brain. J. Neurophysiol. 89, 3294–3303. Su, X., Sengupta, J. N., and Gebhart, G. F. 1997. Effects of opioids on mechanosensitive pelvic nerve afferent fibers innervating the urinary bladder of the rat. J. Neurophysiol. 77, 1566–1580. Sugiura, T., Bielefeldt, K., and Gebhart, G. F. 2004. TRPV1 function in mouse colon sensory neurons is enhanced by metabotropic 5-hydroxytryptamine receptor activation. J. Neurosci. 24, 9521–9530. Sugiura, T., Bielefeldt, K., and Gebhart, G. F. 2007. Mouse colon sensory neurons detect extracellular acidosis via TRPV1. Am. J. Physiol. 292, C1768–C1774. Sugiura, T., Dang, K., Lamb, K., Bielefeldt, K., and Gebhart, G. F. 2005. Acid-sensing properties in rat gastric sensory neurons from normal and ulcerated stomach. J. Neurosci. 25, 2617–2627. Tache´, Y., Martinez, V., Wang, L., and Million, M. 2004. CRF1 receptor signaling pathways are involved in stress-related alterations of colonic function and viscerosensitivity: implications for irritable bowel syndrome. Br. J. Pharmacol. 141, 1321–1330. Torebjo¨rk, H. E., Schmelz, M., and Handwerker, H. O. 1996. Functional Properties of Human Cutaneous Nociceptors and their Role in Pain and Hyperalgesia. In: Neurobiology of Nociceptors (eds. C. Belmonte and F. Cervero), pp. 349–369. Oxford University Press. Undem, B. J., Carr, M. J., and Kollarik, M. 2002. Physiology and plasticity of putative cough fibres in the Guinea pig. Pulm. Pharmacol. Ther. 15, 217–219. Undem, B. J., Chuaychoo, B., Lee, M. G, Weinreich, D., Myers, A. C., and Kollarik, M. 2004. Sybtypes of vagal afferent c-fibres in guinea-pig lungs. J. Physiol. 556, 905–917. Vandenberghe, J., Vos, R., Persoons, P., Demyttenaere, K., Janssens, J., and Tack, J. 2005. Dyspeptic patients with visceral hypersensitivity: sensitisation of pain specific or multimodal pathways? Gut 54, 914–919. Vera-Portocarrero, L. P., Yie, J., Kowal, J., Ossipov, M., King, T., and Porreca, F. 2006. Descending facilitation from the rostral ventromedial medulla maintains visceral pain in rats with experimental pancreatitis. Gastroenterology 130, 2155–2164. Wang, F. B. and Powley, T. L. 2000. Topographic inventories of vagal afferents in gastrointestinal muscle. J. Comp. Neurol. 421, 302–324. Wemmie, J., Price, M., and Welsh, M. 2006. Acid-sensing ion channels: advances, questions and therapeutic opportunities. Trends Neurosci. 29, 578–586. Whitehead, W., Palsson, O., and Jones, K. 2002. Systematic review of the comorbidity of irritable bowel syndrome with other disorders: What are the causes and implications? Gastroenterology 122, 1140–1156. Willert, R. P., Woolf, C. J., Hobson, A. R., Delaney, C., Thompson, D. G., and Aziz, Q. 2004. The development and maintenance of human visceral pain hypersensitivity is dependent on the N-methyl-D-aspartate receptor. Gastroenterology 126, 683–692. Winnard, K. P., Dmitrieva, N., and Berkley, K. 2006. Cross-organ interactions between reproductive, gastrointestinal, and

urinary tracts: modulation by estrous stage and involvement of the hypogastric nerve. Am. J. Physiol. 291, R1592–R1601. Woolf, C. J. and Thompson, S. W. 1991. The induction and maintenance of central sensitization is dependent on Nmethyl-D-aspartic acid receptor activation: implications for the treatment of post-injury pain hypersensitivity states. Pain 44, 293–299. Wynn, G., Ma, B., Ruan, H. Z., and Burnstock, G. 2004. Purinergic component of mechanosensory transduction is increased in a rat model of colitis. Am. J. Physiol. 287, G647–G657. Wynn, G., Rong, W., Xiang, Z., and Burnstock, G. 2003. Purinergic mechanisms contribute to mechanosensory transduction in the rat colorectum. Gastroenterology 25, 1398–1409. Xu, G., Winston, J., Shenoy, M., Yin, H., and Pasricha, P. J. 2006. Enhanced excitability and suppression of A-type Kþ current of pancreas-specific afferent neurons in a rat model of chronic pancreatitis. Am. J. Physiol. 291, G424–G431. Ya´gu¨ez, L., Coen, S., Gregory, L. J., Amaro, E., Jr., Altman, C., Brammer, M. J., Bullmore, E. T., Williams, S. C. R., and Aziz, Q. 2005. Brain response to visceral aversive conditioning: a functional magnetic resonance imaging study. Gastroenterology 128, 1819–1829. Yoshimura, N. and de Groat, W. C. 1999. Increased excitability of afferent neurons innervating rat urinary bladder after chronic bladder inflammation. J. Neurosci. 19, 4644–4653. Yoshimura, N., Seki, S., Erickson, K. A., Erickson, V. L., Chancellor, M. B., and de Groat, W. C. 2003. Histological and electrical properties of rat dorsal root ganglion neurons innervating the lower urinary tract. J. Neurosci. 23, 4355–4361. Yoshimura, N., Seki, S., Novakovic, S. D., Tzoumaka, E., Erickson, V. L., Erickson, K. A., Chancellor, M. B., and de Groat, W. C. 2001. The involvement of the tetrodotoxinresistant sodium channel nav1.8 (pn3/sns) in a rat model of visceral pain. J. Neurosci. 21, 8690–8696. Yu, S., Undem, B. J., and Kollarik, M. 2005. Vagal afferent nerves with nociceptive properties in guinea-pig oesophagus. J. Physiol. 563, 831–842. Zagorodnyuk, V. P. and Brookes, S. J. H. 2000. Transduction sites of vagal mechanoreceptors in the guinea pig esophagus. J. Neurosci. 20, 6249–6255. Zagorodnyuk, V. P., Chen, B. N., Costa, M., and Brookes, J. H. 2003. Mechanotransduction by intraganglionic laminar endings of vagal tension receptors in the guinea-pig oesophagus. J. Physiol. 553, 575–587. Zhuo, M. and Gebhart, G. F. 2002. Facilitation and attenuation of a visceral nociceptive reflex from the rostroventral medulla in the rat. Gastroenterology 122, 1007–1019. Zhuo, M., Sengupta, J. N., and Gebhart, G. F. 2002. Biphasic modulation of spinal visceral nociceptive transmission from the rostroventral medial medulla in the rat. J. Neurophysiol. 87, 2225–2236.

Further Reading Berkley, K. J., Robbins, A., and Sato, Y. 1988. Afferent fibers supplying the uterus in the rat. J. Neurophysiol. 59, 142–163. Brune, K. and Handwerker, H. O. (eds.) 2004. Hyperalgesia: Molecular Mechanisms and Clinical Implications, Progress in Pain Research and Management,, Vol. 30. IASP Press. Carr, M. J. and Undem, B. J. 2003. Bronchopulmonary afferent nerves. Respirology 8, 291–301. Cervero, F. 1994. Sensory innervation of the viscera: peripheral basis of visceral pain. Physiol. Rev. 74, 95–138.

Visceral Pain Francis, C. Y., Duffy, J. N., Whorwell, P. J., and Morris, J. 1997. High prevalence of irritable bowel syndrome in patients attending urological outpatient departments. Dig. Dis. Sci. 42, 404–407. Gebhart, G. F. (ed.) 1995. Visceral Pain, Progress in Pain Research and Management, , Vol. 5. IASP Press. Ja¨nig, W. 2006. The Integrative Action of the Autonomic Nervous System. Cambridge University Press. Kollarik, M. and Undem, B. J. 2002. Mechanisms of acid-induced activation of airway afferent nerve fibres in guinea-pig. J. Physiol. 543, 591–600. Kollarik, M. and Undem, B. J. 2003. Activation of bronchopulmonary vagal afferent nerves with bradykinin, acid and vanilloid receptor agonists in wild-type and TRPV1/ mice. J. Physiol. 555, 115–123. Kreis, M. E., Jiang, W., Kirkup, A. J., and Grundy, D. 2002. Cosensitivity of vagal mucosal afferents to histamine

569

and 5-HT in the rat jejunum. Am. J. Physiol. 283, G612–G617. Linden, D. R., Chen, J.-X., Gershon, M. D., Sharkey, K. A., and Mawe, G. M. 2003. Serotonin availability is increased in mucosa of guinea pigs with TNBS-induced colitis. Am. J. Physiol. 285, G207–G216. Ness, T. J. and Gebhart, G. F. 1990. Visceral pain: a review of experimental studies. Pain 41, 167–234. Pan, H. L. and Longhurst, J. C. 1996. Ischaemia-sensitive sympathetic afferents innervating the gastrointestinal tract function as nociceptors in cats. J. Physiol. 492, 841–850. Pasricha, P. J., Willis, W. D.,, and Gebhart, G. F. (eds.) 2007. Chronic Abdominal and Visceral Pain., Informa Healthcare. Spiller, R. and Grundy, D. (eds.) 2004. Pathophysiology of the Enteric Nervous System., Blackwell Publishing.

This page intentionally left blank

38 Irritable Bowel Syndrome S Bradesi and E A Mayer, University of California, Los Angeles, CA, USA I Schwetz, Medical University, Graz, Austria ª 2009 Elsevier Inc. All rights reserved.

38.1 38.2 5.38.3 5.38.4 5.38.4.1 5.38.4.2 5.38.5 5.38.6 References

Introduction Clinical Presentation and Epidemiology The Bidirectional Brain–Gut Axis Model Visceral Hypersensitivity Peripheral Up-Regulation of Visceral Afferent Sensitivity Spinal and Supraspinal Up-Regulation of Visceral Afferent Sensitivity Treatment Options Summary and Conclusions

38.1 Introduction Recurrent abdominal pain or discomfort in the absence of detectable structural or biochemical abnormalities, associated with alterations in bowel habits, are the principal symptoms of irritable bowel syndrome (IBS) (Drossman, D. A. et al., 2002). Due to the likely heterogeneity of the syndrome (Mayer, E. A. and Collins, S. M., 2002) and the lack of reliable organic markers, the development of a unifying, and generally agreed upon, hypothesis of the pathophysiology of IBS has remained an elusive goal. Many investigators in the field agree that an enhanced perception of physiologically occurring, or experimentally generated visceral events (visceral hypersensitivity) (Mayer, E. A. and Gebhart, G. F., 1994; see Vagal Afferent Neurons and Pain and Visceral Pain) in conjunction with alterations in gastrointestinal motility and secretory function, are key pathophysiological mechanisms underlying the cardinal clinical features of IBS. In contrast, many other alterations reported in IBS patients over the past decades, including altered mucus production and altered gastrointestinal motility, have turned out to be epiphenomena which are unlikely to be essential for symptom generation. Considerable evidence supports the role of psychosocial (Bennett, E. J. et al., 1998; Collins, S. M., 2002) and physical (Gwee, K. A. et al., 1996) (i.e., acute gastroenteric infections) stressors as central and peripheral triggers of first symptom onset or symptom exacerbation of longstanding IBS (Mayer, E. A. et al., 2001), and an IBS

571 571 572 572 573 574 575 575 575

hypothesis of hyperresponsiveness of central stress circuits has been proposed (Mayer, E. A. and Collins, S. M., 2002).

38.2 Clinical Presentation and Epidemiology IBS is one of the most common and most thoroughly studied functional disorders of the gastrointestinal tract (Drossman, D. A. et al., 2002). In additional to chronic abdominal pain, the clinical presentation of IBS typically also includes nonpainful abdominal discomfort (sensations of urgency, bloating, fullness, gas and constipation) (Lembo, T. J. and Fink, R. N., 2002) and visible abdominal distension. These gastrointestinal symptoms are frequently associated with extraintestinal symptoms such as fatigue, decreased energy level, impaired sleep, depression, and anxiety (Zimmerman, J., 2003). In the absence of generally agreed upon reliable biological markers, the diagnosis of IBS remains one based on the presence of the so-called symptom criteria (Thompson, W. G. et al., 1999). The most widely accepted diagnostic criteria are the Rome II Criteria that evolved from the Rome I and the Manning criteria initially defined about a decade ago (Longstreth, G. F., 2005). Different IBS patient subtypes have been identified based on their bowel habit predominance and have been classified as: constipation, diarrhea, or alternating periods of both. In a large US sample, approximately 50% of IBS patients present alternating bowel habit (IBS-A), 571

572 Irritable Bowel Syndrome

30% diarrhea (IBS-D), and 20% constipation (IBSC) (Tillisch, K. et al., 2005). Large population based studies in the US have found a prevalence of IBS of about 14% with a greater proportion of women affected (female-tomale ratio approximately 3:1 to 3:2). The socioeconomic consequences of IBS are considerable with a large impact on work productivity and absenteeism (Dean, B. B. et al., 2005). In addition, a substantial reduction in health-related quality of life (HRQoL) has been observed in IBS patients with moderate to severe symptoms who are seen in a referral setting compared with healthy controls (Spiegel, B. M. et al., 2004). Interestingly, bowel habit alterations contributed little to the HRQoL impairment in this study, while extraintestinal manifestations such as loss of energy, fatigue, and excessive worry were important determinants. The annual cost of IBS in the US has been estimated to be between $1.7 billion and $10 billion in direct medical cost (repetitive use of multiple healthcare resources) and $20 billion for indirect costs (work absenteeism and impaired productivity) representing a high socioeconomic burden on society (Inadomi, J. M. et al., 2003). While research over the past few years has provided significant advances in the understanding of IBS pathophysiology, the precise mechanism(s) underlying symptom generation remains incompletely understood, generating considerable controversy among investigators. As a result, the development of effective IBS therapies has been slow and disappointing (Bradesi, S. et al., 2006). IBS pathophysiology is often viewed within the so-called biopsychosocial model in which altered physiology (gastrointestinal motility and secretion, enhanced perception of visceral stimuli (visceral hypersensitivity) and psychosocial factors interact and determine the clinical expression of IBS (Schwetz, I. et al., 2004). From a biological perspective, IBS symptomatology can be viewed as the manifestation of alterations in the brain–gut axis, specifically as a dysregulation in the complex interplay between events occurring within the gut, the enteric nervous system, and the central nervous system (Mulak, A. and Bonaz, B., 2004).

38.3 The Bidirectional Brain–Gut Axis Model Brain-gut interactions play a prominent role in the modulation of gut function in health and disease (Mayer, E. A. et al., 2001; Tache´, Y. et al., 2001).

Therefore, every conceptual model of IBS has to take into account that neither the central nervous system nor the gastrointestinal tract function in isolation, but that both systems interact with each other under normal conditions and particularly during perturbations of homeostasis. Afferent signals arising from the lumen of the gut are transmitted via various visceral afferent pathways (enteric, spinal, vagal) to the central nervous system. Homeostatic reflexes, which generate appropriate gut responses to physiological as well as pathological visceral stimuli, occur at the level of the enteric nervous system, the spinal cord, and pontomedullary nuclei and limbic regions. Vagal visceral afferent inputs may also play an important role in such diverse functions as modulation of emotion, pain sensitivity, satiety, and immune response ( Ja¨nig, W. and Habler, H.-J., 2000). Whereas the reflex circuits within the enteric nervous system in principle can regulate and synchronize all basic gastrointestinal functions (motility, secretion, blood flow), coordination of gut functions with the overall homeostatic state of the organism requires continuous communication between the central nervous system and the gastrointestinal tract (Mayer, E. A. and Collins, S. M., 2002). Descending cortico-limbic influences can set the gain and responsiveness of these reflexes, or impose distinct patterns of motor responses on lower circuits, should the overall condition of the body make it necessary. Such top-down override of local reflex function occurs during sleep, during the stress response, or during strong emotions such as fear and anger (Ito, M., 2002; Mayer, E. A., 2000a; Tache´, Y. et al., 2001; Welgan, P. et al., 1988). While the great majority of homeostatic afferent input from the gut (as well as other viscera) to the central nervous system is not consciously perceived, there are both peripheral and central adaptive mechanisms which can result in enhanced perception and altered reflex responses to visceral stimuli (Mayer, E. A. and Gebhart, G. F., 1994).

38.4 Visceral Hypersensitivity The initial clinical observations that led to the hypothesis that IBS patients exhibit visceral hypersensitivity include recurring abdominal pain, tenderness during palpation of the sigmoid colon during physical examination, and excessive pain during endoscopic evaluation of the sigmoid colon (Mayer, E. A. and Gebhart, G. F., 1994). Multiple human experimental studies using barostat-controlled balloon distension

Irritable Bowel Syndrome

paradigms have reported lowered colorectal perceptual thresholds, increased sensory ratings and viscerosomatic referral areas in IBS patients compared to healthy individuals (Bouin, M. et al., 2002; Chang, L. et al., 2000a; Mertz, H. et al., 1995). Despite the uncertainty about the underlying mechanism(s), this kind of experimentally induced visceral hypersensitivity has been considered a pathophysiological hallmark of the disease. Within the framework of homeostatic afferents, the finding of chronic, conscious awareness of unpleasant visceral sensations, together with the presence of altered reflex regulation in the gut, could be explained by several different mechanisms, including the following: (1) a peripheral up-regulation of the sensitivity of visceral afferent pathways which may be related to alterations in the activity of various effector cells within the gut (enteric nerves, enterochromaffin cells, immune cells); (2) a spinal or brainstem alteration in the sensitivity to incoming visceral afferents which could be a consequence of primary peripheral or central inputs; or (3) a primary central amplification of perceptual and reflex responses to incoming visceral afferent signals. In addition, the frequent presence of compromised vital functions such as sleep, mood, sexual drive, and affect, suggest a possible involvement of other homeostatic mechanisms, such as tonic serotonergic pontomedullary systems (Mason, P., 2005). It remains to be determined if these various abnormalities occur in distinct subsets of patients, at different stages of the disorder, or if various combinations of them generate a heterogeneous patient population. 38.4.1 Peripheral Up-Regulation of Visceral Afferent Sensitivity The concept that gut mucosal alterations may play a role in the pathophysiology of IBS has been prompted by several lines of clinical and preclinical evidence including: (1) alterations in the number of immune cells, particularly mast cells, within intestinal biopsies of patients meeting diagnostic criteria for IBS (Barbara, G. et al., 2004; O’Sullivan, M. et al., 2000; Weston, A. P. et al., 1993), and the demonstration in rodent studies that mucosal mast cells play a prominent role of transducers within the brain–gut axis (Santos, J. et al., 2005; Soderholm, J. D. et al., 2002; Wilson, L. M. and Baldwin, A. L., 1999); (2) demonstration of visceral hypersensitivity in different animal models of gut immune system activation (Barbara, G. et al., 1997; Barreau, F. et al., 2004; La, J. H. et al., 2003;

573

Lamb, K. et al., 2006); (3) preliminary evidence that supernatants from human mucosal biopsies (taken from IBS patients) have a unique effect on visceral afferent function in rodent bioassays (Barbara, G. et al., 2005a; Barbara, G. et al., 2005b); (4) the development of IBSlike symptoms in a small number of individuals following an episode of acute gastroenteritis (Gwee, K. A. et al., 1998; Spiller, R. C., 2005) and in a subset of patients with inflammatory bowel disease (Bernstein, C. N. et al., 1996); (5) evidence for alteration in the normal gut flora (including bacterial overgrowth) (Balsari, A. et al., 1982; O’Leary, C. and Quigley, E. M., 2003; Swidsinski, A. et al., 1999); and (6) therapeutic responses to treatment with antibiotics and probiotic treatments (Madden, J. A. and Hunter, J. O., 2002; Pimentel, M. et al., 2000, 2003). Without discussing this large body of evidence supporting each of these points (Barbara, G. et al., 2006; Crowell, M. D. et al., 2005; Schwetz, I. et al., 2003; Spiller, R. C., 2005), it is assumed, by many investigators focusing on peripheral etiologies of visceral hypersensitivity, that the mucosal immune activation plays some role in maintaining a chronic state of visceral afferent sensitization. Based on recent preclinical evidence, it is conceivable that transient peripheral sensitization may result in long-lasting up-regulation of spino-bulbo-spinal pain amplification mechanisms (Suzuki, R. et al., 2005). While such peripheral mechanisms (in particular an increase in mucosal mast cells and intestinal enterochromaffin cells) may play an important role in a subset of IBS patients, or in the mediation of certain types of IBS symptoms, a series of observations argues against a simple relationship between peripheral mucosal events and IBS symptoms. For example, it has long been known that some patients in remission from inflammatory bowel disease, especially ulcerative colitis, report symptoms similar to those of IBS patients (Isgar, B. et al., 1983; Simren, M. et al., 2000). In contrast, inflammatory bowel disease patients (without associated IBS features) who have chronically recurring gut inflammation do not exhibit visceral hypersensitivity (Chang, L. et al., 2000b) or enhanced central nervous system responses to visceral distension during periods of remission (LoennigBaucke, V. et al., 1989; Rao, S. S. C. et al., 1987). In addition, clinical states characterized by chronic inflammation of the esophagus (gastroesophageal reflux disease) and stomach (Helicobacter pylori chronic gastritis) are also not associated with visceral mechanical hyperalgesia (Fass, R. et al., 1998; Mertz, H. et al., 1998). On the contrary, it has been reported that

574 Irritable Bowel Syndrome

Crohn’s patients with isolated inflammation in the small bowel have elevated discomfort thresholds to controlled distension of the rectum (Bernstein, C. N. et al., 1996), and that patients with ulcerative colitis do not show sensitization following repetitive noxious distension of the sigmoid colon (Chang, L. et al., 2000b). Taken together, these data are consistent with the interpretation that chronic mucosal inflammatory changes in the esophagus, stomach, or colon by themselves do not necessarily result in mechanical visceral hypersensitivity. Chronic intestinal inflammation in inflammatory bowel disease seems to be associated with the activation of counterregulatory antinociceptive systems, inhibition of pain facilitatory pathways or both, resulting in a reduced perception of visceral afferent information (Chang, L. et al., 2000b). One may speculate that genetic polymorphisms recently identified as being associated with greater pain sensitivity may be related to such compromised endogenous pain modulation systems (Diatchenko, L. et al., 2005). 38.4.2 Spinal and Supraspinal UpRegulation of Visceral Afferent Sensitivity A growing body of literature supports the concept of an enhanced stress responsiveness playing a role in the development of IBS symptoms in a subset of patients (reviewed in Mayer, E. A., 2000b; Mayer, E. A. et al., 2001). An individual’s response to stress (perturbation of homeostasis) is generated by a central network comprised of integrative brain structures, referred to as the emotional motor system (EMS) (for a detailed review see Mayer, E. A., 2000b); Mayer, E. A. et al., 2001). The main output systems of the EMS are ascending monoaminergic pathways, the autonomic nervous system, the hypothalamic–pituitary– adrenal axis and endogenous pain modulatory systems. The neuropeptide, corticotropin-releasing factor (CRF), plays a prominent role in integrating these various outputs in response to physical and psychological stressors (Bale, T. L., 2005). The responsiveness of the EMS and its various output pathways is under partial genetic control (Pezawas, L. et al., 2005) and is programmed by prenatal (Matthews, S. G., 2002) and postnatal (Ladd, C. O. et al., 2000) aversive events and by certain types of pathological stress (Fuchs, E. and Fluegge, G., 1995). In humans, early (pre- and postnatal) life adverse experiences can lead to longlasting stress hyperresponsiveness, which in turn has been associated with a wide range of health

impairments in adult life (Whitehead, M. and Holland, P., 2003). Long-term consequences of early aversive events also include an increased vulnerability for stress-sensitive disorders such as IBS and posttraumatic stress disorder (Lowman, B. C. et al., 1987). Stress hyperresponsiveness is related in part to permanent, stress-induced hypersecretion of CRF (Heim, C. et al., 2000). A number of preclinical studies support the concept of centrally mediated alteration of visceral perception. Different stress paradigms were found to lead to enhanced visceral response to colonic distension (Bradesi, S. et al., 2002; Gue, M. et al., 1997; Schwetz, I. et al., 2005), which can be mimicked or abolished by central administration of pharmacological agents. For example, central CRF injection was found to mimic the effect of stress on visceral sensitivity, whereas stress-induced visceral hyperalgesia may be reduced by central injection of a CRF receptor subtype 1 antagonist (Tache´, Y. et al., 2004). Similarly, a neurokinin-1 receptor antagonist injected into the spinal cord in stress-sensitized guinea pigs (Greenwood-Van Meerveld, B. et al., 2003) or rats (Bradesi, S. et al., 2005) abolished the stress-induced visceral hyperalgesia to colorectal distension. Together, the data available suggest the role of central stress circuits in the alteration of visceral nociceptive response in animal models for IBS. In contrast to the well-known analgesic response to severe acute stressors (stress-induced somatic analgesia), prolonged and milder stressors that are associated with anxiety-like states are commonly associated with hyperalgesic responses (Boccalon, S. et al., 2006; Vendruscolo, L. F. et al., 2004). Suggestive evidence for an alteration in central pain modulation mechanisms in IBS patients comes from a series of functional brain-imaging studies. In response to rectal balloon distension, IBS patients have shown increased activation of subregions of the dorsal anterior cingulate cortex (ACC) (Naliboff, B. D. et al., 2001b; Porreca, F. et al., 2002; Verne, G. N. et al., 2003), a brain region involved in attentional and emotional modulation of stimulus perception (Petrovic, P. and Ingvar, M., 2002). Dorsal ACC subregions provide input to subcortical endogenous pain inhibitory circuits (Petrovic, P. and Ingvar, M., 2002), as well as to subcortical pain facilitatory circuits (Zhuo, M. and Gebhart, G. F., 2002). The relative balance between these simultaneously activated pain modulation systems determines the overall modulation of perception (Porreca, F. et al., 2002). Thus, the finding of greater dorsal ACC

Irritable Bowel Syndrome

activation by a visceral stimulus in IBS may be related to greater attention and possibly associated activation of pain facilitation circuits to a visceral stimulus in IBS. On the other hand, the lesser activation of the periaqueductal gray (PAG) reported in some studies (Naliboff, B. D. et al., 2001b) is consistent with possible deficiencies in the cortical activation of endogenous pain inhibition systems. Several recent studies (Chang, L., 2005) provide further support for the hypothesis of altered endogenous pain modulation in IBS patients. In one study (Mayer, E. A. et al., 2005), IBS patients were compared to patients with ulcerative colitis and with healthy control subjects. IBS patients showed consistently greater activation of limbic/paralimbic brain regions (amygdala, hypothalamus, ventral/rostral ACC, dorsomedial prefrontal cortex) suggestive of increased activation of arousal circuits by a visceral stimulus. In addition, the results showed activation in the ulcerative colitis and control subjects, but not in IBS patients, in the lateral prefrontal regions and a midbrain region including the PAG. A connectivity analysis using structural equation modeling supported these regions acting as part of a pain inhibition network that involves lateral and medial prefrontal influences on the PAG. Another study provided evidence for the abnormal activation of diffuse noxious inhibitory control systems in response to a noxious stimulus in IBS patients (Wilder-Smith, C. H. et al., 2004). Several lines of evidence indicate that patients with IBS and other functional disorders have hypervigilance for symptom relevant sensations (Berman, S. M. et al., 2002). In a recent longitudinal study of IBS patients exposed to six sessions of rectal inflations over a 1-year period, regional cerebral blood flow to the inflations and anticipation of inflations using H15 2 O positron emission tomography (PET) at the first and last session were evaluated (Naliboff, B. D. et al., 2001a). Subjective ratings of the rectal inflations normalized over the course of the study consistent with decreased vigilance towards the visceral stimuli. Stable activation of the central pain matrix (including thalamus and insula) by the rectal stimulus was observed over the 12-month period, while activity in limbic, paralimbic ,and pontine regions decreased. An analysis examining the co-variation of these brain regions supported the hypothesis of changes in an arousal network including limbic, pontine, and cortical areas underlying the decreased perception seen over the multiple stimulation studies.

575

38.5 Treatment Options Despite its high prevalence and considerable impact on patients’ HRQoL, treatment options for IBS continue to be limited and there are few well designed studies to support the effectiveness of some of the most commonly used therapies (for review see Camilleri, M., 2004). Traditional treatment algorithms have primarily been aimed at peripheral targets and are largely symptom-based (e.g., laxatives, antidiarrheals, prokinetics). In addition, centrally targeted therapies include various forms of cognitive behavioral therapy (Hutton, J., 2005), lowdose tricyclic antidepressants (Drossman, D. A. et al., 2003) and, in patients with co-morbid psychiatric conditions, full dose serotonin reuptake inhibitors (Creed, F. et al., 2003). A series of compounds are currently in development, which is targeted at central circuits involved in stress responsiveness and pain modulation (Bradesi, S. et al., 2006).

38.6 Summary and Conclusions Despite its high prevalence, and considerable burden of illness, treatment of IBS remains unsatisfactory. However, considerable progress has been made to identify alterations at different levels of the brain– gut axis which may contribute to characteristic symptoms. In the absence of generally agreed upon animal models of the syndrome, functional brainimaging techniques in well defined human patient populations has a high promise to identify central abnormalities related to altered stress responsiveness and associated pain modulation circuits. A number of novel treatment approaches aimed at these central abnormalities are currently under development.

References Bale, T. L. 2005. Sensitivity to stress: Dysregulation of CRF pathways and disease development. Horm. Behav. 48, 1–10. Balsari, A., Ceccarelli, A., Dubini, F., Fesce, E., and Poli, G. 1982. The fecal microbial population in the irritable bowel syndrome. Microbiologica 5, 185–194. Barbara, G., Cremon, C., Riccardo, V., Elisabetta, C., Balestra, B., Di Nardo, G., De Giorgio, R., Stanghellini, V., Corinaldesi, R., and Tonini, M. 2005a. Colonic mucosal mast cell mediators from patients with irritable bowel syndrome excite enteric cholinergic motor neurons. Gastroenterology 128, A58 (abstract). Barbara, G., Stanghellini, V., De Giorgio, R., and Corinaldesi, R. 2006. Functional gastrointestinal disorders and mast cells: Implications for therapy. Neurogastroenterol. Motil. 18, 6–17.

576 Irritable Bowel Syndrome Barbara, G., Stanghellini, V., De Giorgio, R., Cremon, C., Cottrell, G. S., Santini, D., Pasquinelli, G., MorselliLabate, A. M., Grady, E. F., Bunnett, N. W., Collins, S. M., and Corinaldesi, R. 2004. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 126, 693–702. Barbara, G., Vallance, B. A., and Collins, S. M. 1997. Persistent intestinal neuromuscular dysfunction after acute nematode infection in mice. Gastroenterology 113, 1224–1232. Barbara, G., Wang, B., Grundy, D., Cremon, C., De Giorgio, R., Di Nardo, G., Trevisani, M., Campi, B., Geppetti, P., Tonini, M., Stanghellini, V., and Corinaldesi, R. 2005b. Mast cells are increased in the colonic mucosa of patients with irritable bowel syndrome and excite visceral sensory pathways. Gastroenterology 128, A-626 (abstract). Barreau, F., Cartier, C., Ferrier, L., Fioramonti, J., and Bueno, L. 2004. Nerve growth factor mediates alterations of colonic sensitivity and mucosal barrier induced by neonatal stress in rats. Gastroenterology 127, 524–534. Bennett, E. J., Tennant, C. C., Piesse, C., Badcock, C. A., and Kellow, J. E. 1998. Level of chronic life stress predicts clinical outcome in irritable bowel syndrome. Gut 43, 256–261. Berman, S. M., Naliboff, B. D., Chang, L., FitzGerald, L., Antolin, T., Camplone, A., and Mayer, E. A. 2002. Enhanced preattentive central nervous system reactivity in irritable bowel syndrome. Am. J. Gastroenterol. 97, 2791–2797. Bernstein, C. N., Niazi, N., Robert, M., Mertz, H., Kodner, A., Munakata, J., Naliboff, B., and Mayer, E. A. 1996. Rectal afferent function in patients with inflammatory and functional intestinal disorders. Pain 66, 151–161. Boccalon, S., Scaggiante, B., and Perissin, L. 2006. Anxiety stress and nociceptive responses in mice. Life Sci. 78, 1225–1230. Bouin, M., Plourde, V., Boivin, M., Riberdy, M., Lupien, F., Laganiere, M., Verrier, P., and Poitras, P. 2002. Rectal distension testing in patients with irritable bowel syndrome: Sensitivity, specificity, and predictive values of pain sensory thresholds. Gastroenterology 122, 1771–1777. Bradesi, S., Eutamene, H., Garcia-Villar, R., Fioramonti, J., and Bueno, L. 2002. Acute and chronic stress differently affect visceral sensitivity to rectal distension in female rats. Neurogastroenterol. Motil. 14, 75–82. Bradesi, S., Kokkotou, E., Song, B., Marvizon, J. C., Mittal, Y., McRoberts, J. A., Ennes, H. S., Pothoulakis, C., Ohning, G., and Mayer, E. A. 2005. Sustained visceral hyperalgesia following chronic psychological stress in rats involves upregulation of spinal NK1 receptors. Gastroenterology 128, A494 (abstract). Bradesi, S., Tillisch, K., and Mayer, E. A. 2006. Emerging drugs for IBS. Expert Opin. Emerg. Drugs 11, 293–313. Camilleri, M. 2004. Treating irritable bowel syndrome: overview, perspective and future therapies. Br. J. Pharmacol. 141, 1237–1248. Chang, L. 2005. Brain responses to visceral and somatic stimuli in irritable bowel syndrome: A central nervous system disorder? Gastroenterol. Clin. North. Am. 34, 271–279. Chang, L., Mayer, E. A., Johnson, T., FitzGerald, L., and Naliboff, B. 2000a. Differences in somatic perception in female patients with irritable bowel syndrome with and without fibromyalgia. Pain 84, 297–307. Chang, L., Munakata, J., Mayer, E. A., Schmulson, M. J., Johnson, T. D., Bernstein, C. N., Saba, L., Naliboff, B., Anton, P. A., and Matin, K. 2000b. Perceptual responses in patients with inflammatory and functional bowel disease. Gut 47, 497–505. Collins, S. M. 2002. A case for an immunological basis for irritable bowel syndrome. Gastroenterology 122, 2078–2080. Creed, F., Fernandes, L., Guthrie, E., Palmer, S., Ratcliffe, J., Read, N., Rigby, C., Thompson, D., Tomenson, B. North of

England IBS Research Group. 2003. The cost-effectiveness of psychotherapy and paroxetine for severe irritable bowel syndrome. Gastroenterology 124, 303–317. Crowell, M. D., Harris, L., Jones, M. P., and Chang, L. 2005. New insights into the pathophysiology of irritable bowel syndrome: Implications for future treatments. Curr. Gastroenterol. Rep. 7, 272–279. Dean, B. B., Aguilar, D., Barghout, V., Kahler, K. H., Frech, F., Groves, D., and Ofman, J. J. 2005. Impairment in work productivity and health-related quality of life in patients with IBS. Am. J. Manag. Care. 11, S17–S26. Diatchenko, L., Slade, G. D., Nackley, A. G., Bhalang, K., Sigurdsson, A., Belfer, I., Goldman, D., Xu, K., Shabalina, S. A., Shagin, D., Max, M. B., Makarov, S. S., and Maixner, W. 2005. Genetic basis for individual variations in pain perception and the development of chronic pain condition. Hum. Mol. Gen. 14, 135–143. Drossman, D. A., Camilleri, M., Mayer, E. A., and Whitehead, W. E. 2002. AGA technical review on irritable bowel syndrome. Gastroenterology 123, 2108–2131. Drossman, D. A., Toner, B. B., Whitehead, W. E., Diamant, N. E., Dalton, C. B., Duncan, S., Emmott, S., Proffitt, V., Akman, D., Frusciante, K., Le, T., Meyer, K., Bradshaw, B., Mikula, K., Morris, C. B., Blackman, C. J., Hu, Y., Jia, H., Li, J. Z., Koch, G. G., and Bangdiwala, S. I. 2003. Cognitivebehavioral therapy versus education and desipramine versus placebo for moderate to severe functional bowel disorders. Gastroenterology 125, 19–31. Fass, R., Naliboff, B., Higa, L., Johnson, C., Kodner, A., Munakata, J., Ngo, J., and Mayer, E. A. 1998. Differential effect of long-term esophageal acid exposure on mechanosensitivity and chemosensitivity in humans. Gastroenterology 115, 1363–1373. Fuchs, E. and Fluegge, G. 1995. Modulation of binding sites for corticotropin-releasing hormone by chronic psychosocial stress. Psychoneuroendocrinology 20, 33–51. Greenwood-Van Meerveld, B., Gibson, M. S., Johnson, A. C., Venkova, K., and Sutkowski-Markmann, D. 2003. NK1 receptor-mediated mechanisms regulate colonic hypersensitivity in the guinea pig. Pharmacol. Biochem. Behav. 74, 1005–1013. Gue, M., Del Rio-Lacheze, C., Eutamene, H., Theodorou, V., Fioramonti, J., and Bueno, L. 1997. Stress-induced visceral hypersensitivity to rectal distension in rats: Role of CRF and mast cells. Neurogastroenterol. Motil. 9, 271–279. Gwee, K. A., Collins, S. M., Marshall, J. S., Underwood, J. E., Moochala, S. M., and Read, N. W. 1998. Evidence of inflammatory pathogenesis in post-infectious irritable bowel syndrome. Gastroenterology 114, 758 (abstract). Gwee, K. A., Graham, J. C., McKendrick, M. W., Collins, S. M., Marshall, J. S., Walters, S. J., and Read, N. W. 1996. Psychometric scores and persistence of irritable bowel after infectious diarrhoea. Lancet 347, 150–153. Heim, C., Ehlert, U., and Hellhammer, D. H. 2000. The potential role of hypercortisolism in the pathophysiology of stressrelated bodily disorders. Psychoneuroendocrinology 25, 1–35. Hutton, J. 2005. Cognitive behaviour therapy for irritable bowel syndrome. Eur. J. Gastroenterol. Hepatol. 17, 11–14. Inadomi, J. M., Fennerty, M. B., and Bjorkman, D. 2003. Systematic review: The economic impact of irritable bowel syndrome. Aliment. Pharmacol. Ther. 18, 671–682. Isgar, B., Harman, M., Kaye, M. D., and Whorwhell, P. J. 1983. Symptoms of irritable bowel syndrome in ulcerative colitis in remission. Gut 24, 190–192. Ito, M. 2002. Controller-regulator model of the central nervous system. J. Integr. Neurosci. 1, 129–143. Ja¨nig, W. and Habler, H.-J. 2000. Specificity in the Organization of the Autonomic Nervous System: A Basis for Precise

Irritable Bowel Syndrome Neural Regulation of Homeostatic and Protective Body Functions. In: The Biological Basis for Mind Body Interactions (ed. E. A. Mayer and C. B. Saper), pp. 351–367. Elsevier Science. La, J. H., Kim, T. W., Sung, T. S., Kang, J. W., Kim, H. J., and Yang, I. S. 2003. Visceral hypersensitivity and altered colonic motility after subsidence of inflammation in a rat model of colitis. World J. Gastroenterol. 9, 2791–2795. Ladd, C. O., Huot, R. L., Thrivikraman, K. V., Nemeroff, C. B., Meaney, M. J., and Plotsky, P. 2000. Long-term Behavioral and Neuroendocrine Adaptations to Adverse Early Experience. In: The Biological Basis for Mind Body Interactions (ed. E. A. Mayer and C. B. Saper), pp. 81–103. Elsevier. Lamb, K., Zhong, F., Gebhart, G. F., and Bielefeldt, K. 2006. Experimental colitis in mice and sensitization of converging visceral and somatic afferent pathways. Am. J. Physiol. Gastrointest. Liver Physiol. 290, G451–G457. Lembo, T. J. and Fink, R. N. 2002. Clinical assessment of irritable bowel syndrome. J. Clin. Gastroenterol. 35, S31–S36. Loennig-Baucke, V., Metcalf, A. M., and Shirazi, S. 1989. Anorectal manometry in active and quiescent ulcerative colitis. Am. J. Gastroenterol. 84, 892–897. Longstreth, G. F. 2005. Definition and classification of irritable bowel syndrome: Current consensus and controversies. Gastroenterol. Clin. North. Am. 34, 173–187. Lowman, B. C., Drossman, D. A., Cramer, E. M., and McKee, D. C. 1987. Recollection of childhood events in adults with irritable bowel syndrome. J. Clin. Gastroenterol. 9, 324–330. Madden, J. A. and Hunter, J. O. 2002. A review of the role of the gut microflora in irritable bowel syndrome and the effects of probiotics. Br. J. Nutr. 88, S67–S72. Mason, P. 2005. Deconstructing endogenous pain modulations. J. Neurophysiol. 94, 1659–1663. Matthews, S. G. 2002. Early programming of the hypothalamopituitary-adrenal axis. Trends Endocrinol. Metab. 13, 373–380. Mayer, E. A. 2000a. Spinal and supraspinal modulation of visceral sensation. Gut 47, iv69–iv72. Mayer, E. A. 2000b. The neurobiology of stress and gastrointestinal disease. Gut 47, 861–869. Mayer, E. A., Berman, S., Suyenobu, B., Labus, J., Mandelkern, M. A., Naliboff, B. D., and Chang, L. 2005. Differences in brain responses to visceral pain between patients with irritable bowel syndrome and ulcerative colitis. Pain 115, 398–409. Mayer, E. A. and Collins, S. M. 2002. Evolving pathophysiologic models of functional gastrointestinal disorders. Gastroenterology 122, 2032–2048. Mayer, E. A. and Gebhart, G. F. 1994. Basic and clinical aspects of visceral hyperalgesia. Gastroenterology 107, 271–293. Mayer, E. A., Naliboff, B. D., Chang, L., and Coutinho, S. V. 2001. Stress and the gastrointestinal tract: V. Stress and irritable bowel syndrome. Am. J. Physiol. Gastrointest. Liver. Physiol. 280, G519–G524. Mertz, H., Fullerton, S., Naliboff, B., and Mayer, E. A. 1998. Symptoms and visceral perception in severe functional and organic dyspepsia. Gut 42, 814–822. Mertz, H., Naliboff, B., Munakata, J., Niazi, N., and Mayer, E. A. 1995. Altered rectal perception is a biological marker of patients with irritable bowel syndrome. Gastroenterology 109, 40–52. Mulak, A. and Bonaz, B. 2004. Irritable bowel syndrome: A model of the brain-gut interactions. Med. Sci. Monit. 10, RA55–RA62. Naliboff, B. D., Derbyshire, S. W. G., Berman, S. M., Mandelkern, M. A., Chang, L., Stains, J., and

577

Mayer, E. A. 2001a. Assessing the stability of brain activation to visceral stimulation in IBS. Gastroenterology 120, A133 (abstract). Naliboff, B. D., Derbyshire, S. W. G., Munakata, J., Berman, S., Mandelkern, M., Chang, L., and Mayer, E. A. 2001b. Cerebral activation in irritable bowel syndrome patients and control subjects during rectosigmoid stimulation. Psychosom. Med. 63, 365–375. O’Leary, C. and Quigley, E. M. 2003. Small bowel bacterial overgrowth, celiac disease, and IBS: What are the real associations? Am. J. Gastroenterol. 98, 720–722. O’Sullivan, M., Clayton, N., Breslin, N. P., Harman, I., Bountra, C., McLaren, A., and O’Morain, C. A. 2000. Increased mast cells in the irritable bowel syndrome. Neurogastroenterol. Motil. 12, 449–457. Petrovic, P. and Ingvar, M. 2002. Imaging cognitive modulation of pain processing. Pain 95, 1–5. Pezawas, L., Meyer-Lindenberg, A., Drabant, E. M., Verchinski, B. A., Munoz, K. E., Kolachana, B. S., Egan, M. F., Mattay, V. S., Hariri, A. R., and Weinberger, D. R. 2005. 5-HTTLPR polymorphism impacts human cingulateamygdala interactions: A genetic susceptibility mechanism for depression. Nat. Neurosci. 8, 828–834. Pimentel, M., Chow, E. J., and Lin, H. C. 2000. Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel syndrome. Am. J. Gastroenterol. 95, 3503–3506. Pimentel, M., Chow, E. J., and Lin, H. C. 2003. Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome. A double-blind, randomized, placebo-controlled study. Am. J. Gastroenterol. 98, 412–419. Porreca, F., Ossipov, M. H., and Gebhart, G. F. 2002. Chronic pain and medullary descending facilitation. Trends Neurosci. 25, 319–325. Rao, S. S. C., Read, N. W., Davison, P. A., Bannister, J. J., and Holdsworth, C. D. 1987. Anorectal sensitivity and responses to rectal distention in patients with ulcerative colitis. Gastroenterology 93, 1270–1275. Santos, J., Guilarte, M., Alonso, C., and Malagelada, J. R. 2005. Pathogenesis of irritable bowel syndrome: The mast cell connection. Scand. J. Gastroenterol. 40, 129–140. Schwetz, I., Bradesi, S., and Mayer, E. A. 2003. Current insights into the pathophysiology of irritable bowel syndrome. Curr. Gastroenterol. Rep. 5, 331–336. Schwetz, I., Bradesi, S., and Mayer, E. A. 2004. The pathophysiology of irritable bowel syndrome. Minerva. Med. 95, 419–426. Schwetz, I., McRoberts, J. A., Coutinho, S. V., Bradesi, S., Gale, G., Fanselow, M., Million, M., Ohning, G., Tache´, Y., Plotsky, P. M., and Mayer, E. A. 2005. Corticotropinreleasing factor receptor 1 mediates acute and delayed stress-induced visceral hyperalgesia in maternally separated Long Evans rats. Am. J. Physiol. Gastrointest. Liver Physiol. 289, G704–G712. Simren, M., Axelsson, J., Abrahamsson, H., Svedlund, J., and Bjsrnsson, E. S. 2000. Symptoms of irritable bowel syndrome in inflammatory bowel disease in remission and relationship to psychological factors. Gastroenterology 118, A702. (Abstract). Soderholm, J. D., Yang, P. C., Ceponis, P., Vohra, A., Riddell, R., Sherman, P. M., and Perdue, M. H. 2002. Chronic stress induces mast cell-dependent bacterial adherence and initiates mucosal inflammation in rat intestine. Gastroenterology 123, 1099–1108. Spiegel, B. M., Gralnek, I. M., Bolus, R., Chang, L., Dulai, G. S., Mayer, E. A., and Naliboff, B. 2004. Clinical determinants of health-related quality of life in patients with irritable bowel syndrome. Arch. Intern. Med. 164, 1773–1780.

578 Irritable Bowel Syndrome Spiller, R. C. 2005. Irritable bowel syndrome. Br. Med. Bull. 72, 15–29. Suzuki, R., Rahman, W., Rygh, L. J., Webber, M., Hunt, S. P., and Dickenson, A. H. 2005. Spinal-supraspinal serotonergic circuits regulating neuropathic pain and its treatment with gabapentin. Pain 117, 292–303. Swidsinski, A., Khilkin, M., Ortner, M., Swidsinski, S., Wirth, J., Weber, J., Schlien, P., Lochs, H. 1999. Alteration of bacterial concentration in colonic biopsies from patients with irritable bowel syndrome (IBS). Gastroenterology 116, A-1. (Abstract). Tache´, Y., Martinez, V., Million, M., and Wang, L. 2001. Stress and the gastrointestinal tract III. Stress-related alterations of gut motor function: Role of brain corticotropin-releasing factor receptors. Am. J. Physiol. Gastrointest. Liver Physiol. 280, G173–G177. Tache´, Y., Martinez, V., Wang, L., and Million, M. 2004. CRF1 receptor signaling pathways are involved in stress-related alterations of colonic function and viscerosensitivity: implications for irritable bowel syndrome. Br. J. Pharmacol. 141, 1321–1330. Thompson, W. G., Longstreth, G. F., Drossman, D. A., Heaton, K. W., Irvine, E. J., and Mu¨ller-Lissner, S. A. 1999. Functional bowel disorders and functional abdominal pain. Gut 45, II43–II47. Tillisch, K., Labus, J. S., Naliboff, B. D., Bolus, R., Shetzline, M., Mayer, E. A., and Chang, L. 2005. Characterization of the alternating bowel habit subtype in patients with irritable bowel syndrome. Am. J. Gastroenterol. 100, 896–904. Vendruscolo, L. F., Pamplona, F. A., and Takahashi, R. N. 2004. Strain and sex differences in the expression of nociceptive

behavior and stress-induced analgesia in rats. Brain Res. 1030, 277–283. Verne, G. N., Himes, N. C., Robinson, M. E., Gopinath, K. S., Briggs, R. W., Crosson, B., and Price, D. D. 2003. Central representation of visceral and cutaneous hypersensitivity in the irritable bowel syndrome. Pain 103, 99–110. Welgan, P., Meshkinpour, H., and Beeler, M. 1988. Effect of anger on colon motor and myoelectric activity in irritable bowel syndrome. Gastroenterology 94, 1150–1156. Weston, A. P., Biddle, W. L., Bhatia, P. S., and Miner, P. B. J. 1993. Terminal ileal mucosal mast cells in irritable bowel syndrome. Dig. Dis. Sci. 38, 1590–1595. Whitehead, M. and Holland, P. 2003. What puts children of lone parents at a health disadvantage? Lancet 361, 271. Wilder-Smith, C. H., Schindler, D., Lovblad, K., Redmond, S. M., and Nirkko, A. 2004. Brain functional magnetic resonance imaging of rectal pain and activation of endogenous inhibitory mechanisms in irritable bowel syndrome patient subgroups and healthy controls. Gut 53, 1595–1601. Wilson, L. M. and Baldwin, A. L. 1999. Environmental stress causes mast cell degranulation, endothelial and epithelial changes, and edema in the rat intestinal mucosa. Microcirculation 6, 189–198. Zhuo, M. and Gebhart, G. F. 2002. Facilitation and attenuation of a visceral nociceptive reflex from the rostroventral medulla in the rat. Gastroenterology 122, 1007–1019. Zimmerman, J. 2003. Extraintestinal symptoms in irritable bowel syndrome and inflammatory bowel diseases: Nature, severity, and relationship to gastrointestinal symptoms. Dig. Dis. Sci. 48, 743–749.

39 Pain in Childbirth U Wesselmann, The Johns Hopkins University School of Medicine, Baltimore, MD, USA ª 2009 Elsevier Inc. All rights reserved.

39.1 39.2 39.2.1 39.2.2 39.2.2.1 39.2.2.2 39.3 39.4 39.5 References

Introduction Physiological Aspects of Labor Pain Variables Associated with the Severity of Labor Pain Treatment of Pain in Childbirth Analgesia for Labor and Delivery Nonpharmacological, complementary and alternative therapies for relief of pain in childbirth Pain during Pregnancy Postpartum Pain Future Aspects

579 579 580 581 581 582 582 582 582 583

Glossary dysmenorrhea Painful cramping of the lower abdomen occurring before or during menses primarily as a result of endogenous prostaglandins, often accompanied by other symptoms such as sweating, tachycardia, headaches, nausea, vomiting, diarrhea, and tremulousness. dyspareunia Painful intercourse. epidural analgesia Regional analgesia produced by injection of local anesthetic solution into the peridural space. postpartum pain Pain after childbirth; the postpartum period starts immediately following

39.1 Introduction The experience of pain during childbirth is a complex, multidimensional response to sensory stimuli generated during labor and delivery. Pain in childbirth occurs in the context of an individual woman’s physiology and psychology, as well as in the context of the sociology of the culture and the health care system and its providers surrounding her. For the majority of women in all societies and cultures, natural childbirth is likely to be one of the most painful events in their lifetime. Average pain scores for labor pain are exceeded only by those for causalgia in chronic-pain patients and amputation of a digit in acute-pain patients

childbirth but the length of the period is not well defined. referred pain Pain perceived in a region different from the injured area during the time of injury. stages of labor pain There are three stages of labor pain. Stage 1 begins with regular uterine contractions and ends with complete cervical dilatation at 10 cm. Stage 2 begins once the cervix has completely dilated and ends with delivery of the fetus. Stage 3 lasts from the delivery of the fetus until the delivery of the placenta.

(Melzack, R., 1984). Different from other acute and chronic pain experiences, pain during childbirth is not associated with a pathological process. It is surprising that this physiological process associated with the most basic and fundamental life experience causes severe pain, and this has been the subject of many philosophic and religious debates. The International Association for the Study of Pain (IASP) defines pain as an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage (Merskey, H., 1979). Traditionally, different approaches to pain management of the pain in childbirth have addressed either the sensory or the affective dimension of 579

580 Pain in Childbirth

pain, while more recently a multidimensional approach has been advocated, addressing both dimensions of labor pain (Lowe, N. K., 2002; Melzack, R., 1984).

39.2 Physiological Aspects of Labor Pain Compared to many other pain conditions, research on the neurophysiological mechanisms of pain in childbirth has been sparse, due to the difficulty of developing animal models that could be studied adequately using electrophysiological and neuroanatomical techniques. Studies examining the influence of pregnancy on somatosensory responses in animals and humans have shown hypoalgesia in late pregnancy prior to the onset of labor and this chance in nociceptive threshold is at least in part opioidmediated (Bajaj, P. et al., 2002; Jarvis, S. et al., 1997). There are three distinct stages of labor pain related to uterine contractions, cervical stretching, and distension of the vaginal canal during fetal descend (for reviews see: McDonald, J. S., 2001; Rowlands, S. and Permezel, M., 1998). The first stage begins with regular uterine contractions and ends with complete cervical dilatation at 10 cm. Stage 1 has been further subdivided into an earlier latent phase and an ensuing active phase, which begins at about 3–4 cm of cervical dilatation and heralds a period of more rapid cervical dilation. Once the cervix has completely dilated, stage 2 of labor has begun. It ends with delivery of the fetus. Stage 3 of labor lasts from the delivery of the fetus until the delivery of the placenta. Pain during the first stage of labor (dilatation phase) is thought to be due to nociceptive stimuli arising from mechanical distension of the lower uterine segment and cervical dilatation. In addition, highthreshold mechanoreceptors in the myometrium may be activated in response to uterine contractions. Several chemical nociceptive mediators have been suggested, including bradykinines, leukotrienes, prostaglandins, serotonin, lactic acid, and Substance P. Pain of the first stage of labor is predominantly mediated by neural pathways involving the T10 to L1 spinal cord segments. Similar to other types of visceral pain, labor pain may present with referred pain to somatic structures in corresponding myotomes and dermatomes, including the abdominal wall, lumbosacral region, iliac crests, gluteal areas and thighs. Pain in the second and third stages of labor involves spinal cord segments S2 to S4, and is

considered to be due to distension and traction on pelvic structures surrounding the vaginal vault and from distension of the pelvic floor and perineum. The mean intensity of pain in childbirth has been reported to be positively correlated with the intensity, duration, and frequency of uterine contractions and with the degree of cervical distension. Pain associated with childbirth provokes a generalized stress response, which has widespread physiological and potentially adverse effects on the progress of labor and the well-being of the mother and the fetus (Brownridge, P., 1995; Beilin, Y., 2002). Respiratory effects include hyperventilation, which might lead to maternal hypocarbia and respiratory alkalosis, and rise in cardiac output, peripheral resistance, and blood pressure. Pain associated with uterine contraction results in stimulation of the release of stress-related hormones from the adrenal sympathetic axis and the hypophyseal–pituitary axis. Labor pain promotes maternal and fetal acidosis, which is due to a catecholamine-induced shift toward lipolytic metabolism, hyperventilation, physical exertion, starvation, and diminished buffering capacity secondary to respiratory alkalosis. While these effects may be largely innocuous during the course of uncomplicated labor, they present a great risk in the presence of certain medical and obstetric complications and in situations where fetal compromise already exists. 39.2.1 Variables Associated with the Severity of Labor Pain There is a very high level of individual variability in the severity of labor pain and this has been correlated with several factors (Melzack, R., 1984; Brownridge, P., 1995). Primiparas and younger women report more pain than multiparas and older women. Women of higher socioeconomic status report less pain than women of lower socioeconomic status. In addition physical factors might play a role in increased pain ratings during labor, including increased fetal size and increased maternal body weight. Labor pain is influenced by maternal positions – women experience more pain when delivering in the horizontal position as compared to the upright position. Childbirth at night has been reported to be less painful than childbirth during the day. Women with a history of dysmenorrhea report higher pain levels during labor as compared to women, who do not have a history of menstrual pain. In contrast, a previous history of

Pain in Childbirth

nongynecological pain is correlated with decreased labor pain. Severe fear of pain associated with childbirth occurs in 6–10% of parturients and is highly correlated to pain levels reported during the first stage of labor (for review see Saisto, T. and Halmesma¨ki, E., 2003). It is not an isolated variable, but associated with the woman’s personal characteristics including general anxiety and fear of pain in general, low selfesteem, depression, dissatisfaction with her partnership, and lack of support. Fear of labor pain is strongly associated with fear of pain in general, independent of parity and is one of the most common reasons for requesting a cesarean section. Fear of childbirth has been reported to complicate about 20% of pregnancies in developed countries. Although it is often assumed that culture and ethnicity have a significant influence on the intensity of labor pain, numerous studies have documented that there is no difference in self-report pain intensity ratings (see Lowe, N. K., 2002 for review). However, pain behavior is significantly influenced by culture and ethnicity, due to learned values and attitudes to the perception and expression of acute pain. The environmental influences on pain perception have been explored in two prospective studies from Scandinavia comparing low-risk women delivering at birth centers and at standard obstetrical hospitalbased units (Skibsted, L. and Lange, A. P., 1992; Waldenstro¨m, U. and Nilsson, C. A., 1994). These studies suggest that the environment provided may affect a woman’s ability to cope with pain. While women delivering in birth centers reported significantly higher pain intensities than women delivering in hospital settings, there were no differences between the two groups with respect to satisfaction with the quality of the birth experience. These results emphasize the importance of differentiation between pain intensity and the attitude toward the pain experienced in labor and delivery. It has been postulated that the memory for pain associated with disease, trauma, or surgical and medical procedures can be more damaging than its initial experience (Song, S.-O. and Carr, D. B., 1999). Although pain in childbirth is one of the most intense pains many women experience in their lifetime, childbirth is one of the most positive events of life for most women. Review of the literature on memory for labor pain shows that while memory of the events of childbirth is very accurate, the accuracy of recalled labor pain remains in question. Memories of labor pain can evoke intense negative reactions in a few

581

women, but are more likely to give rise to positive consequences related to coping, self-efficacy and self-esteem (Niven, C. A. and Murphy-Black, T., 2000). It is important to emphasize that labor pain, although being a very prominent aspect of childbirth, is just one aspect of the childbirth experience. A recent systematic review of the literature on pain and women’s satisfaction with the experience of childbirth demonstrated that the influences of pain, pain relief, and intra-partum medical interventions on subsequent satisfaction are not as powerful as the personal expectations, the amount of support from caregivers, the quality of the caregiver-patient relationship, and involvement of decision making (Hodnett, E. D., 2002).

39.2.2 39.2.2.1

Treatment of Pain in Childbirth

Analgesia for Labor and Delivery Analgesia for labor and delivery is now safer than ever and can be offered during all stages of labor, targeted to the individual needs and wishes of the pregnant woman, without compromising the safety of her or her unborn child (for reviews see Beilin, Y., 2002; Caton, D. et al., 2002; Nystedt, A. et al., 2004). Anesthesia related maternal mortality has decreased from 4.3 million live births during the years 1979–81 to 1.7 per million live births during the years 1988– 90. The increased use of regional anesthesia techniques is partially responsible for this decrease in mortality. The most popular method for analgesia during labor and delivery is epidural analgesia using a combination of local anesthetics and opioids. Its popularity is related to its efficacy and safety. Drugs can be applied as continuous epidural infusions or as patient-controlled epidural analgesia. During the early stages of labor dilute solutions of local anesthetic can be used to achieve analgesia. As labor progresses, more concentrated solutions of local anesthetics can be used and opioids can be added. Typically the epidural catheter is inserted to maintain a low dermatomal level of analgesia for vaginal delivery (T10 to L1). If a cesarean section is required, the dermatomal level can be raised to T4. Combined spinal epidural techniques offer the advantage of a very rapid onset of analgesia with minimal motor block. The future of obstetric anesthesia lies in refining currently available drugs and techniques to make obstetric anesthesia even safer and more efficacious.

582 Pain in Childbirth

39.2.2.2 Nonpharmacological, complementary and alternative therapies for relief of pain in childbirth

Many nonpharmacological, complementary and alternative medicine methods exist to relieve labor pain (for reviews see Simkin, P. P. and O’Hara M., 2002; Smith, C. A. et al., 2003; Cluett, E. R. et al., 2004; Cyna, A. M. et al., 2004; Huntley, A. L. et al., 2004; Lee, H. and Ernst, E., 2004). These methods appeal to women and caregivers who are interested to reduce labor pain without creating potentially serious side-effects and high costs. In addition many women appreciate the simplicity of these approaches and the sense of control they gain from actively managing their pain. However, few of these therapies have been subjected to proper scientific study. Meta-analysis of randomized controlled trials has indicated that acupuncture and hypnosis may be beneficial for the management of pain in childbirth. There is evidence that water immersion during the first stage of labor reduces the use of analgesia and reported pain intensity, without adverse outcomes on labor duration, operative delivery, or neonatal outcomes. The effects of water immersion during the later stages of labor are not clear. No differences were observed for women receiving aromatherapy, music, or audio analgesia.

39.3 Pain during Pregnancy While the focus of this review is on pain associated with childbirth, it is important to note that pain is also a significant issue during pregnancy (Stuge, B. et al., 2003). Approximately 50% of women experience back pain and/or pelvic pain during their pregnancy, and in up to 15% of the cases the pain is rated as severe. Several hypotheses have been suggested to explain the etiology of this pain, including increased weight, decreased stability of the pelvic girdle due to hormonal changes and referred visceral pain mechanisms. The role of the hormone relaxin and pelvic pain in pregnancy is controversial. Physical therapy is often recommended for the prevention and treatment of these pregnancy-related pains, but the effects of these interventions have not been systematically studied and thus it is not clear if they are of any benefit to the pregnant women.

39.4 Postpartum Pain While most of the discussion of adverse sequelae of labor and delivery has focused on urinary and fecal incontinence, there is now increasing awareness that pain associated with childbirth is not only related to the process of labor and delivery. Women report significant pains in many sites of the body after delivery, a phenomenon which has been defined as postpartum pain. Postpartum pains may include urogenital, pelvic, back and breast pains as well as headaches, persisting for months to years after labor and delivery (Audit Commission, 1997). It has been hypothesized that anesthetic techniques during labor and delivery and gonadal hormonal changes may play a role in the etiology of these pain complaints. Forty-nine percent of women report significant dyspareunia when resuming sexual intercourse after childbirth (Buhling, K. J. et al., 2005). Women with a history of operative vaginal delivery have the highest prevalence of severe perineal pain when resuming sexual intercourse. The persistence of dyspareunia for longer than 6 months after delivery ranges from 3.4% to 14% based on mode of delivery. Treatment approaches for early intervention to prevent persistent perineal pain after childbirth have not been explored in detail. A meta-analysis assessing the effectiveness of topically applied anesthetics to the perineal region in the early postpartum period showed no compelling evidence of pain reduction (Hedayati, H. et al., 2005). However, there has been no evaluation of the long-term effects of topically applied local anesthetics.

39.5 Future Aspects Pain in childbirth is a complex, multidimensional experience. While the focus of this chapter is on the pain aspect of childbirth, it is important to keep in mind that pain is an important aspect, but not the only aspect of the childbirth experience. The acknowledgment of the existence of pain associated with labor and delivery and the recognition of the severity of this pain by the medical community over the last 50 years has resulted in a broad spectrum of pharmacological and nonpharmacological pain management options that can be offered to the parturient today. There have been tremendous advancements in the pharmacological treatment of pain in labor and delivery over the last 25 years, mainly due to

Pain in Childbirth

improved regional anesthesia techniques. The future of obstetric anesthesia lies in refining currently available drugs and techniques and in developing new drugs targeted at specific pathophysiological mechanisms to make obstetric anesthesia even safer and more efficacious. This will require translational research efforts ranging from basic science to clinical research. As a first step an animal model has recently been developed in the rat to study the neurophysiological and neuropharmacological mechanisms of pain associated with uterine cervical distension (Liu, B. et al., 2005). Neuroanatomical studies of the sensory pathways from the uterine cervix have shown that P2X3-receptor-expressing sensory neurons might play a role during birthing and signal nociceptive information such as labor pain (Papka, R. E. et al., 2005). Numerous nonpharmacological and alternative treatments are available for the treatment of pain in childbirth. While there is experience with some of those approaches already for centuries, many of these treatments have not been subjected to proper scientific study. Clinical studies assessing the effects of these interventions on pain in childbirth and on a woman’s satisfaction with the childbirth experience, as well as studies assessing the effects on the safety for the pregnant woman and her child are urgently needed.

Acknowledgments Ursula Wesselmann is supported by NIH grants DK57315 (NIDDK), DK066641 (NIDDK), and HD39699 (NICHD, Office of Research for Women’s Health).

References Audit Commission 1997. First Class Delivery: improving Maternity Services in England and Wales. Audit Commission. Bajaj, P., Madsen, H., Moller, M., and Arendt-Nielsen, L. 2002. Antenatal women with or without pelvic pain can be characterized by generalized or segmental hypoalgesia in late pregnancy. J. Pain 3, 451–460. Beilin, Y. 2002. Advances in labor analgesia. Mt. Sinai J. Med. 69, 38–44. Brownridge, P. 1995. The nature and consequences of childbirth pain. Eur. J. Obstet. Gynecol. Reprod. Biol. 59 Suppl, S9–15. Buhling, K. J., Schmidt, S., Robinson, J. N., Klapp, C., Siebert, G., and Dudenhausen, J. W. 2005. Rate of dyspareunia after delivery in primiparae according to mode of delivery. Eur. J. Obstet. Gynecol. Reprod. Biol.124, 42–46. Caton, D., Corry, M. P., Frigoletto, F. D., Hopkins, D. P., Lieberman, E., Mayberry, L., Rooks, J. P., Rosenfield, A.,

583

Sakala, C., Simkin, P., and Young, D. 2002. The nature and management of labor pain: executive summary. Am. J. Obstet. Gynecol. 186, S1–15. Cluett, E. R., Nikodem, V. C., McCandlish, R. E., and Burns, E. E. 2004. Immersion in water in pregnancy, labor and birth. Cochrane Database Syst. Rev. CD000111. Cyna, A. M., McAuliffe, G. L., and Andrew, M. I. 2004. Hypnosis for pain relief in labor and childbirth: a systematic review. Br. J. Anaesth. 93, 505–511. Hedayati, H., Parsons, J., and Crowther, C. A. 2005. Topically applied anaesthetics for treating perineal pain after childbirth. Cochrane Database Syst. Rev. CD004223. Hodnett, E. D. 2002. Pain and women’s satisfaction with the experience of childbirth: a systematic review. Am. J. Obstet. Gynecol. 186, S160–172. Huntley, A. L., Coon, J. T., and Ernst, E. 2004. Complementary and alternative medicine for labor pain: a systematic review. Am. J. Obstet. Gynecol. 191, 36–44. Jarvis, S., McLean, K. A., Chirnside, J., Deans, L. A., Calvert, S. K., Molony, V., and Lawrence, A. B. 1997. Opioidmediated changes in nociceptive threshold during pregnancy and parturition in the sow. Pain 72, 153–159. Lee, H. and Ernst, E. 2004. Acupuncture for labor pain management: A systematic review. Am. J. Obstet. Gynecol. 191, 1573–1579. Liu, B., Eisenach, J. C., and Tong, C. 2005. Chronic estrogen sensitizes a subset of mechanosensitive afferents innervating the uterine cervix. J. Neurophysiol. 93, 2167–2173. Lowe, N. K. 2002. The nature of labor pain. Am. J. Obstet. Gynecol. 186, S16–24. McDonald, J. S. 2001. Pain of Childbirth. In: Bonica’s Management of Pain, 3rd edn. (ed. J. D. Loeser), pp. 1388–1414. Lippincott Williams & Wilkins. Melzack, R. 1984. The myth of painless childbirth (the John J. Bonica lecture). Pain 19, 321–337. Merskey, H. 1979. Pain terms: a list with definitions and a note on usage. Recommended by the IASP Subcommittee on Taxonomy. Pain 6, 249–252. Niven, C. A. and Murphy-Black, T. 2000. Memory for labor pain: a review of the literature. Birth 27, 244–253. Nystedt, A., Edvardsson, D., and Willman, A. 2004. Epidural analgesia for pain relief in labor and childbirth – a review with a systematic approach. J. Clin. Nurs. 13, 455–466. Papka, R. E., Hafemeister, J., and Storey-Workley, M. 2005. P2X receptors in the rat uterine cervix, lumbosacral dorsal root ganglia, and spinal cord during pregnancy. Cell Tissue Res. 321, 35–44. Rowlands, S. and Permezel, M. 1998. Physiology of pain in labor. Baillieres Clin. Obstet. Gynaecol. 12, 347–362. Saisto, T. and Halmesmaki, E. 2003. Fear of childbirth: a neglected dilemma. Acta Obstet. Gynecol. Scand. 82, 201–208. Simkin, P. P. and O’Hara, M. 2002. Nonpharmacologic relief of pain during labor: systematic reviews of five methods. Am. J. Obstet. Gynecol. 186, S131–159. Skibsted, L. and Lange, A. P. 1992. The need for pain relief in uncomplicated deliveries in an alternative birth center compared to an obstetric delivery ward. Pain 48, 183–186. Smith, C. A., Collins, C. T., Cyna, A. M., and Crowther, C. A. 2003. Complementary and alternative therapies for pain management in labor. Cochrane Database Syst. Rev. CD003521. Song, S-O. and Carr, D. B. 1999. Pain and memory. IASP Clin. Updates 7, 1–4. Stuge, B., Hilde, G., and Vollestad, N. 2003. Physical therapy for pregnancy-related low back and pelvic pain: a systematic review. Acta Obstet. Gynecol. Scand. 82, 983–990. Waldenstro¨m, U. and Nilsson, C. A. 1994. Experience of childbirth in birth center care. A randomized controlled study. Acta Obstet. Gynecol. Scand. 73, 547–554.

This page intentionally left blank

40 Urothelium as a Pain Organ L A Birder, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA ª 2009 Elsevier Inc. All rights reserved.

40.1 40.1.1 40.1.2 40.2 40.3

Urothelial Cells: Detectors of Mechanical, Chemical, and Thermal Stimuli Sensor Molecules Expressed in Urothelium Which Could Contribute to Bladder Pain Response to Stimuli: Transducer Function of Urothelial Cells How Might Urothelial Cells Influence Pain Processes? Potential Clinical Implications: Urothelial Receptors/Release Mechanisms as Targets for Drug Treatment

References

40.1 Urothelial Cells: Detectors of Mechanical, Chemical, and Thermal Stimuli The urothelium is a specialized lining of the urinary tract, extending from the renal pelvis to the urethra. The urothelium is composed of at least three layers: a basal cell layer attached to a basement membrane, an intermediate layer, and a superficial apical layer with large hexagonal cells (diameters of 25–250 mm) which are also termed umbrella cells (Lewis, S. A., 2000; Apodaca, G., 2004). The umbrella cells, and, perhaps, intermediate cells may have projections to the basement membrane (Martin, B.F., 1972; Hicks M., 1975; Apodaca, G., 2004). Basal cells, which are thought to be precursors for other cell types, normally exhibit a low (3–6 months) turnover rate; however, accelerated proliferation can occur in pathology. For example, using a model (protamine sulfate) that selectively damages the umbrella cell layer has shown that the urothelium rapidly undergoes both functional and structural changes in order to restore the barrier following injury (Lavelle, J. et al., 2002). While the urothelium has been historically viewed primarily as a barrier, it is becoming increasingly appreciated as a responsive structure capable of detecting physiological and chemical stimuli, and releasing a number of signaling molecules. A number of investigators have described the release of diffusible mediators from the urothelium which could influence urinary bladder function (Ferguson, D.R. et al., 1997; Hawthorn, M.H. et al., 2000; Burnstock, G., 2001; Chess-Williams, R., 2002). There is now abundant evidence which indicates that urothelial cells display a number of properties similar to sensory neurons (nociceptors/mechanoreceptors) (see Table 1; Lewis, S. A. and Hanrahan, J. W., 1985;

585 585 587 588 589 589

Birder, L. et al., 1998; 2004; Smith, P. R. et al., 1998; Birder, L. et al., 2001; 2002a; 2002b; Chess-Williams, R., 2002; Beckel, J. et al., 2004; Birder, L., et al., 2004; Chess-Williams, R., 2004; Burnstock, G. and Knight, G. E., 2004; Murray, E. et al., 2004; Tempest, H. V. et al., 2004; Chopra, B. et al., 2005; Birder, L. et al., 2007) and that both types of cells use diverse signal transduction mechanisms to detect physiological stimuli. 40.1.1 Sensor Molecules Expressed in Urothelium Which Could Contribute to Bladder Pain One example of a urothelial sensor molecule is the TRP channel, TRPV1, known to play a prominent role in nociception and in urinary bladder function (Szallasi, A., 2001). It is well established that painful sensations induced by capsaicin, the pungent substance in hot peppers, are caused by stimulation of TRPV1, an ion channel protein (Caterina, M. J. et al., 1997; Caterina, M. J., 2001) which is activated by capsaicin as well as by moderate heat, protons, and lipid metabolites such as anandamide (endogenous ligand of both cannabinoid and vanilloid receptors). TRPV1 is expressed throughout the afferent limb of the micturition reflex pathway, Figure 1, including urinary bladder unmyelinated (C-fiber) nerves that detect bladder distension or the presence of irritant chemicals (Chancellor M. B. and de Groat, W. C., 1999). In the urinary bladder, TRPV1 is not only expressed by afferent nerves or myofibroblasts that form close contact with urothelial cells, but also by the urothelial cells themselves (Birder, L. et al., 2001). Urothelial TRPV1 receptor expression correlates with the sensitivity to vanilloid compounds, as exogenous application of capsaicin or resiniferatoxin to cultured cells increases intracellular calcium and 585

586 Urothelium as a Pain Organ Table 1 Examples of sensor molecules (i.e., receptors/ion channels) associated with neurons that have been identified in urothelial cells Sensor function/stimuli

Urothelial sensor molecules

Neuronal sensor molecules

ATP Capsaicin resiniferatoxin Heat Cold Hþ Osmolarity Bradykinin Acetylcholine Norepinephrine Nerve growth factor Mechanosensitivity

P2X/P2Y TRPV1 TRPV1; TRPV2; TRPV4 TRPM8; TRPA1 TRPV1; ? In part TRPV4 B1; B2 Nicotinic/muscarinic / subtypes p75/trkA Amiloride sensitive Naþ channels

P2X/P2Y TRPV1 TRPV1; TRPV2; TRPV3; TRPV4 TRPM8; TRPA1 TRPV1; ASIC; DRASIC In part TRPV4 B1; B2 Nicotinic/muscarinic / subtypes p75/trkA Amiloride sensitive Naþ channels

(c)

(d)

Small-medium diameter DRG neurons

Superficial spinal cord dorsal horn

DRG Spinal cord

Urinary bladder

(a)

(e) (b)

Urothelial cells

Submucosal bladder nerves Afferent terminals near preganglionic neurons

Figure 1 TRPV1 is expressed throughout the afferent limb of the micturition reflex pathway. TRPV1-immunoreactivity (cy-3, red) in basal epithelial cells (cyt 17, FITC green) (a); in nerve fibers (cy-3, red) located in close proximity to basal cells (FITC, green) (b) (punctate TRPV1 staining in urothelial cells was electronically subtracted to facilitate imaging of the TRPV1immunoreactive nerve fiber); in small to medium diameter dorsal root ganglion (DRG) neurons (c); and in superficial regions of the spinal cord dorsal horn (d) (staining indicate TRPV1 nerve fibers). (e) TRPV1-positive afferent terminals (in black) are localized in close proximity to pre-ganglionic neurons (PGN neurons labeled by injection of a tracer dye, fast blue, into the major pelvic ganglion). Reproduced from Birder, L. A. 2005. More than just a barrier: Urothelium as a drug target for urinary bladder pain. Am. J. Physiol. Renal. Physiol. 289(3): F489–F495, used with permission from the American Physiological Society.

Urothelium as a Pain Organ

evokes transmitter (NO, nitric oxide; ATP, adenosine triphosphate) release (Birder, L. et al., 2001; 2002a). In neurons, TRPV1 is thought to integrate/ amplify the response to various stimuli playing an essential role in the development of inflammationinduced hyperalgesia (Ghuang, H. H. et al., 2001; Holzer, P., 2004). Thus, it seems likely that urothelial TRPV1 might participate in a similar manner, in the detection of irritant stimuli following bladder inflammation or infection. Anatomically normal, TRPV1-null mice exhibited a number of alterations in bladder urothelial cell function including a reduction of in vitro, stretch-evoked ATP release and membrane capacitance as well as a decrease in hypotonic-evoked ATP release (Birder, L. et al., 2002a). These findings demonstrate that the functional significance of TRPV1 in the bladder extends beyond pain sensation to include participation in normal bladder function, and is essential for normal mechanically evoked purinergic signaling by the urothelium. In addition to TRPV1, urothelial cells also express additional TRP channels, including TRPV2, TRPV4, TRPM8, and TRPA1. In contrast to TRPV1, TRPV2, and TRPV4, which are detectors of warm temperatures (TRPV4 can also be gated by hypotonic stimuli) (Liedtke, W. et al., 2000; Alessandri-Haber, N. et al., 2003; Chung, M. K. et al., 2003), TRPM8 and TRPA1 have been shown to be activated by cold (25–28  C) temperatures as well as by cooling agents (menthol, icilin) and are expressed in a subset of sensory neurons as well as in nonneural cells. This expression suggests that these cells express a range of thermoreceptors underlying both cold and heat stimuli (Stein, R. J. et al., 2004). While the functional role of these thermosensitive channels in urothelium remains to be clarified, it seems likely that a primary role for these proteins may be to recognize noxious stimuli in the bladder. However, the diversity of stimuli which can activate these proteins suggests a much broader sensory and/ or cellular role. For example, TRPM8 expression has been shown to be increased in some epithelia in malignant disorders (prostate tumors), suggesting a role in proliferating cells (Tsavaler, L. et al., 2001). Thus, further studies are needed to fully elucidate the role of TRP channels in urothelium and their influence on bladder function. Purinergic receptors, which are activated by ATP and related nucleotides, are known to play an important role in bladder function and chronic pain (Burnstock, G., 2001; North, R. A., 2004). Two

587

families of purinergic receptors have been identified, P2X and P2Y, both of which are expressed in urothelial cells (Lee, H.Y. et al., 2000; Birder, L. et al., 2004; Tempest, H. V. et al., 2004). Although the function of purinergic receptors in nonexcitable cells is less clear than in afferent neurons, the presence of such receptors may be associated with cell proliferation, apoptosis, secretion, and sensory transduction (Coutinho-Silva R. et al., 2005; Greig, A. V. et al., 2003). In the urinary bladder, recent studies have shown that urothelial-derived ATP release can act as a trigger for exocytosis, in part, via autocrine activation of urothelial purinergic (P2X; P2Y) receptors (Wang, E. C. et al., 2005). This type of signaling may be similar to that in airway epithelium, where nucleotides released to the epithelial surface may act in a paracrine/autocrine manner to regulate ion transport and/or other functions via interactions with luminal epithelial purinergic receptors (Poulsen, A. N. et al., 2005).

40.1.2 Response to Stimuli: Transducer Function of Urothelial Cells Release of chemical mediators (NO, ATP, acetylcholine (ACh); substance P; prostaglandins (PG)) (Ferguson, D. R. et al., 1997; Birder, L. et al., 1998; Burnstock, G., 2001; Birder, L. et al., 2003; ChessWilliams, R., 2004) from urothelial cells suggests that these cells exhibit specialized sensory and signaling properties that could allow reciprocal communication with neighboring urothelial cells as well as nerves or other cells (i.e., immune, myofibroblasts, inflammatory) in the bladder wall. Recent studies have shown that both afferent as well as autonomic axons are located in close proximity to the urothelium (Wayabayashi, Y. et al., 1995; Birder, L. et al., 2001). For example, peptide and TRPV1 immunoreactive nerve fibers have been found localized throughout the urinary bladder musculature and in a plexus beneath and extending into the urothelium. Confocal microscopy revealed that TRPV1 immunoreactive nerve fibers are in close association with basal urothelial cells such that their fluorescent signals overlapped within 0.5 mm optical sections. This type of communication suggests that these cells may be targets for transmitters released from bladder nerves or other cells, or that chemicals released by urothelial cells may also alter the excitability of bladder nerves.

588 Urothelium as a Pain Organ

Studies have demonstrated that ATP released from urothelium during bladder stretch could contribute to activation of bladder afferents. That ATP released from urothelial cells during stretch can activate a population of suburothelial bladder afferents expressing P2X3 receptors, signaling changes in bladder fullness and pain supports this idea (Ferguson, D. R. et al., 1997; Burnstock, G., 2001). Accordingly, P2X3 null mice exhibit a urinary bladder hyporeflexia, suggesting that this receptor and neural–epithelial interactions are essential for normal bladder function (Cockayne, D. A. et al., 2000). This type of regulation may be similar to epithelialdependent secretion of mediators in airway epithelial cells which is thought to modulate submucosal nerves and bronchial smooth muscle tone and may play an important role in inflammation (Homolya, L. et al., 2000; Jallat-Daloz, I. et al., 2001). Thus, it is possible that activation of bladder nerves and urothelial cells can modulate bladder function directly or indirectly via the release of chemical factors in the urothelial layer.

40.2 How Might Urothelial Cells Influence Pain Processes? Recent evidence has demonstrated that urothelial cells exhibit plasticity whereby inflammation or injury can alter the expression and/or sensitivity of a number of urothelial-sensor molecules. Examples include changes in urothelial expression of various receptors including tyrosine kinase (trk), low-affinity nerve growth factor (p75), bradykinin, TRPV1, protease-activated receptors (PPARs), and purinergic receptor (P2X and P2Y) subtypes in animal models as well as in patients diagnosed with a number of bladder disorders including neurogenic bladder and interstitial cystitis (IC) – a chronic clinical disease characterized by urgency, frequency, and bladder pain upon filling (an innocuous stimulus) (Murray, E. et al., 2004; North, R. A., 2004; Tempest, H. V. et al., 2004; Chopra, B. et al., 2005; Dattilio, A. and Vizzard, M. A., 2005). Such changes could contribute to pain and hypersensitivity exhibited in these painful syndromes. Because urothelial cells appear to exhibit sensory function, it is possible that plasticity in urothelial receptors is then linked with pain in various bladder syndromes. Sensitization can be triggered by various mediators (ATP, NO, nerve growth factor (NGF), PGE2) which may be released by both neuronal and non-

neuronal cells (urothelial cells, fibroblasts, mast cells) located near the bladder luminal surface. An important component of the inflammatory response is ATP release from various cell types including urothelium, which can initiate painful sensations by exciting purinergic (P2X) receptors on sensory fibers (Cockayne, D. A. et al., 2000; Burnstock, G., 2001). Recently, it has been shown in sensory neurons that ATP can potentiate the response of vanilloids by lowering the threshold for protons, capsaicin, and heat (Tominaga, M. et al., 2001). This represents a novel mechanism by which large amounts of ATP released from damaged or sensitized cells in response to injury or inflammation may trigger the sensation of pain. These findings have clinical significance and suggest that alterations in afferents or epithelial cells in pelvic viscera may contribute to the sensory abnormalities in a number of pelvic disorders, such as IC, which is consistent with augmented release of ATP in urothelial cells from some patients with IC (Sun, Y. et al., 2001). A comparable disease in cats is termed feline interstitial cystitis (FIC) (Buffington, C. A. et al., 1999; 2001), which is also accompanied by alterations in stretch-evoked release of urothelially derived ATP (Birder, L. et al., 2003). Though the urothelium maintains a tight barrier to ion and solute flux, a number of factors such as tissue pH, mechanical or chemical trauma, or bacterial infection can modulate this barrier function of the urothelium (Hicks, M., 1975; Anderson, G. et al., 2003). When this function is compromised during injury or inflammation, it can result in the passage of toxic substances into the underlying tissue (neural/muscle layers) resulting in urgency, frequency, and pain during bladder distension. For example, inflammation, injury (spinal cord transection), or IC, all of which increase endogenously generated levels of NO, increase permeability to water/urea in addition to producing ultrastructural changes in the apical layer (Lavelle, J. et al., 2000; Apodaca, G. et al., 2003). Although the mechanism is unknown, these findings may be similar to that in other epithelia where excess production of NO has been linked to changes in epithelial integrity (Han, X. et al., 2004). Disruption of epithelial integrity may also be due to substances such as antiproliferative factor (APF), which has been shown to be secreted by bladder epithelial cells from IC patients and can inhibit epithelial proliferation thereby adversely affecting barrier function (Keay, S. et al., 1999; 2004).

Urothelium as a Pain Organ

40.3 Potential Clinical Implications: Urothelial Receptors/Release Mechanisms as Targets for Drug Treatment It is conceivable that the effectiveness of some agents currently used in the treatment of bladder disorders may involve urothelial receptors and/or release mechanisms. For example, intravesical instillation of vanilloids (capsaicin or resiniferatoxin) improves urodynamic parameters in patients with neurogenic detrusor overactivity and reduces bladder pain in patients with hypersensitivity disorders, presumably by desensitizing bladder nerves (Szallasi, A. and Fowler, C. J., 2002; Kim, J. H. et al., 2003). This treatment could also target TRPV1 on urothelial cells, whereby a persistent activation might lead to receptor desensitization or depletion of urothelial transmitters. Recent studies have demonstrated that intradetrusor injection with botulinum neurotoxin type A (BoNTA) is an effective treatment for bladder hypersensitivity disorders including neurogenic detrusor overactivity (Harper, M. et al., 2004; Reitz, A. and Schurch, B., 2004). Following injection, the toxin binds to bladder cholinergic nerve terminals and cleaves the protein, SNAP25, necessary for exocytosis and release of acetylcholine (Harper M. et al., 2004). There is evidence the BoNTA can suppress the release of a number of mediators (acetylcholine, ATP, and neuropeptides) from both neural and non-neural cells (Morris, J. L. et al., 2001). Suppression of neurotransmitter release from urothelium would serve to blunt afferent activity driven by urothelial-derived release of mediators in a number of lower urinary tract dysfunctions. These findings suggest that urothelial cells exhibit specialized sensory and signaling properties that could allow them to respond to their chemical and physical environments and to engage in reciprocal communication with neighboring urothelial cells as well as nerves within the bladder well. Taken together, pharmacologic interventions aimed at targeting urothelial receptor/ion channel expression or release mechanisms may provide a new strategy for the clinical management of bladder disorders.

Acknowledgments This work was supported by grants to L.A.B. from the NIH (RO1 DK54824 and RO1 DK57284).

589

References Alessandri-Haber, N., Yeh, J. J., Boyd, A. E., Parada, C. A., Chen, X., Reichling, D. B., and Levine, J. D. 2003. Hypotonicity induces TRPV4-mediated nociception in rat. Neuron 39, 497–511. Anderson, G., Palermo, J., Schilling, J., Roth, R., Heuser, J., and Hultgren, S. 2003. Intracellular bacterial biofilm-like pods in urinary tract infections. Science 301, 105–107. Apodaca, G. 2004. The uroepithelium: not just a passive barrier. Traffic 5, 1–12. Apodaca, G., Kiss, S., Ruiz, W. G., Meyers, S., Zeidel, M. L., and Birder, L. 2003. Disruption of barrier epithelium function after spinal cord injury. Am. J. Physiol. 284, F966–F970. Barrick, S. R., Lee, H., Meyers, S., Caterina, M. J., Kanai, A. J., Zeidel, M. L., Chopra, B., de Groat, W. C., and Birder, L. 2003 Expression and function of TRPV4 in urinary bladder urothelium. Soc. Neurosci. Abstr. 26, 608.6. Beckel, J., Barrick, S. R., Keast, J.R., Meyers, S., Kanai, A. J., de Groat, W. C., Zeidel, M. L., and Birder, L. 2004. Expression and function of urothelial muscarinic receptors and interactions with bladder nerves. Soc. Neurosci. 26, 846.23. Birder, L., Apodaca, G., de Groat, W. C., and Kanai, A. J. 1998. Adrenergic- and capsaicin-evoked nitric oxide release from urothelium and afferent nerves in urinary bladder. Am. J. Physiol. 275, F226–F229. Birder, L., Kanai, A. J., de Groat, W. C., Kiss, S., Nealen, M. L., Burke, N. E., Dineley, K. E., Watkins, S., Reynolds, I. J., and Caterina, M. J. 2001. Vanilloid receptor expression suggests a sensory role for urinary bladder epithelial cells. Proc. Natl. Acad. Sci. U. S. A. 98, 13396–13401. Birder, L., Kullmann, A., Lee, H., Barrick, S., de Groat, W., Kanai, A., and Caterina, M. 2007. Activation of UrothelialTRPV4 by 4-PDD contributes to altered bladder reflexes in the rat. JPET (in press). Birder, L., Nakamura, Y., Kiss, S., Nealen, M. L., Barrick, S. R., Kanai, A. J., Wang, E., Ruiz, W. G., de Groat, W. C., Apodaca, G., Watkins, S., and Caterina, M. J. 2002a. Altered urinary bladder function in mice lacking the vanilloid receptor TRPV1. Nat. Neurosci. 5, 856–860. Birder, L., Nealen, M. L., Kiss, S., de Groat, W. C., Caterina, M. J., Wang, E., Apodaca, G., and Kanai, A. J. 2002b. Beta-adrenoceptor agonists stimulate endothelial nitric oxide synthase in rat urinary bladder urothelial cells. J. Neurosci. 22, 8063–8070. Birder, L., Barrick, S. R., Roppolo, J. R., Kanai, A. J., de Groat, W. C., Kiss, S., and Buffington, C. A. 2003. Feline interstitial cystitis results in mechanical hypersensitivity and altered ATP release from bladder urothelium. American J. Physiol. 285, F423–F429. Birder, L., Ruan, H. Z., Chopra, B., Xiang, Z., Barrick, S. R., Buffington, C. A., Roppolo, J. R., Ford, A. P., de Groat, W. C., and Burnstock, G. 2004. Alterations in P2X and P2Y purinergic receptor expression in urinary bladder from normal cats and cats with interstitial cystitis. Am. J. Physiol. 287, F1084–F1091. Buffington, C. A. 2001. Visceral pain in humans: lessons from animals. Curr. Pain Headache Rep. 5, 44–51. Buffington, C. A., Chew, D. J., and Woodworth, B. E. 1999. Feline interstitial cystitis. J. Am. Vet. Med. Assoc. 215, 682–687. Burnstock, G. 2001. Purine-mediated signalling in pain and visceral perception. Trends Pharmacol. Sci. 22, 182–188. Burnstock, G. and Knight, G. E. 2004. Cellular distribution and functions of P2 receptor subtypes in different systems. Int. Rev. Cytol. 240, 301–304. Caterina, M. J. 2001. The vanilloid receptor: a molecular gateway to the pain pathway. Ann. Rev. Neurosci. 24, 602–607.

590 Urothelium as a Pain Organ Caterina, M. J., Schumacher, M. A., Tominaga, M., Rosen, T. A., Levine, J. D., and Julius, D. 1997. The capsaicin receptor: a heat activated ion channel in the pain pathway. Nature 389, 816–824. Chancellor, M. B. and de Groat, W. C. 1999. Intravesical capsaicin and resiniferatoxin therapy: spicing up the ways to treat the overactive bladder. J. Urol. 162, 3–11. Chess-Williams, R. 2002. Muscarinic receptors of the urinary bladder: detrusor, urothelial and prejunctional. Auton. Autacoid. Pharmacol. 22, 133–145. Chess-Williams, R. 2004. Potential therapeutic targets for the treatment of detrusor overactivity. Expert Opin. Ther. Targets 8, 95–106. Chopra, B., Barrick, S. R., Meyers, S., Beckel, J., Zeidel, M. L., Ford, A. P., de Groat, W. C., and Birder, L. A. 2005. Expression and function of bradykinin B1 and B2 receptors in normal and inflamed rat urinary bladder urothelium. J. Physiol. 562, 859–871. Chung, M. K., Lee, H., and Caterina, M. J. 2003. Warm temperatures activate TRPV4 in mouse 308 keratinocytes. J. Biol. Chem. 278, 32037–32046. Cockayne, D. A., Hamilton, S. G., Zhu, Q. M., Dunn, P. M., Zhong, Y., Novakovic, S., Malmberg, A. B., Cain, G., Berson, A., Kassotakis, L., Hedley, L., Lachnit, W. G., Burnstock, G., McMahon, S. B., and Ford, A. P. D. W. 2000. Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X(3)-deficient mice. Nature 407, 1011–1015. Coutinho-Silva, R., Stahl, L., Cheung, K. K., de Campos, N. E., de Oliveira Souza, C., Ojcius, D. M., and Burnstock, G. 2005. P2X and P2Y purinergic receptors on human intestinal epithelial carcinoma cells: effects of extracellular nucleotides on apoptosis and cell proliferation. Am. J. Physiol. 288, G1024–G1035. Dattilio, A. and Vizzard, M. A. 2005. Up-regulation of protease activated receptors in bladder after cyclophosphamide induced cystitis and colocalization with capsaicin receptor (VR1) in bladder nerve fibers. J. Urol. 173, 635–639. Ferguson, D. R., Kennedy, I., and Burton, T. J. 1997. ATP is released from rabbit urinary bladder epithelial cells by hydrostatic pressure changes – a possible sensory mechanism? J. Physiol. 505.2, 503–511. Ghuang, H. H., Prescott, E. D., Kong, H., Shields, S., Jordt, S. E., Basbaum, A. I., Chao, M. V., and Julius, D. 2001. Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition. Nature 411, 957–962. Greig, A. V., Linge, C., Terenghi, G., McGrouther, D. A., and Burnstock, G. 2003. Purinergic receptors are part of a functional signaling system for proliferation and differentiation of human epidermal keratinocytes. J. Invest. Dermatol. 120, 1007–1015. Han, X., Fink, M. P., Uchiyama, T., Yang, R., and Delude, R. L. 2004. Increased iNOS activity is essential for pulmonary epithelial tight junction dysfunction in endotoxemic mice. Am. J. Physiol. 286, L259–L267. Harper, M., Fowler, C. J., and Dasgupta, P. 2004. Botulinum toxin and its applications in the lower urinary tract. BJU Int. 93, 702–706. Hawthorn, M. H., Chapple, C. R., Cock, M., and ChessWilliams, R. 2000. Urothelium-derived inhibitory factor(s) influences on detrusor muscle contractility in vitro. Br. J. Pharmacol. 129, 416–419. Hicks, M. 1975. The mammalian urinary bladder: an accommodating organ. Biol. Rev. 50, 215–246. Holzer, P. 2004. TRPV1 and the gut: from a tasty receptor for a painful vanilloid to a key player in hyperalgesia. Eur. J. Pharmacol. 500, 231–241. Homolya, L., Steinberg, T. H., and Boucher, R.. C. 2000. Cell to cell communication in response to mechanical stress via

bilateral release of ATP and UTP in polarized epithelia. J. Cell Biol. 150, 1349–1360. Jallat-Daloz, I., Cognard, J. L., Badet, J. M., and Regnard, J. 2001. Neural-epithelial cell interplay: in vitro evidence that vagal mediators increase PGE2 production by human nasal epithelial cells. Allerg. Asthma Proc. 22, 17–23. Keay, S., Warren, J. W., Zhang, C. O., Tu, L. M., Gordon, D. A., and Whitmore, K. E. 1999. Antiproliferative activity is present in bladder but not renal pelvic urine from interstitial cystitis patients. J. Urol. 162, 1487–1489. Keay, S. K., Szekely, Z., Conrads, T. P., Veenstra, T. D., Barchi, J. J., Zhang, C. O., Koch, K. R., and Michejda, C. J. 2004. An antiproliferative factor from interstitial cystitis patients is a frizzled 8 protein-related sialoglycopeptide. Proc. Natl. Acad. Sci. U. S. A. 101, 11803–11808. Kim, J. H., Rivas, D. A., Shenot, P. J., Green, B., Kennelly, M., Erickson, J. R., O’Leary, M., Yoshimura, N., and Chancellor, M. B. 2003. Intravesical resiniferatoxin for refractory detrusor hyperreflexia: a multicenter, blinded, randomized, placebo-controlled trial. J. Spinal Cord Med. 26, 358–363. Lavelle, J., Meyers, S., Ramage, R., Bastacky, S., Doty, D., Apodaca, G., and Zeidel, M. L. 2002. Bladder permeability barrier: recovery from selective injury of surface epithelial cells. Am. J. Physiol. 283, F242–F253. Lavelle, J., Meyers, S., Ruiz, W. G., Buffington, C. A., Zeidel, M. L., and Apodaca, G. 2000. Urothelial pathophysiological changes in feline interstitial cystitis: a human model. Am. J. Physiol. 278, F540–F553. Lee, H. Y., Bardini, M., and Burnstock, G. 2000. Distribution of P2X receptors in the urinary bladder and the ureter of the rat. J. Urol. 163, 2002–2007. Lewis, S. A. 2000. Everything you wanted to know about the bladder epithelium but were afraid to ask. Am. J. Physiol. 278, F867–F874. Lewis, S. A. and Hanrahan, J. W. 1985. Apical and basolateral membrane ionic channels in rabbit urinary bladder epithelium. Pflugers Arch 405, S83–S88. Liedtke, W., Choe, Y., Marti-Renom, M. A., Bell, A. M., Denis, C. S., and Sali, A. 2000. Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor. Cell 103, 525–535. Martin, B. F. 1972. Cell replacement and differentiation in transitional epithelium: a histological and autoradiographic study of the guinea-pig bladder and ureter. J. Anat. 112, 433–455. Morris, J. L., Jobling, P., and Gibbins, I. L. 2001. Differential inhibition by botulinum neurotoxin A of cotransmitters released from autonomic vasodilator neurons. Am. J. Physiol. 281, H2124–H2127. Murray, E., Malley, S. E., Qiao, L. Y., Hu, V. Y., and Vizzard, M. A. 2004. Cyclophosphamide induced cystitis alters neurotrophin and receptor kinase expression in pelvic ganglia and bladder. J. Urol. 172, 2434–2439. North, R. A. 2004. P2X3 receptors and peripheral pain mechanisms. J. Physiol. 554, 301–308. Poulsen, A. N., Klausen, T. L., Pedersen, P. S., Willumsen, N. J., and Frederidsen, O. 2005. Regulation of ion transport via apical purinergic receptors in intact rabbit airway epithelium. Pflugers Arch. 450(4), 227–235. Reitz, A. and Schurch, B. 2004. Intravesical therapy options for neurogenic detrusor overactivity. Spinal Cord 42, 267–272. Smith, P. R., Mackler, S. A., Weiser, P. C., Brooker, D. R., Ahn, Y. J., Harte, B. J., McNulty, K. A., and Kleyman, T. R. 1998. Expression and localization of epithelial sodium channel in mammalian urinary bladder. Am. J. Physiol. 274, F91–F96. Stein, R. J., Santos, S., Nagatomi, J., Hayashi, Y., Minnery, B. S., Xavier, M., Patel, A. S., Nelson, J. B., Futrell, W. J.,

Urothelium as a Pain Organ Yoshimura, N., Chancellor, M. B., and deMiguel, F. 2004. Cool (TRPM8) and hot (TRPV1) receptors in the bladder and male genital tract. J. Urol. 172, 1175–1178. Sun, Y., Keay, S., DeDeyne, P. G., and Chai, T. C. 2001. Augmented stretch activated adenosine triphosphate release from bladder uroepithelial cells in patients with interstitial cystitis. J. Urol. 166, 1951–1956. Szallasi, A. 2001. Vanilloid receptor ligands: hopes and realities for the future. Drugs Aging 18, 561–573. Szallasi, A. and Fowler, C. J. 2002. After a decade of intravesical vanilloid therapy: still more questions than answers. Lancet Neurol. 1, 167–172. Tempest, H. V., Dixon, A. K., Turner, W. H., Elneil, S., Sellers, L. A., and Ferguson, D. R. 2004. P2X and P2Y receptor expression in human bladder urothelium and changes in interstitial cystitis. BJU Int. 93, 1344–1388. Tominaga, M., Wada, M., and Masu, M. 2001. Potentiation of capsaicin receptor activation by metabotropic ATP

591

receptors: a possible mechanism for ATP-evoked pain and hypersensitivity. Proc. Natl. Acad. Sci. USA 29, 820–825. Tsavaler, L., Shapero, M. H., Morkowski, S., and Laus, R. 2001. TRP-p8, a novel prostate specific gene, is up regulated in prostate cancer and other malignancies and shares high homology with transient receptor potential calcium channel proteins. Cancer Res. 61, 3760–3769. Wang, E. C., Lee, J. M., Ruiz, W. G., Balestreire, E. M., von Bodungen, M., Barrick, S., Cockayne, D. A., Birder, L. A., and Apodaca, G. 2005. ATP and purinergic-receptors dependent membrane traffic in bladder umbrella cells. J. Clin. Invert. 115, 2412–2422. Wayabayashi, Y., Kojima, Y., Makiura, Y., Tomoyoshi, T., and Maeda, T. 1995. Acetylcholinesterase positive axons in the mucosa of urinary bladder of adult cats: retrograde tracing and degeneration studies. Histol. Histopathol. 10, 523–530.

This page intentionally left blank

41 The Brainstem and Nociceptive Modulation M M Heinricher, Oregon Health & Science University, Portland, OR, USA S L Ingram, Washington State University, Vancouver, WA, USA ª 2009 Elsevier Inc. All rights reserved.

41.1 41.1.1 41.1.2 41.2 41.2.1 41.2.2 41.2.3 41.2.4 41.2.5 41.2.5.1 41.2.5.2 41.2.5.3 41.2.5.4 41.3 41.3.1 41.3.2 41.3.3 41.3.3.1 41.3.3.2 41.3.3.3 41.3.4 41.3.4.1 41.3.4.2 41.3.4.3 41.3.4.4 41.3.4.5 41.3.4.6 41.3.4.7 41.3.5 41.3.5.1 41.3.5.2 41.3.5.3 41.3.5.4 41.4 References

The Periaqueductal Gray–Rostral Ventromedial Medulla Pain-Modulating System Functional Characterization of the Periaqueductal Gray–Rostral Ventromedial Medulla Pain-Modulating System Pain Modulation as Part of Adaptive Responses to Behavioral and Physiological Challenges The Periaqueductal Gray The Periaqueductal Gray and Facilitation of Nociception Afferents to the Periaqueductal Gray Efferents from the Periaqueductal Gray Columnar Organization of the Periaqueductal Gray Intrinsic Circuitry and Neurotransmitters in the Periaqueductal Gray Endogenous opioids Norepinephrine Substance P Cannabinoids The Rostral Ventromedial Medulla Connections of the Rostral Ventromedial Medulla The Rostral Ventromedial Medulla and Facilitation of Nociception The Neural Basis for Bidirectional Control from the Rostral Ventromedial Medulla: On- and Off- Cells Physiological classification of rostral ventromedial medulla neurons based on reflex-related activity Role of on- and off-cells in pain modulation Role of neutral cells Pharmacology of Nociceptive Modulation in the Rostral Ventromedial Medulla Gamma-aminobutyric acid and glutamate: the off-cell pause and on-cell burst Opioid actions in the rostral ventromedial medulla Norepinephrine Cannabinoids Cholecystokinin Neurotensin Nociceptin/orphanin FQ Physiological Activation of Nociceptive Modulatory Neurons in the Rostral Ventromedial Medulla Response of RVM neurons to noxious stimulation: does pain inhibit pain? Behavioral state control: anesthesia and sleep/waking cycle Micturition Environmental analgesia Conclusion

594 594 595 596 597 597 598 598 599 599 603 603 604 604 604 604 605 605 607 608 609 609 610 611 612 612 612 612 613 613 613 614 614 615 616

593

594 The Brainstem and Nociceptive Modulation

Glossary cyclooxygenase An enzyme–protein complex that catalyzes the production of prostaglandins from arachidonic acid. Cyclooxygenase activity is inhibited by nonsteroidal anti-inflammatory drugs, such as aspirin and ibuprofen. GIRK G-protein-activated inwardly rectifying potassium channel. A potassium-selective channel that is gated by activated betagamma subunits of Gi/Go G proteins. Kv channel Voltage-gated potassium channel.

41.1 The Periaqueductal Gray–Rostral Ventromedial Medulla Pain-Modulating System The idea that there are well-defined central systems that selectively modulate nociception is usually traced to the demonstration that electrical stimulation in the periaqueductal gray (PAG) region of rats produced potent analgesia. This phenomenon came to be called stimulation-produced analgesia when subsequent work confirmed this finding using quantitative tests of nociception in animals, and when such stimulation was shown to produce clinical analgesia in humans. This was an important advance in documenting that the brain itself could regulate the processing of nociceptive information. Inspired by stimulation-produced analgesia, a significant research effort led to the definition of a brainstem pain modulatory network with critical links in the rostral ventromedial medulla (RVM) as well as the PAG (Figure 1). The antinociception resulting from stimulation in these structures is in large part due to regulation of nociceptive processing at the level of the spinal cord. The PAG–RVM system mediates the analgesic actions of opioids, and it is recruited by internal and environmental challenges. Accumulating evidence from neuroimaging studies supports a role for this system in top-down modulation of pain in humans, such as that produced by placebo or shifts in attention. An overview of descending control, including that mediated by the PAG– RVM system, is provided in Chapter Descending Control Mechanisms. The purpose of this chapter is to review the properties of pain-modulating neurons within the PAG and RVM, and to place this circuitry in a behavioral context.

12-lipoxygenase An enzyme that catalyzes the conversion of arachidonic acid to the hydroxyeicosenoic acid (12-HETE) structure. NSAIDs Nonsteroidal anti-inflammatory drugs. Drugs that inhibit cyclooxygenases and the production of prostaglandins involved in the inflammatory response (e.g., aspirin, ibuprofen, naproxen). phospholipase A2 An enzyme that catalyes the formation of arachidonic acid from phospholipids.

41.1.1 Functional Characterization of the Periaqueductal Gray–Rostral Ventromedial Medulla Pain-Modulating System The PAG is a cell-rich region surrounding the cerebral aqueduct in the midbrain. The RVM is defined functionally, rather than cytoarchitecturally, and includes the nucleus raphe magnus and adjacent reticular formation. Numerous behavioral studies have demonstrated that nonselective activation of neurons within the PAG or RVM produces a potent antinociception. Activation of PAG–RVM output neurons must mediate this antinociception, as direct excitation of either PAG or RVM neurons produces antinociception and inhibition of noxiousevoked activity of dorsal horn neurons, whereas inactivation of either the PAG or RVM does not. The PAG–RVM modulatory network is also an important substrate for opioid analgesia. Focal application of morphine or mu-opioid agonists at either site is sufficient to produce antinociception comparable to that resulting from systemic morphine administration (see Fields, H. L. et al., 2005 or Heinricher, M. M. and Morgan, M. M., 1999 for reviews). Along with the evidence that this system mediates the analgesic actions of exogenous and endogenous opioids, the fact that the net behavioral effect of nonselective experimental activation of the PAG or RVM is antinociception led to a general view of the PAG–RVM system as an analgesia system. This system is indeed activated by acute stress and opioid analgesics to inhibit spinal nociceptive processing. However, there is now increasing evidence that the system, especially the

The Brainstem and Nociceptive Modulation

595

41.1.2 Pain Modulation as Part of Adaptive Responses to Behavioral and Physiological Challenges PAG

RVM Pain

+ –

Figure 1 Functional organization of brainstem painmodulating system with links in midbrain periaqueductal gray (PAG) and rostral ventromedial medulla (RVM). The PAG projects to the RVM. The RVM in turn regulates spinal nociceptive circuitry via a projection through the dorsolateral funiculus to the dorsal horn. This system exerts bidirectional control, and separate populations of RVM neurons mediate descending inhibition and descending facilitation. The PAG is reciprocally linked with forebrain structures including prefrontal cortex, amygdala, and hypothalamus. These substantial interconnections provide an anatomical substrate through which emotional and cognitive variables could influence nociception via the PAG–RVM system.

RVM, also facilitates nociception. The RVM has been implicated in hyperalgesia and allodynia associated with inflammation, nerve injury, acute opioid withdrawal, chronic opioid administration, and the sickness response (see Sections 41.2.1 and 41.3.2, also Porreca, F. et al., 2002 and Heinricher, M. M. et al., 2003 for recent reviews). The PAG–RVM circuit should therefore be viewed not specifically as an analgesia system, but more generally, as a pain-modulation system. From this perspective, the system has the potential for graded enhancement or inhibition of nociception under different conditions.

One of the earliest hints that stimulation-produced analgesia was not an experimental curiosity was the demonstration of environmental or stress-induced analgesia. Stress-induced analgesia refers to the fact that any number of situations or experimental procedures that could be characterized as stressful induce behaviorally measurable, and in some cases quite potent, analgesia. For example, stress-induced analgesia can be produced by electric shock, forced swim, and centrifugal rotation as well as biologically relevant threat stimuli such as odors from stressed animals of the same species or exposure to a predator. Analgesia is also elicited as a conditioned response to cues that have been paired previously with noxious or aversive events. This analgesia can be opioid or nonopioid in nature and has been shown by a number of investigators to be mediated by the PAG–RVM system (Bodnar, R. J. et al., 1980; Lewis, J. W. et al. 1980; Watkins, L. R. et al. 1982; Fanselow, M. S. 1986). In addition to antinociception, electrical or chemical stimulation of the PAG also evokes autonomic changes commonly associated with cardiovascular aspects of defense, including hypertension (in anesthetized animals) and altered heart rate (Lovick, T. A., 1993; Bandler, R. et al., 2000; Morgan, M. M. and Carrive, P., 2001). Patients in whom deep brain electrodes were implanted in the rostral midbrain/PAG region for relief of intractable pain often found the stimulation to be distinctly disquieting, with reports of a feeling of impending doom or a desire to flee when the stimulation was activated (Nashold, B. S. et al., 1969). Consistent with these reports in humans, rats will work to terminate electrical stimulation in the dorsal PAG (Kiser, R. S. et al., 1978). Moreover, stimulation-produced antinociception in rats is accompanied by species-specific defense behaviors, which include immobility and escape or attack (Bandler, R. and DePaulis, A., 1991; Fanselow, M. S. 1991; Morgan, M. M. and Carrive, P. 2001; Carrive, P. and Morgan, M. M. 2004). Two factors contributed to the idea that antinociception is recruited as part of defense behaviors: the fact that antinociception is readily evoked by learned or innate danger signals and the observation that stress induces analgesia through activation of the PAG–RVM system. Pain behaviors must sometimes be inhibited in order to give higher precedence to more pressing needs such as escaping from an aggressor or avoiding detection by a predator. However, a more

596 The Brainstem and Nociceptive Modulation

general view of pain modulation has now developed. Pain inhibition is currently viewed as one component of a number of organized responses that allow an organism to prioritize nociceptive behaviors relative to other internal and external demands. In addition to antinociception, such responses typically include autonomic, endocrine, and motor elements. One example of such an organized defense response would be antinociception as part of preparation for fight or flight when confronted by a predator. Although the circuitry through which the PAG–RVM system is brought into play in response to threat remains to be fully elucidated, inputs from the amygdala and hypothalamus are likely to be critical (Helmstetter, F. J., 1992; Lovick, T. A., 1993; Lumb, B. M. et al., 2002). There is also evidence that the PAG–RVM system is engaged as part of the response to general immune challenge, as occurs with systemic bacterial infection. Thus, systemic administration of lipopolysaccharide (LPS), a well-accepted model for bacterial infection and sickness, results in changes in nociception mediated at least in part by the RVM (Watkins, L. R. et al., 1994; Romanovsky, A. A. et al., 1996). Just as antinociception is viewed as an adaptive response to external threat, hyperalgesia associated with sickness may promote recuperative behaviors and facilitate healing. As with the defense response to external threat, the system is engaged during sickness to prioritize processing of nociceptive information in accord with other physiological and behavioral goals. It is likely that the PAG–RVM system also mediates the more subtle shifts in pain processing that occur in the absence of extreme challenge. For example, reflexes or other more highly organized behaviors evoked by noxious stimuli would be expected to interfere with feeding or other homeostatic behaviors. Nociceptive threshold is increased in hungry cats given access to food (Casey, K. L. and Morrow, T. J. 1988; 1989). Moreover, there appears to be an equilibrium between responding to noxious inputs and the need to maintain energy balance. Feeding is suppressed in favor of pain behaviors during the first phase of the formalin response, generally thought to represent a relatively intense sensation. By contrast, pain behaviors are reduced in favor of feeding during the second, less intense, phase of the formalin response (LaGraize, S. C. et al., 2004a). Similarly, paw withdrawal to noxious heat is attenuated during micturition, presumably allowing complete emptying of the bladder without interruption by noxiousevoked movements (Baez, M. A. et al. 2005).

Distraction or more global variables such as positive or negative mood also alter pain (see Villemure, C. and Bushnell, M. C., 2002 for a review). Similarly, expectation that a particular manipulation will relieve pain can lead to inhibition of pain (Price, D. D. et al., 1999). Understanding the neural mechanisms through which these and other higher psychological factors modulate pain has been challenging, as these variables are at best difficult to study in nonhuman subjects. Moreover, some modulation of pain perception undoubtedly occurs within thalamocortical circuits. However, imaging studies in humans have now demonstrated that the PAG is activated in placebo and distraction paradigms. There are also changes in activation of this system and associated structures when subjects anticipate pain, and in functional pain disorders (see Tracey, I., in press for a recent review). Studies of opioiddependent placebo have been most compelling. Petrovic P. et al. (2002) found that a placebo procedure (infusion of an inactive vehicle in subjects who had been given the powerful opiate remifentanil in a separate trial) resulted in reduced pain reports and activation of the PAG. This region had previously been activated by the exogenous opiate, suggesting that the placebo manipulation recruited endogenous opioid circuitry within the PAG. Wager T. D. et al. (2004) saw similar activation of the anterior cingulate and PAG in a conditioned placebo paradigm. These two studies suggest that recruitment of the PAG contributes to the pain inhibition produced by placebo. Similar studies investigating the effects of attention on pain responses also suggest that activation of the PAG–RVM system contributes to pain suppression when attention is redirected from the noxious stimulus to inputs that have greater behavioral significance (Tracey, I. et al., 2002; Valet, M. et al., 2004). Although correlative, these imaging studies suggest that the PAG–RVM system plays a role in pain modulation produced by placebo, shifts in attention and presumably other cognitive and affective variables.

41.2 The Periaqueductal Gray The PAG comprises heterogeneous cell populations surrounding the cerebral aqueduct. It extends rostrally from the pericoerulear area of the pons to the opening of the third ventricle. As described above, electrical stimulation or focal application of opioids in the PAG produces behaviorally measurable antinociception. However, in addition to pain modulation, it integrates a variety of complex functions, including

The Brainstem and Nociceptive Modulation

cardiovascular and other aspects of defense, general autonomic control, reproductive behaviors, and vocalization (Bandler, R. and Shipley, M. T., 1994). 41.2.1 The Periaqueductal Gray and Facilitation of Nociception The idea that the PAG–RVM system exerts bidirectional control is now well accepted (Porreca, F. et al., 2002; Heinricher, M. M. et al., 2003). Although the focus of functional studies of descending facilitation has been primarily on the RVM (see below, Section 41.3.2), there is some evidence that the PAG also contributes to hyperalgesia under some conditions. First, the PAG contributes to normal levels of responsiveness on the formalin test and to enhanced nociceptive behaviors after foot shock, suggesting a net facilitating output from this region in these paradigms (McLemore, S. et al., 1999; Berrino, L. et al., 2001). Dorsolateral PAG may be important in a generalized sensory sensitization induced by footshock (Crown, E. D. et al., 2004), a facilitation that is recruited in parallel with the well-documented descending inhibition evoked by footshock. Second, focal application of capsaicin or bradykinin into the PAG has a pronociceptive effect (Burdin, T. A. et al., 1992; McGaraughty, S. et al., 2003). Third, prostaglandin release within the PAG apparently recruits descending facilitation, possibly under conditions of inflammation or systemic infection (Vanegas, H. and Tortorici, V. 2002). Thus, cyclooxygenase is constitutively expressed in PAG, and direct microinjection of cyclooxygenase inhibitors in this region reduces responding on cutaneous and visceral nociceptive tests. Moreover, direct application of prostaglandin E2 in the PAG produces behavioral hyperalgesia and activates RVM neurons that facilitate nociception (Heinricher, M. M. et al., 2004a). Taken together, these findings document the ability of the PAG to facilitate nociception. Consistent with this idea, a recent imaging study demonstrated that stimulation of an area of capsaicin-induced secondary hyperalgesia in human subjects was associated with activation of the PAG (Zambreanu, L. et al., 2005). 41.2.2 Gray

Afferents to the Periaqueductal

The PAG integrates information from all levels of the central nervous system. The spinal cord sends direct, somatotopically organized projections from the dorsal horn and the intermediate gray to the

597

ventrolateral and lateral PAG (Menetrey, D. et al., 1982; Yezierski, R. P. and Mendez, C. M. 1991). These afferents convey innocuous and noxious information from cutaneous, musculoskeletal, and visceral structures (Wiberg, M. et al., 1987; Yezierski, R. P., 1988; Yezierski, R. P. and Mendez, C. M., 1991; Clement, C. I. et al., 2000). Inputs from the lumbosacral cord arise from a number of regions, including those receiving afferents from pelvic and pudendal nerves (Vanderhorst, V. G. et al., 1996). These latter afferents are proposed to provide important sensory information contributing to PAG functions in sexual behavior and micturition. Approximately half of the spinal input to the PAG is from the upper cervical spinal cord, but the significance of this cervical predominance has not been determined (Vanderhorst, V. G. et al., 2002). The most substantial afferent inputs to the PAG are from forebrain, including prefrontal and agranular insular cortices as well as the amygdala and hypothalamus (Bandler, R. and Shipley, M. T., 1994; An, X. et al., 1998; Floyd, N. S. et al., 2000). Connections from medial prefrontal cortex are part of a medial prefrontal network associated with visceromotor control through links with the hypothalamus (Ongur, D. and Price, J. L., 2000). Stimulation in the anterior cingulate has been reported by different laboratories to facilitate or suppress nociceptive responses (Hardy, S. G., 1985; Fuchs, P. N. et al., 1996; Calejesan, A. A. et al., 2000). Lesions of the anterior cingulate are generally agreed to reduce nociception in animal models (Pastoriza, L. N. et al., 1996; Donahue, R. R. et al., 2001; LaGraize, S. C. et al., 2004b; in press), consistent with reports in human patients (Foltz, E. L. and Lowell, E. W. 1962; Davis, K. D. et al., 1994; Talbot, J. D. et al., 1995). However, the antinociceptive effect of lesions is presumably due to interference with cortical processing, rather than to activation of descending control. Effects of experimental manipulation of the ventrolateral orbital cortex (VLO) on nociception are similarly complex. Stimulation of the VLO has been reported by one group of investigators to facilitate nociception (Hutchison, W. D. et al., 1996) and another to suppress nociception (Zhang, Y. Q. et al., 1997). The antinociceptive effect of VLO stimulation was blocked by lesion of the PAG, indicating that the connections from this cortex to the PAG are relevant to nociceptive modulation (Zhang, Y. Q. et al., 1997). Hypothalamic afferents to the PAG are predominantly from the lateral hypothalamus and the anterior hypothalamus/medial preoptic area (MPO)

598 The Brainstem and Nociceptive Modulation

(Shipley, M. T. et al., 1991; Semenenko, F. M. and Lumb, B. M. 1992; Behbehani, M. M. and Da Costa Gomez, T. M., 1996). At least some of the anterior hypothalamic neurons projecting to the PAG are nociceptive (Lumb, B. M. et al., 2002; Parry, D. M. et al., 2002). The MPO has important roles in autonomic regulation including thermoregulation and fever, as well as in sleep, mating, and maternal behaviors. Electrical stimulation of the MPO produces c-fos labeling throughout the PAG (Rizvi, T. A. et al., 1996) and activates PAG–RVM output neurons (Semenenko, F. M. and Lumb, B. M., 1999). Direct application of prostaglandin E2 in the MPO at low doses produces hyperalgesia that is likely mediated by the PAG–RVM system (Hosoi, M. et al., 1997; Abe, M. et al., 2001; Heinricher, M. M. et al., 2004b). The central nucleus of the amygdala has massive reciprocal connections with the PAG (Rizvi, T. A. et al., 1991; da Costa Gomez, T. M. and Behbehani, M. M., 1995). The central nucleus receives inputs from the basolateral nucleus, which is a major target of cortical afferents to the amygdala. The central nucleus of the amygdala also receives nociceptive input from the spinal cord, both directly and indirectly via the parabrachial nucleus (Burstein, R. and Potrebic, S., 1993; Gauriau, C. and Bernard, J. F., 2004). PAG neurons respond to stimulation in the amygdala (da Costa Gomez, T. M. et al., 1996), and both stimulation and injection of morphine into the amygdala result in antinociception that is dependent on activation of the descending pathway from PAG to RVM (Pavlovic, Z. W. et al., 1996; Helmstetter, F. J. et al., 1998; McGaraughty, S. and Heinricher, M. M., 2002; 2004). Afferents to the PAG from the brainstem arise from the medulla, including the RVM. Other brainstem sources of inputs to the PAG include the nucleus tractus solitarius, adjacent nucleus cuneiformis, pontine reticular formation, and the locus coeruleus and other catecholaminergic nuclei (Beitz, A. J., 1982; Herbert, H. and Saper, C. B., 1992). The strong input to the PAG from forebrain and hypothalamus provides an anatomical substrate through which emotional and cognitive variables could influence pain via the PAG. Information related to motivation and emotion thus converges with direct and indirect visceral and somatic afferent input in the PAG. This convergence is presumably important to pain modulation in allowing the organism to regulate nociceptive processing in accord with current needs and motivational state, particularly in response to environmental or internal challenge.

41.2.3 Gray

Efferents from the Periaqueductal

The PAG has only a sparse projection to the spinal cord, but a dense projection to the RVM, which in turn projects to the dorsal horn via the dorsolateral funiculus. Inactivation of the RVM prevents the antinociceptive effects of PAG manipulations, indicating that the connection from the PAG to the RVM is the neuroanatomical basis for descending modulation of nociception by the PAG. PAG–RVM projection neurons express neuropeptides, excitatory amino acids, and serotonin. Functional studies implicate excitatory amino acids, serotonin, and endogenous opioids in recruitment of the RVM by the PAG to produce antinociception. A second relay through which the PAG is likely to influence spinal nociceptive processing is pontine catecholaminergic cell groups, as ultrastructural studies demonstrate that these neurons receive inputs from the ventrolateral PAG (see Fields, H. L. et al., 2005 for a recent review).

41.2.4 Columnar Organization of the Periaqueductal Gray Based on both connectivity and function, the PAG has been subdivided into rostrocaudaully oriented columns, designated as dorsomedial (or dorsal), dorsolateral, lateral, and ventrolateral (Carrive, P. and Morgan, M. M., 2004). These columns roughly correspond with subdivisions based on cytoarchitecture that were proposed previously by Beitz A. J. (1985) and Beitz A. J. and Shepard R. D. (1985). Cortical, hypothalamic, and spinal afferents show a preferential distribution to different columns, although there is substantial spread across columnar boundaries (Rizvi, T. A. et al., 1992; An, X. et al., 1998; Floyd, N. S. et al., 2000). Projections to the RVM arise in the dorsomedial, lateral, and ventrolateral columns, but not the dorsolateral column (Abols, I. A. and Basbaum, A. I., 1981; Van Bockstaele, E. J. et al., 1991). Pain modulation is not constrained by columnar boundaries, and electrical stimulation or microinjection of mu-opioid agonists or neuroexcitant agents throughout the dorsoventral extent of the PAG produces analgesia, particularly at more caudal levels (Waters, A. J. and Lumb, B. M., 1997 Carrive, P. and Morgan, M. M., 2004; Morgan, M. M. and Clayton, C. C. 2005). Antinociception resulting from stimulation in the ventrolateral PAG must be mediated by an endogenous opioid connection, as it is blocked by naloxone. By contrast, the antinociception resulting from

The Brainstem and Nociceptive Modulation

electrical stimulation more dorsally is not mediated by endogenous opioids (Morgan, M. M. 1991). Antinociception evoked by stimulation of the dorsal and lateral columns is often associated with escape-like behaviors or defensive posturing, hypertension, and tachycardia. By contrast, antinociception produced by stimulation of the ventrolateral PAG is often accompanied by immobility, bradycardia, and in anesthetized animals, hypotension (Depaulis, A. et al., 1994; Morgan, M. M. and Carrive, P., 2001). These findings gave rise to the proposal that the lateral/dorsolateral columns function specifically in active coping, particularly when confronted with an external threat. By contrast, the ventrolateral column was hypothesized to be important in passive coping and recuperation, for example, in response to visceral pain or some other challenge that cannot be controlled or escaped (Keay, K. A. and Bandler, R., 2001). Two aspects of this framework for PAG organization have been controversial. The first issue is the interpretation of immobility evoked by stimulation in the ventrolateral column. It is not possible to determine from lack of movement alone whether an animal should be viewed as engaging in recuperative behaviors or whether it is instead freezing, that is, exhibiting an active cryptic defense that reduces the likelihood of detection by a predator (Blanchard, R. J. et al. 1986; Fanselow, M. S., 1991; Bittencourt, A. S. et al., 2004). The argument that immobility represents passive coping rather than a defensive response is based largely on observations that stimulation in the ventrolateral column in anesthetized animals produce hypotension (Keay, K. A. and Bandler, R., 2001). However, hypotension is not evoked by such stimulation in awake behaving animals (Morgan, M. M. and Carrive, P., 2001). Furthermore, hypotension may not imply a quiescence or recuperative state. For example, although the freezing in a conditioned fear paradigm is associated with hypertension (Carrive, P. 2000), defensive freezing to various threat stimuli can be associated with profound hypotension in various species of wild-trapped rodents (Hofer, M. A., 1970). A second contentious issue is whether active offensive and escape behaviors should be associated specifically with the lateral/dorsolateral columns, whereas immobility is a function of the ventrolateral column. Immobility as well as escape can be evoked with stimulation of the lateral/dorsolateral columns. Notably, the current needed to induce immobility is lower than that required for active flight behaviors with stimulation in this column (Bittencourt, A. S. et al., 2004). Conversely, bursts of running are often

599

interspersed with periods of inactivity during antinociception evoked from the ventrolateral column (Vianna, D. M. et al., 2001; Morgan, M. M. and Clayton, C. C., 2005). As in the lateral/dorsolateral columns, the current needed to elicit freezing with stimulation in the ventrolateral PAG is lower than that required to elicit jumping (Vianna, D. M. et al., 2001). Moreover, although lesions of the ventrolateral PAG reduce freezing and release running behavior in response to threat (Walker, P. and Carrive, P., 2003, Farook, J. M. et al., 2004), lesions of the dorsolateral PAG have no effect on either freezing or running evoked by exposure to a cat or to a context associated with footshock. In addition, changes in heart rate and activity in this paradigm are seen only when the animal is denied access to a safe hiding place (Dielenberg, R. A. et al., 2004; Farook, J. M. et al., 2004; Leman, S. et al., 2003). Thus, neither active fight or flight behaviors nor immobility appears to be a specific output of a particular column. These observations suggest that although the idea that the lateral/dorsolateral and ventral columns of the PAG represent centers for active and passive coping has had great heuristic value, a full understanding of the functional significance of the PAG columns is likely to require sophisticated analyses of the neural circuitry of these regions in relevant behavioral paradigms. 41.2.5 Intrinsic Circuitry and Neurotransmitters in the Periaqueductal Gray 41.2.5.1

Endogenous opioids All three opioid receptors, mu (MOR), delta (DOR), and kappa (KOR) opioid receptors, are moderately to densely expressed in the PAG (Mansour, A. et al., 1995; Gutstein H. B. et al., 1998; Kalyuzhny, A. E. and Wessendorf, M. W., 1998). The PAG is also rich in endogenous opioids (Mansour, A. et al., 1995). Enkephalin-like immunoreactivity is most dense in the ventrolateral PAG and enkephalin-containing terminals are found apposed to both gamma aminobutyric acid (GABA)ergic and non-GABAergic dendrites, including those of a small percentage of PAG–RVM neurons (Williams, F. G. and Beitz, A. J., 1990). Endomorphin-2 (Tyr-Pro-Phe-Phe-NH2), an endogenous peptide with high selectivity for the MOR (Zadina, J. E. et al., 1997), is concentrated in the PAG as well as the dorsal horn of the spinal cord (Schreff, M. et al., 1998). Although the endomorphins have a high affinity for the MOR, it appears that these

600 The Brainstem and Nociceptive Modulation

peptides are only partial agonists for the MOR in the PAG (Narita, M. et al., 2000). Another endogenous opioid found in the PAG is -endorphin. Discrete populations of -endorphin-containing neurons in the ventromedial hypothalamus project to the PAG and have been implicated in analgesia produced by electrical stimulation and stress (Millan, M. J., 2002). MOR agonists produce potent antinociception when applied directly in the PAG (Heinricher, M. M. and Fields, H. L., 2003). The behavioral antinociception produced by these agents is mediated by activation of output neurons projecting to the RVM (Sandku¨hler, J. and Gebhart, G. F., 1984; Tortorici, V. and Morgan, M. M., 2002). However, as the direct postsynaptic action of MOR agonists on PAG neurons is hyperpolarization (Chieng, B. and Christie, M. J., 1994a; Osborne, P. B. et al., 1996), activation of the output neurons must be via disinhibition. MOR agonists are thought to act presynaptically to block GABAergic inhibition of PAG output neurons. Consistent with this hypothesis, blockade of GABA transmission within the PAG by microinjection of a GABAA receptor antagonist produces antinociception (Moreau, J. L. and Fields, H. L., 1986; Depaulis,

A. et al., 1987). Also consistent with this hypothesis are observations that MOR1 is frequently expressed in GABAergic neurons within the PAG. However, a substantial subset of PAG–RVM projection neurons do express MOR1 (Kalyuzhny, A. E. and Wessendorf, M. W., 1998; Commons, K. G. et al., 2000). These MOR1-positive neurons may target nociceptive facilitating neurons in the RVM (Vanegas, H. et al., 1984; Cheng, Z. F. et al., 1986; Morgan, M. M. et al., 1992;). If so, these MOR1-positive output neurons would be involved in descending facilitation rather than descending inhibition. Postsynaptic effects of MOR agonists on PAG neurons include hyperpolarization (via activation of a postsynaptic G-protein-activated inwardly rectifying potassium conductance, GIRK) and inhibition of calcium channels (Connor, M. and Christie, M. J., 1998) (Figure 2). MOR agonists also have presynaptic effects, inhibiting GABA and glutamate release from terminals within the ventrolateral PAG (Chieng, B. and Christie, M. J., 1994b; Vaughan, C. W. and Christie, M. J. 1997; Vaughan, C. W. et al., 1997). Presynaptic inhibition of GABAergic neurotransmission is through activation of the arachidonic acid–

Figure 2 Cellular mechanisms of opioid action within the periaqueductal gray (PAG). Enkephalin-containing synapses are apposed to cell bodies as well as to GABA- and glutamate-containing terminals. The postsynaptic mu-uopoid receptor (MOR) activates G-protein-activated inwardly rectifying potassium channels (GIRKs) and inhibits voltage-gated Ca2þ channels to hyperpolarize cells and decrease cell activity. Presynaptic MORs inhibit both GABA and glutamate release on ventrolateral PAG neurons, and apparently use different signal transduction pathways in the terminals. MORs localized to GABA terminals are coupled to voltage-gated potassium channels via activation of the arachidonic acid/12-lipoxygenase (12-LOX) second messenger pathway. Hyperpolarization of the terminal decreases GABA release. The signal transduction pathway for MOR inhibition of glutamate release is currently unknown. MORs are found on GABA containing interneurons in the PAG, as well as on PAG output neurons projecting to the rostral ventromedial medulla (RVM). Activation of the descending antinociceptive pathway by opioids occurs via disinhibition. 12-HETE, 12-hydroxyeicosenoic acid; Kv, voltage-gated potassium; PLA2, phospholipase A2.

The Brainstem and Nociceptive Modulation

phospholipase A2 second messenger pathway. Stimulation of this pathway results in activation of voltage-gated potassium channels (Kv channels) by metabolites of 12-lipoxygenase (Vaughan, C. W. and Christie, M. J., 1997; Vaughan, C. W. et al., 1997). This pathway is independent of adenylyl cyclase, protein kinase A or protein kinase C activity (Vaughan, C. W. et al., 1997). Further research is needed to determine the relevance of the various presynaptic versus postsynaptic opioid actions to the nociceptive modulatory function of the PAG. As already noted, there is good evidence that the behavioral antinociception produced by local application of MOR agonists involves activation of the PAG–RVM output neurons via disinhibition. Whether postsynaptic inhibition or the suppression of glutamatergic transmission plays a role in antinociception is unknown. However, at least in the PAG slice, the effect of presynaptic inhibition of GABAergic transmission apparently predominates, because bath application of the MOR agonist [D-Ala2, N-Met-Phe4, Gly-015] enkephalin (DAMGO) results in activation of neurons that are also directly hyperpolarized by the opioid (Chiou, L. C. and Huang, L. Y., 1999). Thus, under in vitro conditions, disinhibition has a relatively large impact, and the net effect of MOR agonist administration is neuronal activation. However, it is not known whether, or under what conditions, endogenous opioids are released to act simultaneously on presynaptic and postsynaptic receptors. In general, activation of DOR and KORs in the PAG does not result in significant antinociception, at least in rats. A number of groups have found no analgesic effect of microinjection of DOR agonists in the PAG in rats (Bodnar, R. J. et al., 1988; Smith, D. J. et al., 1988; Ossipov, M. H. et al., 1995), although there is one report that microinjection of the delta2 agonist deltorphin into the PAG produces a modest increase in latency of the tail flick response (Rossi, G. C. et al., 1994). KOR agonists are also ineffective in producing analgesia in the PAG (Fang, F. G. et al., 1989). At the cellular level, DOR and KOR agonists have no effect on presynaptic GABA release and in rat do not activate postsynaptic potassium channels (Vaughan, C. W. and Christie, M. J., 1997). However, in mice, KOR agonists inhibit presynaptic GABA release in the PAG, and agonists of all three opioid receptor subtypes activate postsynaptic potassium channels (Vaughan, C. W. et al., 2003). The functions of the three receptors may therefore be different in the two species, and it would obviously be of interest

601

to test the behavioral effects of DOR- and KORselective agonists in the PAG in the mouse. 41.2.5.1.(i) Opioid/nonsteroidal anti-inflammatory drugs interactions Microinjections of nonsteroidal

anti-inflammatory drugs (NSAIDs) into the PAG produce analgesia (Tortorici, V. and Vanegas, H., 1995). This antinociception is apparently mediated at least in part by an endogenous opioid peptide, as the analgesia produced by NSAIDs microinjected into the PAG and RVM is attenuated by the opioid antagonist naloxone (Vanegas, H. and Tortorici, V., 2002). In addition to stimulating release of endogenous opioids, recent evidence at the cellular level suggests that NSAIDs may also augment the signaling pathway used by opiates, potentiating the actions of exogenous opioids (Figure 3). Coapplication of NSAIDs potentiates the inhibition of GABA release by the MOR partial agonist morphine, although NSAIDs have no effect on GABA release in the absence of morphine (Vaughan, C. W. et al., 1997). NSAIDs primarily inhibit cyclooxygenases (COX-1 and COX-2), one of three types of enzymes (cyclooxygenases, 5-lipoxygenases, and 12-lipoxygenases) that metabolize arachidonic acid. One hypothesis proposed to explain the mechanism of increased analgesia with coapplication of opioids and NSAIDs is that blockade of COX-1 shunts arachidonic acid metabolism through the lipoxygenase pathways to increase the potency of opioid receptor agonists (Vaughan, C. W. et al., 1997; Vaughan, C. W. 1998; Christie, M. J. et al., 1999). The fact that inhibitors of 5-lipoxygenases also appear to potentiate the effects of opioid agonists in the PAG adds further weight to this proposal (Vaughan, C. W. et al., 1997; Christie, M. J. et al., 1999). These results are important in that the combined administration of NSAIDs and opiates may allow lower doses of morphine to be used to provide adequate analgesia while reducing the probability of the development of tolerance and side effects (such as respiratory depression) associated with high doses of opiates. Functional studies of NSAID/ opioid interactions in the PAG would therefore be of great interest. 41.2.5.1.(ii)

Opioid tolerance and dependence

The PAG has been implicated in opioid tolerance as well as dependence. Opioid tolerance is the diminished responsiveness to the antinociceptive actions of opioids with chronic administration. Dependence refers to the occurrence of withdrawal signs and/or rebound responses upon removal of the opioid or

602 The Brainstem and Nociceptive Modulation

GABA terminal

Acute morphine

Chronic morphine

MOR

MOR

–

AC

–

–

+

AA –

–

AC

AC

2

PL A

NSAIDs

AC

–

AC 12-LOX

+

COX

+

+

cAMP

PKA

Kv

K+

MOR agonists

GABA release

MOR agonists

MOR potent GABA release

Figure 3 Mu-opioid receptor (MOR) coupling in presynaptic GABA terminals changes with chronic morphine administration. Acute administration of MOR agonists activates MORs coupled to phospholipase A2 (PLA2). Activation of PLA2 increases production of arachidonic acid, which is further metabolized by 12-lipoxygenase (12-LOX). Lipoxygenase metabolites such as 12-HETE activate voltage-gated potassium channels (Kv channels) to hyperpolarize and decrease GABA release from the terminals. Nonsteroidal anti-inflammatory drugs (NSAIDs) potentiate this action of opioids by inhibiting cyclooxygenase (COX)-mediated arachidonic acid metabolism, thereby shunting arachidonic acid to the 12-LOX pathway. Activation of MORs presumably also acutely inhibits adenylyl cyclase (AC) activity in these terminals. Chronic morphine administration upregulates AC and protein kinase A (PKA) activity. After chronic, but not acute, opioid treatment, GABA release is enhanced by increased PKA activity. MOR agonists are more potent inhibitors of this PKA-dependent release, so that opioid removal or blockade of MORs by antagonists results in a rebound increase in GABA release. This increased GABA release may contribute to withdrawal behaviors mediated by the PAG.

administration of an opioid antagonist. Animals exhibit tolerance to the antinociceptive actions of MOR agonists when morphine or MOR agonists are applied directly in the PAG, especially in the caudal ventrolateral aspect (Morgan, M. M. et al., 2005). This tolerance is not due to associative mechanisms, as continuous administration via an implanted pump leads to tolerance in the absence of cues associated with drug administration (Lane, D. A. et al., 2004). The PAG is apparently critical for the development of antinociceptive tolerance when opioids are given systemically because animals chronically treated with morphine microinjected into the PAG display cross-tolerance with morphine given systemically

(Jacquet, Y. F. and Lajtha, A., 1976; Siuciak, J. A. and Advokat, C., 1987). Moreover, blockade of PAG opioid receptors using local microinjection of the opioid antagonist naltrexone prevents the development of tolerance to systemically administered morphine (Lane, D. A. et al., 2005). Although RVM neurons lose their responsiveness to PAG morphine administration in tolerant animals (Tortorici, V. et al., 2001), tolerance does not develop as readily when morphine is microinjected into the RVM itself (Morgan, M. M. et al., 2005), and blockade of the RVM does not interfere with the development of tolerance when morphine is applied directly in the PAG (Lane, D. A. et al., 2005). In addition, animals do

The Brainstem and Nociceptive Modulation

not develop behavioral tolerance to direct activation of PAG output neurons that mediate antinociception, for example by microinjecting kainic acid (Morgan, M. M. et al., 2003). These latter two findings demonstrate that tolerance is not a result of adaptations downstream from the opioid-sensitive PAG neuron, and indicate that the search for molecular and cellular mechanisms of opioid tolerance should focus on these opioid-sensitive neurons. The idea that the PAG has a role in opioid dependence derives primarily from observations that blockade of PAG opioid receptors produces a number of withdrawal signs in tolerant animals, and that chronic administration of morphine in the PAG leads to the development of dependence (Bozarth, M. A. 1994). In addition, precipitated withdrawal is associated with increased expression of c-fos throughout the PAG, especially in the ventrolateral and lateral aspects (Chieng, B. et al., 1995). A substantial number of neurons expressing c-fos after precipitated withdrawal are GABAergic (Chieng, B. et al., 2005), and neurons positive for c-fos do not project to the RVM (Bellchambers, C. E. et al., 1998). Thus, as was the case with tolerance, the locus for withdrawal signs in the PAG appears to be upstream from the output neuron projecting to the RVM. Studies of the membrane properties of PAG neurons following chronic opioid treatment and withdrawal document a host of changes that could contribute to tolerance and/or dependence (Williams, J. T. et al., 2001; Bailey, C. P. and Connor, M., 2005). These studies have emphasized altered effects of opioids on GABAergic inhibition and potassium channels. Opioid tolerance is widely assumed to involve a functional uncoupling between opioid receptors and their effectors. The decreased ability of opioids to inhibit the firing of PAG neurons after chronic morphine treatment is consistent with this idea (Bagley E. E. et al., 2005; Chieng, B. and Christie, M. D., 1996). However, MOR activation of GIRK channels in PAG is not reduced in animals subjected to repeated intermittent morphine administration that is sufficient to induce antinociceptive tolerance (Ingram, S. L. et al., 2007), and the ability of MOR agonists to inhibit GABA release is potentiated rather than reduced in slices from animals treated with chronic morphine. These enhanced actions of MOR agonists are mediated by upregulation of the protein kinase A pathway (Ingram S. L. et al., 1998; Hack, S. P. et al., 2003). Moreover, recent findings demonstrate that induction of a GABA transporter-mediated cation current in opioid-sensitive neurons in the PAG may

603

be the mechanism of the increased firing rate of these neurons during withdrawal (Bagley, E. E. et al., 2005). These latter observations would argue that uncoupling of MOR from pre- or postsynaptic effectors does not underlie antinociceptive tolerance in the PAG. Rather, compensatory mechanisms may mask an underlying increase in the coupling of presynaptic MOR to its effectors that is revealed upon removal of the opioid, leading to withdrawal behaviors. Further work will be needed to bridge the gap between the cellular and behavioral analyses of tolerance and dependence. 41.2.5.2

Norepinephrine The PAG has reciprocal connections with pontomedullary catecholaminergic cell groups (Herbert, H. and Saper, C. B. 1992; Bajic, D. et al., 2001). Norepinephrine has multiple effects on PAG neurons that are mediated by 1- and 2-adrenergic receptors. Activation of 1-receptors depolarizes all PAG neurons, whereas 2-receptor activation hyperpolarizes all neurons, suggesting that both receptors are colocalized on PAG neurons (Vaughan, C. W. et al., 1996). However, most neurons preferentially display either a hyperpolarizing or depolarizing response to norepinephrine itself. Neurons in ventrolateral PAG were more likely to be depolarized (85%), whereas lateral PAG neurons were split equally in exhibiting depolarizing and hyperpolarizing responses. The 2-mediated hyperpolarization is due to activation of a potassium conductance while the 1-mediated depolarization depends on inhibition of a potassium conductance and an unidentified norepinephrine-sensitive conductance (Pan, Z. Z. et al., 1994; Vaughan, C. W. et al., 1996). The 2-adrenoceptor agonist clonidine also suppresses GABAergic synaptic transmission, and this suppression is enhanced after chronic morphine treatment (Ingram, S. L. et al., 1998). This action of clonidine may be related to its ability to suppress many of the signs of the opioid withdrawal syndrome (Christie, M. J. et al., 1997). 41.2.5.3

Substance P NK1 receptors are found in the PAG (Commons, K. G. and Valentino, R. J., 2002), and substance P activates both opioid-sensitive and opioid-insensitive neurons in this region (Ogawa, S. et al., 1992; Drew, G. M. et al., 2005). In primary afferents and the dorsal horn, substance P has long been associated with nociceptive transmission, and noxious stimulation also increases the release of substance P in the

604 The Brainstem and Nociceptive Modulation

PAG. This observation would suggest that substance P plays a role in nociceptive transmission in the PAG as in the dorsal horn. However, local morphine administration also increases substance P release in the PAG, and microinjection of exogenous substance P in this region produces significant antinociception (Xin, L. et al., 1997; Rosen, A. et al., 2004). The role of substance P in nociceptive transmission or modulation thus remains to be determined. Substance P has also been implicated in defensive behaviors and aggression, and it produces a conditioned place aversion when microinjected into the dorsolateral PAG (Aguiar, M. S. and Brandao, M. L., 1994). These results point to a more general role for this peptide in defense. Thus substance P may apparently influence a number of functions in the PAG, and functional studies using antagonists are needed to determine the role of endogenous substance P in nociceptive processing and modulation. 41.2.5.4

Cannabinoids Cannabinoids have been used for centuries to provide pain relief (Walker, J. M. and Huang S. M., 2002a) but are of limited utility today because of the significant psychoactive side effects and illegal status in the United States. CB1 receptors are dense throughout the PAG (Herkenham, M. et al., 1991; Tsou, K. et al., 1998). Cannabinoids, like opioids, can mediate antinociception by activating the PAG–RVM descending pathway (see Iversen, L. and Chapman, V., 2002 and Walker, J. M. and Huang, S. M., 2002b for reviews). Endocannabinoids, like endogenous opioids, contribute to the antinociceptive effect of activating the PAG–RVM system (Walker, J. M. et al., 1999; Hough, L. B. et al., 2002), and endocannabinoids in the PAG were recently shown to contribute to stress-induced analgesia (Hohmann, A. G. et al., 2005). Activation of CB1 receptors inhibits both GABA and glutamate release via presynaptic mechanisms. However, cannabinoids have negligible postsynaptic actions on PAG neurons (Vaughan, C. W. et al., 2000).

41.3 The Rostral Ventromedial Medulla 41.3.1 Connections of the Rostral Ventromedial Medulla The RVM can be viewed as the brainstem output from the PAG–RVM system, receiving a dense innervation from the PAG and projecting to the dorsal horn through the dorsolateral funiculus.

Forebrain structures and the hypothalamus/MPO thus influence the RVM through the PAG, as well as by means of less dense connections directly to the RVM itself. In addition, RVM neurons are likely to receive spinothalamic inputs, either through direct connections to their widespread dendritic arbors or relayed via other brainstem regions such as nucleus reticularis gigantocellularis or the PAG (see Fields, H. L. et al., 2005, for a review.) In addition to a direct projection to the dorsal horn, the RVM can apparently influence spinal nociceptive processing via catecholamine cell groups in the pons, particularly the A7 cell group. Although there are no noradrenergic neurons within the RVM, antinociception produced by electrical or chemical stimulation in this region is frequently attenuated or blocked by intrathecal administration of noradrenergic antagonists (Hammond, D. L. and Yaksh, T. L., 1984; Proudfit, H. K., 1992). This indicates that part of the antinociceptive effect of RVM stimulation is relayed through one of the descending catecholaminergic pathways, most likely the A7 cell group in the mesopontine tegmentum. The RVM sends connections to the A7 region (Clark, F. M. and Proudfit, H. K., 1991), and these axons originate from a population of neurons distinct from that projecting to the dorsal horn (Buhler, A. V. et al., 2004). This connection to A7 allows the RVM to engage spinally projecting noradrenergic neurons, which would parallel the direct projections from the RVM to the dorsal horn. The primary outputs from the RVM are thus descending projections to the dorsal horn, both directly and via the mesopontine tegmentum. Ascending connections have also been demonstrated anatomically (Zagon, A. et al., 1994; Hermann, D. M. et al., 1996), but whether these rostral projections play a role in nociceptive modulation is unknown. 41.3.2 The Rostral Ventromedial Medulla and Facilitation of Nociception Although the most robust effect of nonselective experimental activation of the RVM is antinociception, low-intensity electrical stimulation of the RVM and infusions of neuropeptides and N-methylD-aspartic acid (NMDA) in this region have been shown by various groups to facilitate nociceptive processing (Zhuo, M. and Gebhart, G. F., 1992; Urban, M. O. and Smith, D. J., 1993; Smith, D. J. et al., 1997; Zhuo, M. and Gebhart, G. F., 1997; Kovelowski, C. J. et al., 2000; Friedrich, A. E. and

The Brainstem and Nociceptive Modulation

Gebhart, G. F., 2003; Heinricher, M. M. and Neubert, M. J., 2004; Neubert, M. J. et al., 2004). Inactivation studies demonstrate that hyperalgesia produced by electrical stimulation is not merely an experimental curiosity: lesions implicate the RVM in a variety of models of hyperalgesia and persistent pain, including sickness, acute opiate withdrawal, chronic opioidinduced hyperalgesia, Freund’s adjuvant, and mustard oil inflammatory hyperalgesia, following noxious stimulation of a remote body part, and in neuropathic pain models (Kaplan, H. and Fields, H. L., 1991; Morgan, M. M. et al., 1994; Watkins, L. R. et al., 1994; Pertovaara, A. et al., 1996; Ren, K. and Dubner, R., 1996; Urban, M. O. et al., 1996; Mansikka, H. and Pertovaara, A., 1997; Wiertelak, E. P. et al., 1997; Terayama, R. et al., 2000; Porreca, F. et al., 2001; Vanderah, T. W. et al., 2001a; 2001b). These inactivation studies clearly demonstrate a role for descending facilitation in a variety of enhanced pain states, including inflammation. Nevertheless, there is evidence for an increase in descending inhibition from the RVM during inflammation (Ren, K. and Dubner, R., 2002), with potentiation of the analgesic effectiveness of opioids in the RVM (Hurley, R. W. and Hammond, D. L., 2000; 2001). One intriguing possibility is that inflammation increases the number of RVM neurons expressing MOR (Zhang, L. et al., 2004). Given both the clear demonstration that descending facilitation contributes to the hyperalgesia associated with inflammation and the apparently contradictory evidence for increased descending inhibition, an important question is whether different aspects of nociceptive transmission are differentially affected by inhibition and facilitation during inflammation (Vanegas, H., 2004; Vanegas, H. and Schaible, H.-G., 2004). 41.3.3 The Neural Basis for Bidirectional Control from the Rostral Ventromedial Medulla: On- and Off- Cells 41.3.3.1 Physiological classification of rostral ventromedial medulla neurons based on reflex-related activity

Initial electrophysiological approaches to the function of the RVM focused on the responses of RVM neurons to noxious stimulation (Anderson, S. D. et al., 1977; Behbehani, M. M. and Pomeroy, S. L., 1978; Guilbaud, G. et al., 1980; Heinricher, M. M. and Rosenfeld, J. P., 1985). In these experiments in deeply anesthetized animals, some neurons were excited,

605

some inhibited, and some unresponsive. The emphasis of most investigators at that time was on the subset of neurons excited by noxious inputs, at least in part because of the idea that pain inhibits pain. However, the notion of recruitment of the paininhibiting output from the RVM by noxious stimulation was difficult to reconcile with the observation that noxious-evoked firing of these neurons was suppressed by opioids given in doses thought sufficient to produce analgesia (Anderson, S. D. et al., 1977; Gebhart, G. F., 1982; Heinricher, M. M. and Rosenfeld, J. P., 1985). The on/off/neutral cell classification, introduced by Fields, H. L. et al. (1983a), was a significant advance in that it provided a defined framework for hypotheses relating RVM neuronal firing to the pain-modulating function of the region. This approach to RVM physiology was based on the recognition that pain-modulating neurons should discharge in relationship to variables implicated in pain modulation, rather than in response to noxious stimulation. Thus, pain-inhibiting neurons should be activated by analgesic drugs, and during periods of suppressed nociceptive responsiveness, such as that induced by intense stress. Conversely, firing of pain-facilitating neurons should be suppressed during analgesia, and enhanced during hyperalgesia (see Fields, H. M. and Heinricher, M. M., 1985 for an early discussion of the implications of the on/off/ neutral cell classification). In the on/off/neutral cell framework, RVM neurons are recorded in lightly anesthetized rats so that cell firing can be related to changes in nociceptive responding, as measured by spinal nocifensor reflexes. Off-cells are characterized by a cessation of firing during nociceptive reflexes (Figure 4). On-cells are defined by a burst of activity during nociceptive reflexes (Figure 4). Onset of the on-cell reflex-related burst and off-cell pause precede the reflex itself, as well as the thalamic response to the noxious stimulus (Hernandez, N. et al., 1989). Because nociceptive reflexes are generally suppressed when RVM neurons are experimentally activated using electrical stimulation or glutamate microinjection, the fact that off-cell activity ceases abruptly just prior to the execution of nociceptive reflexes suggested that offcells are the antinociceptive output neurons of the RVM, and that the pause in firing permits responses to occur. Conversely, because on-cells are active during the animal’s response to a noxious stimulus, it seemed unlikely that they exert a significant inhibitory effect on nociception. Rather, the reflexrelated burst suggested that these neurons have

606 The Brainstem and Nociceptive Modulation

Off-cell

On-cell

Heat controller

Computer

Figure 4 Two cell populations in the rostral ventromedial medulla (RVM), on- and off-cells, explain descending inhibition and facilitation from the RVM. Bottom: Experimental setup shows simultaneous brainstem recording and reflex testing. Top: Single oscilloscope sweeps show activity of a representative off- and on-cell during a tail heat trial. Upper trace is cell discharge, lower trace shows tail position, with arrowhead indicating tail movement. Heat is applied starting at the beginning of the trace. Each trace is 10 s.

a pronociceptive role. Both hypotheses have subsequently received ample confirmation in experiments using selective pharmacological manipulation of the different cell classes (see Section 41.3.3.2). At least some cells of both classes project to the dorsal horn (Fields, H. L. et al., 1995). The remaining cells in the RVM are classified as neutral cells because they show no change in activity associated with nociceptive reflexes. Whether neutral cells have a role in pain modulation remains to be determined (see Section 41.3.3.3). Noxious pinch typically activates on-cells and suppresses off-cell firing. Cutaneous application of mustard oil, which produces an acute inflammation, evokes a strong activation of on-cells and suppresses off-cell firing, leaving neutral cells unaffected (Kincaid, W. et al., in press). Occasional discrepancies between responses to heat and pinch are most likely explained by the fact that the heat-related classification is based on the reflex response evoked by a

stimulus at just threshold intensity (Fields, H. L. et al., 1983a; Jinks, S. L. et al., 2004a), whereas pinch stimuli in work published to date have not been limited to withdrawal threshold in intensity, and have not been linked to a withdrawal reflex (Leung, C. G. and Mason, P., 1998; Ellrich, J. et al., 2000; 2001). On- and off-cell firing is not constant over time. In animals lightly anesthetized with barbiturates, onand off-cells frequently show alternations between periods of silence and spontaneous discharge. Simultaneous recordings from pairs of on- and offcells show that excitability within each class varies across the population, but that firing within each class is in phase. Consequently, a subset of either the onor off-cell class is active at any given time (Barbaro, N. M. et al., 1989), but the two populations are not active simultaneously. By contrast, serotonergic neurons (which can be considered a specific division of neutral cells (Gao, K. et al., 1997; Mason, P., 1997; Gao, K. et al., 1998)) display regular, more or less

The Brainstem and Nociceptive Modulation

constant activity. Nonserotonergic neutral cells vary in their firing, but are often continuously active for prolonged periods. If a withdrawal reflex is evoked when on-cells are in an active period, there is little or no discernible increase in firing (Barbaro N. M. et al., 1986). Because on-cell firing apparently approaches this ceiling during active phases, definitive classification of a neuron as a neutral cell rather than an oncell requires extensive characterization, with reflex trials delivered during periods of low spontaneous activity. Indeed, Barbaro N. M. et al. (1986) noted that earlier work from the Fields group had likely misclassified a number of on-cells as neutral cells. On-, off-, and neutral cell classes can be identified in awake behaving animals (Oliveras, J. L. et al., 1990; 1991a; 1991b; Leung, C. G. and Mason, P., 1999; Foo, H. and Mason, P., 2005). However, on-cells are more active during waking than sleep, firing in association with the animals’ movements. Neurons of this class are also generally more responsive when animals are awake, and more easily activated by innocuous stimulation than when the animals are anesthetized or asleep. Off-cells are more active when the animal is sleeping, and are inhibited in association with movement in awake animals (Leung, C. G. and Mason, P., 1999; Foo, H. and Mason, P., 2005). 41.3.3.2 Role of on- and off-cells in pain modulation

Initial functional investigations revealed a number of correlations consistent with the idea that off-cells suppress, while on-cells facilitate, nociception. Both onand off-cell classes respond to experimental manipulations of the PAG that produce behavioral analgesia (Vanegas, H. et al., 1984; Hutchison, W. D. et al., 1996; Tortorici, V. and Morgan, M. M., 2002). Withdrawal reflexes can generally be elicited at a lower threshold or with shorter latency if on-cells are active and offcells inactive (Heinricher, M. M. et al., 1989; Ramirez, F. and Vanegas, H., 1989; Bederson, J. B. et al., 1990; Foo, H. and Mason, P., 2003). Antinociception produced by administration of morphine systemically or within the PAG is associated with a uniform activation of off-cells and inhibition of on-cells. Importantly, in animals in which opioid administration fails to produce behavioral analgesia, changes in cell firing are inconsistent. Thus, changes in on- and off-cell firing are related to antinociception rather than to opioid administration as such (Fields, H. L. et al., 1983b; Cheng, Z. F. et al., 1986.). Reduced nociceptive thresholds in acute opioid withdrawal and secondary hyperalgesia during noxious stimulation of a distant

607

body region are correlated with on-cell activation (Bederson, J. B. et al., 1990; Morgan, M. M. and Fields, H. L., 1994). On-cells also facilitate escape responses to intense noxious stimulation, and probably contribute to secondary hyperalgesia during acute inflammation ( Jinks, S. L. et al., 2004b; Kincaid, W. et al., in press). Finally, on-cells have been implicated in hyperalgesia associated with the sickness response. Hyperalgesia produced by systemic administration of bacterial endotoxin is blocked by lesion of the RVM (Watkins, L. R. et al., 1994; Wiertelak, E. P. et al., 1997). Although on-cells have not been studied in animals challenged with endotoxin, these neurons are activated by direct administration of prostaglandin E2 in the MPO (Heinricher, M. M. et al., 2004b), which can be considered a model for central components of the sickness response (Oka, T. et al., 1994; Hosoi, M. et al., 1997). The obvious limitation of these observations is that they are correlative. The RVM plays an important role in a number of functions other than pain modulation, and many neurons in this region are known to exhibit correlations with various physiological parameters including EEG, blood pressure, and body temperature. Causal inferences relating on- or off-cell discharge to altered nociceptive processing thus require selective experimental manipulation of each cell class as a whole, for example, by microinjection of drugs that differentially alter the firing of the different classes. If altered firing of a particular class leads to modified nociceptive responses, one can conclude that the observed change in cell activity mediated the resulting change in behavior. A series of studies using the above approach of manipulating RVM circuitry directly have demonstrated that activation of off-cells is sufficient to produce analgesia, and required for the antinociceptive actions of systemically administered morphine (Heinricher, M. M. and Tortorici, V., 1994; Heinricher, M. M. et al., 1994; 1997; 1999; 2001a; 2001b; Meng, I. D. and Johansen, J. P., 2004; Neubert, M. J. et al., 2004; Meng, I. D. et al., 2005). Similar approaches have recently been extended to testing the effects of off-cell activation. Such studies show that on-cells do not contribute significantly to nociceptive threshold under basal conditions as suppression of the reflex-related firing of on-cells does not by itself reduce responding (Heinricher, M. M. and McGaraughty, S., 1998; Meng, I. D. et al., 2005). However, direct activation of on-cells has a pronociceptive effect: microinjection of neurotensin or cholecystokinin (CCK) at doses that activate on-cells

608 The Brainstem and Nociceptive Modulation

selectively produces thermal hyperalgesia (Heinricher, M. M. and Neubert, M. J., 2004; Neubert, M. J. et al., 2004). Activation of on-cells by CCK likely contributes to nerve injury pain (Kovelowski, C. J. et al., 2000; Porreca, F. et al., 2001; Burgess, S. E. et al., 2002). Microinjection of a CCK-2 receptor antagonist in the RVM also interferes with the paradoxical hyperalgesia associated with prolonged opioid administration (Xie, J. Y. et al. 2005), indicating that CCK-mediated activation of on-cells is also involved in this phenomenon. Viewed collectively, the above data provide strong evidence that off-cells suppress nociception, and that on-cells facilitate nociception. The balance of activity between the on- and off-cell populations therefore allows graded bidirectional control of nociceptive responding (Figure 5). Functional studies demonstrate that the RVM exerts bidirectional control over visceral, as well as cutaneous, hyperalgesia (Coutinho, S. V. et al., 1998). The behavioral response to colorectal distension is suppressed by microinjection of morphine in the RVM (Friedrich, A. E. and Gebhart, G. F., 2003), which is known to activate off-cells (Heinricher, M. M. et al., 1994). Conversely, microinjection of CCK, at a dose that likely activates on-cells (Heinricher, M. M. and Neubert, M. J., 2004), enhances the behavioral response to colorectal distension (Friedrich, A. E. and Gebhart, G. F., 2003). Thus, on- and off-cells appear to modulate behavioral responses evoked by colorectal distension just as they modulate responses evoked by cutaneous heat. The lack of congruence between visceral inputs to RVM neurons and heat-evoked reflexrelated responses of these neurons (Brink, T. S. and Mason, P., 2004) may be related to the inhibitory effect of colorectal distension on sensory processing of cutaneous stimuli (Bouhassira, D. et al., 1994; 1998; Pertovaara, A. and Kalmari, J., 2002; Kalmari, J. and Pertovaara, A., 2004). More generally, a difference in

on- and off-cell firing associated with cutaneous versus visceral noxious-evoked reflexes emphasizes the basic principle that the functions of RVM neurons must be inferred from their outputs (i.e., from the behavioral or physiological effect of selective manipulation of the difference cell classes), rather from inputs. 41.3.3.3

Role of neutral cells All cells that are not classified as on- or off-cells are grouped together under the heading of neutral cells. Whether these neurons have any role in pain modulation has long been an important question. By definition, the firing of neutral cells is unchanged during behavioral responses to noxious stimulation, and neutral cell firing is also unaffected by MOR or DOR agonists, norepinephrine, neurotensin, or CCK, all of which alter firing of on- and/or off-cells and nociceptive behavior when applied in the RVM (Heinricher, M. M. et al., 1994; 1988; Harasawa, I. et al., 2000; Heinricher, M. M. et al., 2001a; Neubert, M. J., et al., 2004). KOR agonists depress the firing of some neutral cells, but the functional implications of this depression have not been explored (Meng, I. D. et al., 2005). The differential pharmacology of neutral cells supports their categorization as distinct from onand off-cells. Neutral cells, or subpopulations of neutral cells, might be involved in some other functions of the RVM, for example thermoregulation (Nakamura, K. et al., 2002; Madden, C. J. and Morrison, S. F., 2003). Despite the lack of direct evidence that neutral cells have a role in pain modulation, interest in this cell class remains high. This is in part because a subset of neutral cells contains serotonin (Potrebic, S. B. et al., 1994; Mason, P., 2001), and serotonin is implicated in descending facilitation as well as descending inhibition of nociception (Le Bars, D., 1988; Calejesan, A. A. et al., 2000; Suzuki, R. et al., 2004). However, there is significant controversy as to

On-cell Off-cell

Reflex Heat

PW

Normal

PW

Analgesia

Hyperalgesia

Figure 5 Balance of activity between on- and off-cell populations allows graded bidirectional control of nociceptive responding. Left column, normal conditions: Application of heat (arrow) to a rat’s tail or paw evokes a paw withdrawal reflex. The off-cell pauses and on-cell becomes active just before the reflex occurs. Middle column, analgesia: Manipulations that cause off-cells to become continuously active also suppress on-cell firing and application of heat does not evoke a response. Right column, hyperalgesia: Reflexes occur with a shorter latency if heat is applied during a period when on-cells are activated (for example, as a consequence of a prior noxious stimulus).

The Brainstem and Nociceptive Modulation

the exact role of serotonergic neutral cells in pain modulation. Immunohistochemically identified serotonergic neurons express MOR, DOR, and KOR (Kalyuzhny, A. E. and Wessendorf, M. W., 1999; Wang, H. and Wessendorf, M.W., 1999; Marinelli, S. et al., 2002). However, neutral cells, including putative serotonergic neutral cells, as a class do not respond to morphine or MOR agonists given systemically or microinjected into the RVM (Barbaro, N. M. et al., 1986; Heinricher, M. M. et al., 1994; Gao, K. et al., 1998). Why neurons that express the MOR fail to respond to MOR agonists remains an important puzzle. A similar mismatch between in vivo functional data and immunohistochemical data arises with the neurotensin receptor. Some immunohistochemically identified serotonergic neurons express neurotensin receptor-like immunoreactivity (NT1ir), and behavioral studies show that microinjection of high doses of neurotensin or a NT1 agonist produce antinociception (Smith, D. J. et al., 1997; Neubert, M. J. et al., 2004; Buhler, A. V. et al. 2005). However, physiologically identified neutral cells do not respond to neurotensin when microinjected into the RVM at a dose sufficient to produce behavioral antinociception (Neubert, M. J. et al., 2004). Again, there is no obvious explanation for why neurons expressing the NT1 receptor show no change in firing following microinjection of neurotensin. Resolution of these discrepancies between immunohistochemical and electrophysiological findings will require immunohistochemical labeling of functionally identified neurons. A second reason for continued interest in neutral cells is the report that the response properties of many neutral cells change to those of on- or off-cells over the course of hours during prolonged inflammation (Miki, K. et al., 2002). A subset of neutral cells may therefore be involved in long-term facilitation or inhibition of nociception, or in other changes in behavior or physiology during inflammation. As discussed above however, the pharmacology of such cells would presumably differ from cells classified as on- or offcells in the absence of inflammation. 41.3.4 Pharmacology of Nociceptive Modulation in the Rostral Ventromedial Medulla Among the neuropeptides and neurotransmitters found in RVM neurons are serotonin, substance P, enkephalin, thyrotropin-releasing hormone, galanin, somatostatin, CCK, GABA, and acetylcholine

609

(Bowker, R. M. et al., 1983; Mantyh, P. W. and Hunt, S. P., 1984; Menetrey, D. and Basbaum, A. I., 1987; Millhorn, D. E. et al., 1987a; 1987b; Bowker, R. M. and Abbott, L. C., 1988; Millhorn, D. E. et al., 1989; Palkovits, M. and Horvath, S., 1994; Skinner, K. et al., 1997). With the exception of serotonin (see above, Section 41.3.3.1), the relationship between physiological/functional class (on-, off-, and neutral cell classification) and expression of different neurotransmitters has yet to be examined. 41.3.4.1 Gamma-aminobutyric acid and glutamate: the off-cell pause and on-cell burst

One approach to identifying the neurotransmitter (s) mediating defined synaptic inputs is to attempt to block those inputs using iontophoretic application of neurotransmitter antagonists (Hicks, T. P., 1983). Iontophoresis of GABAA receptor antagonists selectively blocks the off-cell pause, demonstrating that this reflex-related inhibition of off-cell firing is mediated by GABA (Heinricher, M. M. et al., 1991). Consistent with the idea that the off-cell pause removes descending inhibition and permits noxious information to be processed, microinjection of GABAA receptor antagonists in the RVM blocks the off-cell pause and produces behavioral antinociception (Drower, E. J. and Hammond, D. L., 1988; Heinricher, M. M. and Kaplan, H. J. 1991; Heinricher, M. M. and Tortorici, V., 1994; Gilbert, A. K. and Franklin, K. B., 2001). Interestingly, Nason M. W., Jr. and Mason P. (2004) recently suggested that the effect of RVM GABA receptor antagonism is selective for stimulation of the tail, with facilitation rather than inhibition of responses evoked by stimulation of the foot. However, this is difficult to reconcile with the antinociception observed by others using the hot plate and formalin tests, as both of these tests involve stimulation of the hindpaw (Gilbert, A. K. and Franklin, K. B., 2001). The source of GABAergic input to off-cells is unknown, but it is presumed to be the target of MOR agonists (see Section 41.3.4.2). Although firing of both on-cells and neutral cells is inhibited by iontophoretically applied GABA, neither cell class displays significant disinhibition during iontophoresis of GABAA receptor antagonists. This observation implies that on-cells and neutral cells express GABA receptors, but that there is little ongoing GABAergic control of their firing, at least in the lightly anesthetized rat (Heinricher, M. M. et al., 1991).

610 The Brainstem and Nociceptive Modulation

Iontophoretic application of excitatory amino acids excites all three classes of RVM neurons. However, antagonist studies specifically implicate excitatory amino acid transmitters in reflex-related activation of on-cells and opioid-induced activation of off-cells. Thus, iontophoretic application of the broad-spectrum excitatory amino acid antagonist kynurenate blocks the reflex-related on-cell burst, without affecting the activity of off-cells or neutral cells (Heinricher, M. M. and Roychowdhury, R., 1997). Kynurenate microinjected into the RVM at a dose that blocks on-cell activation does not result in increased withdrawal latency to noxious heat, indicating that the on-cell burst does not control nociceptive threshold, at least under normal conditions (Heinricher, M. M. and McGaraughty, S., 1998). However, it is possible that the firing of on-cells during and after the withdrawal modulates the magnitude or force of the reflex, or primes responses to subsequent stimuli (Ramirez, F. and Vanegas, H., 1989; Jinks, S. L. et al., 2004b). A second important role for excitatory amino acid transmission in the RVM is the recruitment of offcells by opioids (Heinricher, M. M. et al., 2001b). Disinhibition of off-cells leads to NMDA-mediated activation of these neurons, amplifying the effect of disinhibition (see the next Section 41.3.4.2). 41.3.4.2 Opioid actions in the rostral ventromedial medulla

All three opioid receptors, MOR, DOR, and KOR, are found in the RVM, although their expression is much less dense than in the PAG (Gutstein H. B. et al., 1998; Kalyuzhny, A. E. et al., 1996; Wang, H. and Wessendorf, M. W., 1999). The RVM, and specifically activation of off-cells, is required for the analgesic actions of systemically administered morphine (Dickenson, A. H. et al., 1979; Azami, J. et al., 1982; Mitchell, J. M. et al., 1998; Heinricher, M. M. et al., 2001a; 2001b; Gilbert, A. and Franklin, K., 2002). Like the PAG, the RVM supports MOR-mediated analgesia. Thus, direct local microinjection of morphine or MOR agonists in the RVM produces an antinociception equivalent to that produced by systemic morphine administration (Heinricher, M. M. and Morgan, M. M., 1999). Moreover, PAG and RVM interact in a synergistic fashion (Rossi, G. C. et al., 1994). This is at least in part because exogenous opioid administration at one site recruits endogenous opioid mechanisms at the other. Thus, microinjection of morphine in the PAG apparently evokes release of endogenous opioids in the RVM (Kiefel, J. M.

et al., 1993; Pan, Z. Z. and Fields, H. L., 1996; Roychowdhury, S. M. and Fields, H. L., 1996) to produce its antinociceptive effect. The local actions of MOR agonists within the RVM are well understood at both the cellular and circuit levels. On-cells are directly inhibited by MOR agonists. Neither neutral cells nor off-cells are directly sensitive to MOR agonists, but off-cells are activated indirectly, most likely via disinhibition (Figure 6). Microinjection of MOR agonists in the RVM suppresses on-cell firing and activates off-cells, resulting in behavioral antinociception (Heinricher, M. M. et al., 1992; 1994). The activation of off-cells is required for the antinociceptive effect (Heinricher, M. M. et al., 1997). Suppression of on-cell firing is not necessary for RVM-mediated analgesia (Heinricher, M. M. et al., 1994; Neubert, M. J. et al., 2004), although it likely contributes. Selective inhibition of on-cell firing reduces the force, although not the latency, of withdrawal to noxious heat (Heinricher, M. M. and McGaraughty, S., 1998; Jinks, S. L. et al., 2004b). Studies at the cellular level reveal that some neurons are inhibited directly by MOR agonists, whereas others are disinhibited via presynaptic inhibition of GABAergic transmission (Pan, Z. Z. et al., 1990). These findings are thus consistent with the direct inhibition of on-cells and indirect activation of offcells observed in vivo. RVM neurons studied in vitro are classified as secondary cells, which are directly

Figure 6 Disinhibition of off-cells, direct inhibition of oncells mediates opioid analgesia. On-cells are inhibited, directly, by morphine and mu-opioid receptor (MOR) agonists. Off-cells are not inhibited by MOR agonists, but are activated, via disinhibition. MORs are thus presumed to be located on on-cells, and on gamma aminobutyric acid (GABA)ergic inputs to off-cells.

The Brainstem and Nociceptive Modulation

inhibited by MOR agonists, and primary cells, which are not. Primary cells do however receive opioidsensitive GABAergic inputs, and are disinhibited by MOR agonists (Pan, Z. Z. et al., 1990). Secondary cells presumably map to on-cells recorded in vivo, and primary cells to off-cells and neutral cells identified in vivo.

Delta opioid receptor Like MOR agonists, DOR agonists, particularly delta2 agonists, produce behavioral hypoalgesia when microinjected into the RVM. The effects of delta1 agonists are less robust than those of delta2 agonists (see Heinricher, M. M. and Fields, H. L., 2003 for review of the role of the DOR in pain modulation in the RVM). In vitro, the DOR agonists deltorphin and [D-Pen2, D-Pen5] enkephalin (DPDPE) elicit hyperpolarizing currents in a substantial minority of RVM neurons (Marinelli S. et al., 2005). Some, but not all, of these neurons were also hyperpolarized by MOR agonists. It thus appears that a subset of DOR-sensitive RVM neurons falls into the secondary cell category. In experiments in vivo, microinjection of deltorphin into the RVM increases the latency and reduces the amplitude of the reflexrelated on-cell burst, reduces the duration of the reflex-related off-cell pause, and evokes a small but statistically significant increase in tail flick latency (Harasawa, I. et al., 2000). Molecular, cellular, and behavioral approaches point to interactions between MOR- and DORmediated processes, but experiments designed to uncover such interactions within the RVM reveal that the effects of MOR and DOR agonists in the RVM are independent under basal conditions (Hurley, R. W. and Hammond, D. L. 2001; Kalra, A. et al., 2001). However, there is a time-dependent recruitment of supraspinal DOR function in inflammation, so that DOR agonists microinjected into the RVM are more effective in animals subjected to longlasting inflammation compared to noninflamed controls. MOR agonists are also more potent in these animals (Hurley, R. W. and Hammond, D. L., 2000; 2001). This increased opioid action may reflect an increase in the release of endogenous opioids acting at the DOR (Williams F. G. et al., 1995) and/or translocation of DOR from the cytoplasm to the plasma membrane (Commons, K. G. et al., 2001; Commons, K. G., 2003). Coexpression of MOR and DOR on individual RVM neurons may also play a role (Marinelli, S. et al., 2005). 41.3.4.2.(i)

611

41.3.4.2.(ii) Kappa opioid receptor The role of the KOR in the pain-modulating functions of the RVM remains controversial. Electrophysiological studies in the RVM slice demonstrate pre- and postsynaptic effects of KOR agonists in the RVM. However, it is unclear whether neurons in which KOR agonists evoke an outward current are a separate population from those inhibited by MOR agonists (Pan, Z. Z. et al., 1997; Ackley, M. A. et al., 2001; Marinelli, S. et al., 2002; Bie, B. and Pan, Z. Z., 2003). Microinjection of a KOR agonist into the RVM has been reported to either have no behavioral effect (Pan, Z. et al., 2000; Meng, I. D. et al., 2005) or to produce antinociception, depending on the nociceptive test as well as the sex of the animal (Tershner, S. A. et al., 2000; Ackley, M. A. et al., 2001). KOR agonists also block the antinociceptive effect of PAG microinjection of a MOR agonist or systemic morphine administration (Pan, Z. et al., 2000; Bie, B. and Pan, Z. Z., 2003; Meng, I. D. et al., 2005) as well as MORmediated conditioned hypoalgesia (Foo, H. and Helmstetter F. J., 2000). This antianalgesic effect of the KOR agonist is presumably due to a blockade of off-cell activation (Bie, B. and Pan, Z. Z., 2003; Meng, I. D et al., 2005). KOR agonists can also block hyperalgesia when microinjected into the RVM, presumably via presynaptic blockade of excitatory inputs to on-cells (Ackley, M. A. et al., 2001; Meng, I. D. et al., 2005).

41.3.4.3

Norepinephrine As with the KOR, norepinephrine likely influences both the nociceptive facilitating and inhibiting outputs from the RVM. Behavioral studies have reported that blockade of 1-adrenergic receptors produces antinociception (Sagen, J. and Proudfit, H. K., 1981) and reduces hyperalgesia associated with acute opioid withdrawal (Bie, B. et al., 2003). Agonists at the 1 receptor produce hyperalgesia and conditioned place avoidance, and the increased nociception is dissociated from the negative affective state in these animals (Hirakawa, N. et al., 2000). Surprisingly, 2 agonists have been reported to produce analgesia (Sagen, J. and Proudfit, H. K., 1985; Haws, C. W. et al., 1990) as well as to block opioid analgesia (Bie, B. et al., 2003) when microinjected into the RVM. The neural basis for these conflicting results is unclear, as electrophysiological studies are also inconsistent. In vivo, iontophoretically applied norepinephrine and 2 agonists suppress the firing of on-cells, whilst 1 agonists activate on-cells. Offcells and neutral cells do not respond to

612 The Brainstem and Nociceptive Modulation

iontophoretically applied norepinephrine or adrenergic agents (Heinricher, M. M. et al., 1988). By contrast, in experiments in the RVM slice, 2 agonists hyperpolarize primary cells (presumably offcells and/or neutral cells), and 1 agonists activate all cells (Bie, B. et al., 2003). The findings from the in vivo study are thus more consistent with an antinociceptive effect of 2 receptor activation, whereas the studies in the slice are more consistent with the antiopioid action of these agents. 41.3.4.4

Cannabinoids As noted above (Section 41.2.5.4), the PAG–RVM system is now recognized to mediate at least part of the antinociceptive effect of cannabinoids. The RVM is required for the antinociceptive action of systemically administered cannabinoid agonists (Meng, I. D. et al., 1998), and microinjection of CB1 agonists into the RVM produces moderate antinociception (Martin, W. J. et al., 1998; Monhemius, R. et al., 2001; Meng, I. D. and Johansen, J. P., 2004). Off-cells display a measurable increase in activity after local infusion of a CB1 agonist in the RVM, and the reflex-related activity of on-cells is significantly reduced (Meng, I. D. and Johansen, J. P., 2004). Both of these effects are presumed to reflect a presynaptic action, as cannabinoids block excitatory and inhibitory synaptic currents, but have negligible postsynaptic effects in RVM (Vaughan C. W. et al., 1999). 41.3.4.5

Cholecystokinin Endogenous CCK has long been recognized to counter opioid analgesia and to contribute to enhanced nociception, particularly in neuropathic pain states (Stanfa, L. et al., 1994; Wiesenfeld-Hallin, Z. et al., 1999). In humans, CCK antagonism increases the analgesic actions of morphine and placebo (Price, D. D. et al., 1985; Benedetti, F. and Amanzio, M., 1997; McCleane, G. J., 1998). CCK is found in the RVM (Skinner, K. et al., 1997), and has both pronociceptive and antiopioid actions in this region. CCK in the RVM is implicated in the expression of allodynia and thermal hyperalgesia in the spinal nerve ligation model of nerve injury pain as well as in hyperalgesia associated with chronic morphine administration (Kovelowski, C. J. et al., 2000; Xie, J. Y. et al., 2005). Furthermore, focal application of relatively high doses of exogenous CCK in the RVM produces cutaneous and visceral hyperalgesia (Kovelowski, C. J. et al., 2000; Friedrich, A. E. and

Gebhart, G. F., 2003; Heinricher, M. M. and Neubert, M. J., 2004). Notably, CCK activates on-cells selectively when microinjected in a dose sufficient to produce behavioral hyperalgesia. This points to oncells as critical mediators of CCK hyperalgesia in the RVM (Heinricher, M. M. and Neubert, M. J., 2004). CCK also has antiopioid actions in the RVM, albeit through a different mechanism than that through which it produces hyperalgesia. Focal application of a low dose of CCK in the RVM attenuates both opioid activation of off-cells and opioid-induced antinociception without affecting baseline nociceptive responding or the activity of on-cells (Heinricher, M. M. et al., 2001a). The signal transduction mechanisms that underlie this antiopioid action of CCK are unknown. In the hippocampus, CCK reduces opioid-induced disinhibition by increasing GABA release (Miller, K. K. et al., 1997), raising the possibility that CCK acts presynaptically to block disinhibition of off-cells in the RVM. 41.3.4.6

Neurotensin Like CCK, neurotensin has multiple effects in the RVM. Microinjection of this peptide within the RVM gives rise to a dose-related, bidirectional effect on nociceptive behaviors (tail flick, hot plate, and visceromotor responses to colorectal distension) and dorsal horn nociceptive neurons. Extremely low doses produce facilitation, whereas high doses produce antinociception. Intermediate doses are without effect (Urban, M. O. and Smith, D. J., 1993; Smith, D. J. et al., 1997; Urban, M. O. and Gebhart, G. F., 1997; Urban, M. O. et al., 1999; Neubert, M. J. et al., 2004.). Behavioral hyperalgesia is mediated by selective activation of on-cells, whereas the hypoalgesia produced by higher doses is due to recruitment of off-cells. Neutral cells do not respond to neurotensin at any dose (Neubert, M. J. et al. 2004). 41.3.4.7

Nociceptin/orphanin FQ The identification of an opioid-like receptor (ORL1) that did not bind classical opioid peptides suggested that additional peptides might exist that could modulate nociception. However, despite its structural and functional similarities to the opioid receptors, activation of ORL-1 by its endogenous ligand, referred to as nociceptin or orphanin FQ (OFQ), does not produce antinociception when applied within the RVM. Rather nociceptin/OFQ potently inhibits all neurons in the RVM. As a consequence, focal application of nociception/OFQ in the RVM is effectively a functional lesion of the

The Brainstem and Nociceptive Modulation

region, and interferes with both antinociceptive and pronociceptive outputs (see Heinricher, M. M., in press for a review). 41.3.5 Physiological Activation of Nociceptive Modulatory Neurons in the Rostral Ventromedial Medulla Given a pronociceptive role for on-cells and an antinociceptive role for off-cells, the obvious question that arises is how and when these two classes of neurons with opposing functions are recruited to modulate nociception. This question remains a significant challenge, in part because a number of factors likely to influence nociception via the RVM involve higher-order neural structures and psychological processes that are difficult to study in rodents, particularly under anesthesia. Nevertheless, we do have some information as to how and when RVM nociceptive modulatory neurons are recruited to modulate nociceptive processing. 41.3.5.1 Response of RVM neurons to noxious stimulation: does pain inhibit pain?

Noxious-evoked withdrawals are associated with a period of on-cell activation and off-cell inhibition that can last from less than a second to many minutes. This period, during which the balance between the on- and off-cell populations is shifted toward on-cell activation, is associated with heightened nociceptive responsiveness that can be blocked by lesion of the RVM (Heinricher, M. M. et al. 1989; Ramirez, F. and Vanegas, H., 1989; Morgan, J. L. and Fields, H. L., 1994; Foo, H. and Mason, P., 2003). Thus noxious stimulation per se recruits the RVM to facilitate nociception. This conclusion is consistent with the early suggestion of Cervero F. and Wolstencroft J. H. (1984) that the RVM is part of a short-term positive feedback loop activated by noxious stimulation. Such a positive feedback process presumably prepares the organism to respond more briskly or at a lower threshold to subsequent damaging inputs. This view of on-cells as part of a positive feedback loop is further supported by evidence that on-cells are activated by acute cutaneous inflammation, and that the RVM is necessary for secondary hyperalgesia in this paradigm (Urban, M. O. et al., 1996; Kincaid, W. et al., in press). The evidence for positive feedback mediated by the RVM is plainly at odds with the long-standing idea that pain inhibits pain, which arose from observations of an

613

apparent lack of pain observed in some patients subjected to intense trauma (Wall, P. D. 1979; Melzack, R. et al., 1982) and the from the ability of footshock or other noxious stimuli to suppress animals’ responses to other painful events (Maier, S. F., 1986). Several factors must be considered in addressing this issue. First, other brainstem pathways, such as that through the medullary subnucleus reticularis dorsalis (Le Bars, D., 2002), act in parallel with the output from the RVM. The net effect of a given noxious stimulus on spinal nociceptive processing and pain sensation will reflect the actions of these pathways as well as that of the RVM. In addition, higher-order processes, such as fear or stress, are likely to be significant when an animal is subjected to an experimental noxious stimulus, particularly one over which it has no control. Such higher influences will be most prominent in awake behaving animals, and may shift the balance in the RVM towards activation of offcells rather than on-cells. Such a shift is presumably the basis for stress-induced analgesia or antinociception associated with fear conditioning (Bodnar, R. J. et al., 1980; Fanselow, M. S. 1986; Helmstetter, F. J. and Tershner, S. A., 1994). Conditioned fear, for example, produces antinociception mediated by the amygdala and the RVM, and direct opioid activation of the amygdala activates RVM off-cells via the PAG (Helmstetter, F. J. and Landeira-Fernandez, J., 1990; Helmstetter, F. J., 1992; Helmstetter, F. J. and Bellgowan, P. S., 1993; Helmstetter, F. J. and Tershner, S. A., 1994; Helmstetter, F. J. et al., 1998; McGaraughty, S. and Heinricher, M. M., 2002; 2004). Thus, because of higher-order inputs to the RVM and the actions of other descending pathways, the behavioral response to a given noxious stimulus may be enhanced or suppressed in the presence of pain. Which behavioral outcome predominates will depend on the stimulus history, the environment in which the stimulus is applied and the behavioral state of the animal. 41.3.5.2 Behavioral state control: anesthesia and sleep/waking cycle

The influence of behavioral state variables on nociceptive processing at the first central relay in the dorsal horn (Hayes, R. L. et al., 1981; Bushnell, M. C. et al., 1984; Soja, P. J. et al., 1999) suggests that pathways descending from the brain to the dorsal horn contribute to the influence of behavioral state on nociception. One possibility that has been considered is that RVM neurons might mediate effects of general anesthesia or sleep/waking on nociceptive processing.

614 The Brainstem and Nociceptive Modulation

Correlative data suggest that on- and/or off-cell firing could contribute to isoflurane-induced motor depression at lighter planes of anesthesia (Jinks, S. L. et al., 2004a). However, firing of both on- and off-cells is depressed when isoflurane concentration is increased to levels above that required to suppress nocifensor reflexes (Leung, C. G. and Mason, P., 1995). These neurons are thus unlikely to mediate the effects of a anesthesia at a surgical plane on nociceptive withdrawals. Analysis of the role of on- and off-cells in mediating changes in nociception across the sleep–waking cycle is impeded by lack of a clear understanding of how nociception changes with sleep/waking. In cats, Kshatri A. M. et al. (1998) demonstrated that the latency of the tail flick reflex was slightly increased during slow-wave sleep compared to waking, but substantially longer during paradoxical sleep. Consistent with this, noxious-evoked activity of trigeminal neurons is depressed during paradoxical sleep, but not slow-wave sleep, compared to waking (Cairns, B. E. et al., 1995; 1996). By contrast, Mason P. et al. (2001) reported that paw withdrawals evoked by heat were enhanced during slow-wave sleep compared to waking, suggesting a disinhibition of nociception during slow-wave sleep. Parallel recording studies from this group demonstrated that offcells were more active during slow-wave sleep and on-cells and neutral cells were less active compared to waking (Leung, C. G. and Mason, P., 1999). It is therefore unlikely that on- or off-cells mediated the enhanced nociception seen in their behavioral analysis. However, these authors noted that rats return to sleep more quickly following noxious stimulation if the stimulus is delivered when the rats are sleeping rather than awake. They suggested that this could point to a role for off-cells in controlling arousal. However, it is not clear that the duration of waking triggered by the noxious stimulus could be differentiated from the ongoing waking pattern in their analysis. It remains to be determined whether offcells control arousal, or mediate the influence of arousal on nociception. A further question is whether on- and off-cells contribute to the atonia of paradoxical sleep. This has not been tested directly. However, although stimulation throughout the length of the medial pontomedullary reticular formation can produce atonia in decerebrate rats (Hajnik, T. et al., 2000), the most effective sites are generally dorsal to the area defined as the RVM. Moreover, microinjection of kainate or morphine in the RVM in intact behaving

rats does not produce loss of motor tone, even though locomotor activity in an open field is reduced (Morgan, M. M. and Whitney, P. K., 2000). Finally, the firing of on- and off-cells does not vary between slow wave sleep and paradoxical sleep (Foo, H. and Mason, P., 2003). Taken together, these data indicate that on- and off-cells are unlikely to mediate atonia during paradoxical sleep. 41.3.5.3

Micturition Baez M. A. et al. (2005) recently reported that paw withdrawal to noxious heat is attenuated during micturition, presumably preventing potential interruption of bladder emptying by noxious stimulusevoked movements. Consistent with the idea that off-cells inhibit and on-cells facilitate nociception during micturition, many presumptive off-cells were active during urine expulsion, whereas presumptive on-cells were inhibited. However, these authors propose a somewhat broader role for RVM neurons, as electrical stimulation in the RVM and morphine microinjection in the PAG are known to suppress bladder contractions (Sugaya, K. et al., 1998; Matsumoto, S. et al., 2004). Baez M. A. et al. (2005) therefore suggested that off-cell activation suppresses voiding, possibly by depressing transmission of bladder afferent information. 41.3.5.4

Environmental analgesia Decreases in pain responsiveness can be induced by a wide range of experimental procedures, including electrical shock, forced swim, and centrifugal rotation (Watkins, L. R and Mayer, D. J., 1982; Bodnar, R. J., 1986; Maier, S. F., 1986). Biologically relevant threat stimuli such as odors from stressed animals of the same species or exposure to a predator also induce antinociception (Fanselow, M. S., 1985; Lester, L. S. and Fanselow, M. S., 1985; Kavaliers, M. 1988; Lichtman, A. H. and Fanselow, M. S., 1990). Activation of endogenous pain-modulating systems can also enhance the analgesic effects of exogenous opioids. Thus, presentation of a stressful shock potentiates morphine-induced antinociception, an effect that increases as the intensity of stress is increased (Grau, J. W. et al., 1981; Rosellini, R. A. et al., 1994). The PAG–RVM system is implicated in at least some of these environmentally induced changes in nociceptive responsiveness. Most important, some forms of environmental analgesia can be attenuated by lesioning the RVM (Prieto, G. J. et al., 1983; Watkins, L. R. et al., 1983b). Moreover, administration of a stressful foot shock blocks both the

The Brainstem and Nociceptive Modulation

pause in firing that characterizes off-cells and the typical on-cell burst of activity (Friederich, M. W. and Walker, J. M., 1990). This indicates that footshock and possibly other stressors affect the activity of on- and off-cell classes in a manner consistent with their respective pronociceptive and antinociceptive roles. Antinociception is also elicited as a conditioned response to previously neutral cues paired with noxious or aversive events (Fanselow, M. S., 1986). This latter phenomenon is termed conditioned antinociception, and has been widely adopted for experimental analysis of endogenous mechanisms involved in nociceptive modulation. In conditioned antinociception paradigms, antinociception is recruited in concert with other behaviors and autonomic adjustments as part of a defensive reaction (Williams, F. G. et al., 1990; Fanselow, M. S., 1991; Harris, J. A. and Westbrook, R. F., 1995). Benzodiazepine receptor inverse agonists have anxiogenic or fear-promoting effects, and yield antinociception after either intracerebral or systemic administration (Rodgers, R. J. and Randall, J. I., 1988; Helmstetter, H. J. et al., 1990; Fanselow, M. S. and Kim, J. J., 1992). Conversely, hypoalgesia is reduced by manipulations that would be expected to reduce fear, such as administration of anxiolytic agents (Fanselow, M. S. and Helmstetter, H. J., 1988). The amygdala, a forebrain structure with a welldocumented role in fear, stress and anxiety, is critical in organization of the fear-related processes described above (Davis, M., 1992a; 1992b). Notably, amygdala lesions attenuate freezing and analgesia in rats exposed to a cat, which is an innate fear stimulus for this species (Blanchard, D. C. and Blanchard, R. J., 1972; Fox, R. J. and Sorenson, C. A., 1994), and to intense, nonnoxious noise (Helmstetter, F. J. and Bellgowan, P. S., 1994; Bellgowan, P. S. and Helmstetter, F. J., 1996). Such lesions have no effect on baseline nociceptive responsiveness (Helmstetter, F. J. 1992; Fox, R. J. and Sorenson, C. A., 1994; Manning, B. H. and Mayer, D. J., 1995; Watkins, L. R. et al., 1993). Antinociception produced by fear-related processes organized in the amygdala is mediated by the PAG–RVM system. Thus, conditioned antinociception involves suppression of nociceptive processing at the level of the spinal cord (Harris, J. A. et al., 1995), and is disrupted by lesions of the PAG or the RVM, or by infusion of an opiate antagonist into the PAG (Watkins, L. R. et al., 1983a; 1983b; Kinscheck, I. B. et al., 1984; Helmstetter, F. J. and Landeira-

615

Fernandez, J., 1990; Helmstetter, F. J. and Tershner, S. A., 1994). The amygdala sends a sparse projection into the RVM region, raising the possibility that the amygdala could directly influence the RVM (Price, J. L. and Amaral, D. G., 1981; Hermann, D. M. et al., 1997). However, the projection from the amygdala to the PAG is much more robust, and the PAG is thought to be a necessary relay in the antinociception associated with conditioned fear. Amygdala projections to the PAG arise from the central nucleus, and to a lesser extent the medial nucleus (Krettek, J. E. and Price, J. L., 1978; Rizvi, T. A. et al., 1991; Canteras, N. S. et al., 1995). Terminations from the central nucleus are concentrated in PAG regions that in turn send projections to the RVM (Rizvi, T. A. et al., 1991). Activation of the central or basolateral nucleus of the amygdala alters the firing of PAG neurons, with approximately equal proportions of PAG neurons showing excitation and inhibition (Sandrew, B. B. and Poletti, C. E., 1984; da Costa Gomez, T. M.and Behbehani, M. M., 1995). Effects of basolateral stimulation are mediated primarily through the central nucleus (da Costa Gomez, T. M. et al., 1996). Finally, microinjection of morphine in the basolateral nucleus of the amygdala activates off-cells and suppresses on-cell firing, and these changes in on- and off-cell activity are associated with behavioral antinociception (McGaraughty, S. and Heinricher, M. M., 2002). Taken together, the above findings indicate that one way in which the modulatory circuitry of the PAG–RVM circuitry is engaged physiologically is via activation of the amygdala by stimuli that induce fear.

41.4 Conclusion The effort to understand the neural basis of nociceptive modulation by the PAG–RVM system highlights the importance of studying functionally identified neurons. The RVM can both facilitate and inhibit nociception. Furthermore, this region is also implicated in a number of functions other than nociceptive modulation, including reproductive behaviors, cardiovascular and respiratory control, sleep–waking and arousal, thermoregulation, and behavioral suppression. A meaningful analysis of how the RVM contributes to enhanced pain states therefore requires functional identification of the neurons under study, so that mechanisms contributing to nociceptive facilitation can be distinguished from those involved in nociceptive inhibition or other functions. The

616 The Brainstem and Nociceptive Modulation

on/off/neutral cell classification introduced over 20 years ago by Fields H. L. et al. (1983a) has been very productive. It has predicted the pharmacology of individual neurons (responses to opioids, norepinephrine, cannabinoids, neurotensin, and CCK) and allowed functional links between activation of on-cells and increased nociception, and between activation of off-cells and decreased nociception. Application of a similar analysis to the PAG, which is implicated in a host of functions from autonomic control to reproductive behavior and vocalization, would greatly advance our understanding of the neural circuitry of pain modulation in this region. Numerous neurotransmitters and neuropeptides have been implicated in pain modulating functions of the PAG and RVM. Under what conditions are these substances released? Are they local or external to the PAG–RVM? Anatomical studies document substantial reciprocal connections between the PAG and limbic forebrain structures. Which of these connections are relevant to pain modulation, and under what conditions are they activated? These and similar questions must be addressed in order to meet the greater challenge of defining how and when this system is brought into play to enhance or inhibit pain.

Acknowledgments MMH was supported by grants from NIDA (DA 05608) and NINDS (NS 40365), and S. L. I. by a NARSAD Young Investigator Award and a grant from NIDA (DA 015498).

References Abe, M., Oka, T., Hori, T., and Takahashi, S. 2001. Prostanoids in the preoptic hypothalamus mediate systemic lipopolysaccharide-induced hyperalgesia in rats. Brain Res. 916, 41–49. Abols, I. A. and Basbaum, A. I. 1981. Afferent connections of the rostral medulla of the cat: a neural substrate for midbrainmedullary interactions in the modulation of pain. J. Comp. Neurol. 201, 285–297. Ackley, M. A., Hurley, R. W., Virnich, D. E., and Hammond, D. L. 2001. A cellular mechanism for the antinociceptive effect of a kappa opioid receptor agonist. Pain 91, 377–388. Aguiar, M. S. and Brandao, M. L. 1994. Conditioned place aversion produced by microinjections of substance p into the periaqueductal gray of rats. Behav. Pharmacol. 5, 369–373. An, X., Bandler, R., Ongur, D., and Price, J. L. 1998. Prefrontal cortical projections to longitudinal columns in the midbrain

periaqueductal gray in macaque monkeys. J. Comp. Neurol. 401, 455–479. Anderson, S. D., Basbaum, A. I., and Fields, H. L. 1977. Response of medullary raphe neurons to peripheral stimulation and to systemic opiates. Brain Res. 123, 363–368. Azami, J., Llewelyn, M. B., and Roberts, M. H. 1982. The contribution of nucleus reticularis paragigantocellularis and nucleus raphe magnus to the analgesia produced by systemically administered morphine, investigated with the microinjection technique. Pain 12, 229–246. Baez, M. A., Brink, T. S., and Mason, P. 2005. Roles for pain modulatory cells during micturition and continence. J. Neurosci. 25, 384–394. Bagley, E. E., Chieng, B. C., Christie, M. J., and Connor, M. 2005. Opioid tolerance in periaqueductal gray neurons isolated from mice chronically treated with morphine. Br. J. Pharmacol. 146, 68–76 Bailey, C. P. and Connor, M. 2005. Opioids: cellular mechanisms of tolerance and physical dependence. Curr. Opin. Pharmacol. 5, 60–68. Bajic, D., Van Bockstaele, E. J., and Proudfit, H. K. 2001. Ultrastructural analysis of ventrolateral periaqueductal gray projections to the a7 catecholamine cell group. Neuroscience 104, 181–197. Bandler, R. and DePaulis, A. 1991. Midbrain Periaqueductal Gray Control of Defensive Behavior in Cat and Rat. In: Midbrain Periaqueductal Gray Matter (eds. A. DePaulis and R. Bandler), pp. 175–198. Plenum. Bandler, R. and Shipley, M. T. 1994. Columnar organization in the midbrain periaqueductal gray: modules for emotional expression? Trends Neurosci. 17, 379–389. Bandler, R., Keay, K. A., Floyd, N., and Price, J. 2000. Central circuits mediating patterned autonomic activity during active vs. passive emotional coping. Brain Res. Bull. 53, 95–104. Barbaro, N. M., Heinricher, M. M., and Fields, H. L. 1986. Putative pain modulating neurons in the rostral ventral medulla: reflex-related activity predicts effects of morphine. Brain Res. 366, 203–210. Barbaro, N. M., Heinricher, M. M., and Fields, H. L. 1989. Putative nociceptive modulatory neurons in the rostral ventromedial medulla of the rat display highly correlated firing patterns. Somatosens. Mot. Res. 6, 413–425. Bederson, J. B., Fields, H. L., and Barbaro, N. M. 1990. Hyperalgesia during naloxone-precipitated withdrawal from morphine is associated with increased on-cell activity in the rostral ventromedial medulla. Somatosens. Mot. Res. 7, 185–203. Behbehani, M. M. and Da Costa Gomez, T. M. 1996. Properties of a projection pathway from the medial preoptic nucleus to the midbrain periaqueductal gray of the rat and its role in the regulation of cardiovascular function. Brain Res. 740, 141–150. Behbehani, M. M. and Pomeroy, S. L. 1978. Effect of morphine injected in periadueductal gray on the activity of single units in nucleus raphe magnus of the rat. Brain Res. 149, 266–269. Beitz, A. J. 1982. The organization of afferent projections to the midbrain periaqueductal gray of the rat. Neuroscience 7, 133–159. Beitz, A. J. 1985. The midbrain periaqueductal gray in the rat. I. Nuclear volume, cell number, density, orientation, and regional subdivisions. J. Comp. Neurol. 237, 445–459. Beitz, A. J. and Shepard, R. D. 1985. The midbrain periaqueductal gray in the rat. Ii. A golgi analysis. J. Comp. Neurol. 237, 460–475. Bellchambers, C. E., Chieng, B., Keay, K. A., and Christie, M. J. 1998. Swim-stress but not opioid withdrawal increases expression of c-fos immunoreactivity in rat periaqueductal

The Brainstem and Nociceptive Modulation gray neurons which project to the rostral ventromedial medulla. Neuroscience 83, 517–524. Bellgowan, P. S. and Helmstetter, F. J. 1996. Neural systems for the expression of hypoalgesia during nonassociative fear. Behav. Neurosci. 110, 727–736. Benedetti, F. and Amanzio, M. 1997. The neurobiology of placebo analgesia: from endogenous opioids to cholecystokinin. Prog. Neurobiol. 52, 109–125. Berrino, L., Oliva, P., Rossi, F., Palazzo, E., Nobili, B., and Maione, S. 2001. Interaction between metabotropic and NMDA glutamate receptors in the periaqueductal grey pain modulatory system. Naunyn Schmiedebergs Arch. Pharmacol. 364, 437–443. Bie, B., Fields, H. L., Williams, J. T., and Pan, Z. Z. 2003. Roles of 1- and 2-adrenoceptors in the nucleus raphe magnus in opioid analgesia and opioid abstinence-induced hyperalgesia. J. Neurosci. 23, 7950–7957. Bie, B. and Pan, Z. Z. 2003. Presynaptic mechanism for antianalgesic and anti-hyperalgesic actions of kappa-opioid receptors. J. Neurosci. 23, 7262–7268. Bittencourt, A. S., Carobrez, A. P., Zamprogno, L. P., Tufik, S., and Schenberg, L. C. 2004. Organization of single components of defensive behaviors within distinct columns of periaqueductal gray matter of the rat: role of n-methyl-Daspartic acid glutamate receptors. Neuroscience 125, 71–89. Blanchard, D. C. and Blanchard, R. J. 1972. Innate and conditioned reactions to threat in rats with amygdaloid lesions. J. Comp. Physiol. Psychol. 81, 281–290. Blanchard, R. J., Flannelly, K. J., and Blanchard, D. C. 1986. Defensive behaviors of laboratory and wild Rattus norvegicus. J. Comp. Psychol. 100, 101–107. Bodnar, R. J. 1986. Neuropharmacological and neuroendocrine substrates of stress-induced analgesia. Ann. N. Y. Acad. Sci. 467, 345–360. Bodnar, R. J., Kelly, D. D., Brutus, M., and Glusman, M. 1980. Stress-induced analgesia: neural and hormonal determinants. Neurosci. Biobehav. Rev. 4, 87–100. Bodnar, R. J., Williams, C. L., Lee, S. J., and Pasternak, G. W. 1988. Role of mu 1-opiate receptors in supraspinal opiate analgesia: a microinjection study. Brain Res. 447, 25–34. Bouhassira, D., Chollet, R., Coffin, B., Lemann, M., Le Bars, D., Willer, J. C., and Jian, R. 1994. Inhibition of a somatic nociceptive reflex by gastric distention in humans. Gastroenterology 107, 985–992. Bouhassira, D., Sabate, J. M., Coffin, B., Le Bars, D., Willer, J. C., and Jian, R. 1998. Effects of rectal distensions on nociceptive flexion reflexes in humans. Am. J. Physiol. 275, G410–417. Bowker, R. M. and Abbott, L. C. 1988. The origins and trajectories of somatostatin reticulospinal neurons: a potential neurotransmitter candidate of the dorsal reticulospinal pathway. Brain Res. 447, 398–403. Bowker, R. M., Westlund, K. N., Sullivan, M. C., Wilber, J. F., and Coulter, J. D. 1983. Descending serotonergic, peptidergic and cholinergic pathways from the raphe nuclei: a multiple transmitter complex. Brain Res. 288, 33–48. Bozarth, M. A. 1994. Physical dependence produced by central morphine infusions: an anatomical mapping study. Neurosci. Biobehav. Rev. 18, 373–383. Brink, T. S. and Mason, P. 2004. Role for raphe magnus neuronal responses in the behavioral reactions to colorectal distension. J. Neurophysiol. 92, 2302–2311. Buhler, A. V., Choi, J., Proudfit, H. K., and Gebhart, G. F. 2005. Neurotensin activation of the NTR1 on spinally-projecting serotonergic neurons in the rostral ventromedial medulla is antinociceptive. Pain 114, 285–294. Buhler, A. V., Proudfit, H. K., and Gebhart, G. F. 2004. Separate populations of neurons in the rostral ventromedial medulla

617

project to the spinal cord and to the dorsolateral pons in the rat. Brain Res. 1016, 12–19. Burdin, T. A., Graeff, F. G., and Pela, I. R. 1992. Opioid mediation of the antiaversive and hyperalgesic actions of bradykinin injected into the dorsal periaqueductal gray of the rat. Physiol. Behav. 52, 405–410. Burgess, S. E., Gardell, L. R., Ossipov, M. H., Malan, T. P., Jr., Vanderah, T. W., Lai, J., and Porreca, F. 2002. Timedependent descending facilitation from the rostral ventromedial medulla maintains, but does not initiate, neuropathic pain. J. Neurosci. 22, 5129–5136. Burstein, R. and Potrebic, S. 1993. Retrograde labeling of neurons in the spinal cord that project directly to the amygdala or the orbital cortex in the rat. J. Comp. Neurol. 335, 469–485. Bushnell, M. C., Duncan, G. H., Dubner, R., and He, L. F. 1984. Activity of trigeminothalamic neurons in medullary dorsal horn of awake monkeys trained in a thermal discrimination task. J. Neurophysiol. 52, 170–187. Cairns, B. E., Fragoso, M. C., and Soja, P. J. 1995. Activity of rostral trigeminal sensory neurons in the cat during wakefulness and sleep. J. Neurophysiol. 73, 2486–2498. Cairns, B. E., McErlane, S. A., Fragoso, M. C., Jia, W. G., and Soja, P. J. 1996. Spontaneous discharge and peripherally evoked orofacial responses of trigemino-thalamic tract neurons during wakefulness and sleep. J. Neurosci. 16, 8149–8159. Calejesan, A. A., Kim, S. J., and Zhuo, M. 2000. Descending facilitatory modulation of a behavioral nociceptive response by stimulation in the adult rat anterior cingulate cortex. Eur. J. Pain 4, 83–96. Canteras, N. S., Simerly, R. B., and Swanson, L. W. 1995. Organization of projections from the medial nucleus of the amygdala: a PHAL study in the rat. J. Comp. Neurol. 360, 213–245. Carrive, P. 2000. Conditioned fear to environmental context: cardiovascular and behavioral components in the rat. Brain Res. 858, 440–445. Carrive, P. and Morgan, M. M. 2004. Periaqueductal Gray. In: The Human Nervous System (eds. G. Paxinos and J. K. Mai), pp. 393–423. Elsevier. Casey, K. L. and Morrow, T. J. 1988. Supraspinal nocifensive responses of cats: spinal cord pathways, monoamines, and modulation. J. Comp. Neurol. 270, 591–605. Casey, K. L. and Morrow, T. J. 1989. Effect of medial bulboreticular and raphe nuclear lesions on the excitation and modulation of supraspinal nocifensive behaviors in the cat. Brain Res. 501, 150–161. Cervero, F. and Wolstencroft, J. H. 1984. A positive feedback loop between spinal cord nociceptive pathways and antinociceptive areas of the cat’s brain stem. Pain 20, 125–138. Cheng, Z. F., Fields, H. L., and Heinricher, M. M. 1986. Morphine microinjected into the periaqueductal gray has differential effects on 3 classes of medullary neurons. Brain Res. 375, 57–65. Chieng, B. and Christie, M. D. 1996. Local opioid withdrawal in rat single periaqueductal gray neurons in vitro. J. Neurosci. 16, 7128–7136. Chieng, B. and Christie, M. J. 1994a. Hyperpolarization by opioids acting on mu-receptors of a sub-population of rat periaqueductal gray neurones in vitro. Br. J. Pharmacol. 113, 121–128. Chieng, B. and Christie, M. J. 1994b. Inhibition by opioids acting on mu-receptors of gabaergic and glutamatergic postsynaptic potentials in single rat periaqueductal gray neurones in vitro. Br. J. Pharmacol. 113, 303–309. Chieng, B. C., Hallberg, C., Nyberg, F. J., and Christie, M. J. 2005. Enhanced c-fos in periaqueductal grey gabaergic

618 The Brainstem and Nociceptive Modulation neurons during opioid withdrawal. Neuroreport 16, 1279–1283. Chieng, B., Keay, K. A., and Christie, M. J. 1995. Increased foslike immunoreactivity in the periaqueductal gray of anaesthetised rats during opiate withdrawal. Neurosci. Lett. 183, 79–82. Chiou, L. C. and Huang, L. Y. 1999. Mechanism underlying increased neuronal activity in the rat ventrolateral periaqueductal grey by a mu-opioid. J. Physiol. 518 (Pt 2), 551–559. Christie, M. J., Vaughan, C. W., and Ingram, S. L. 1999. Opioids, NSAIDs and 5-lipoxygenase inhibitors act synergistically in brain via arachidonic acid metabolism. Inflamm. Res. 48, 1–4. Christie, M. J., Williams, J. T., Osborne, P. B., and Bellchambers, C. E. 1997. Where is the locus in opioid withdrawal? Trends Pharmacol. Sci. 18, 134–140. Clark, F. M. and Proudfit, H. K. 1991. Projections of neurons in the ventromedial medulla to pontine catecholamine cell groups involved in the modulation of nociception. Brain Res. 540, 105–115. Clement, C. I., Keay, K. A., Podzebenko, K., Gordon, B. D., and Bandler, R. 2000. Spinal sources of noxious visceral and noxious deep somatic afferent drive onto the ventrolateral periaqueductal gray of the rat. J. Comp. Neurol. 425, 323–344. Commons, K. G. 2003. Translocation of presynaptic delta opioid receptors in the ventrolateral periaqueductal gray after swim stress. J. Comp. Neurol. 464, 197–207. Commons, K. G. and Valentino, R. J. 2002. Cellular basis for the effects of substance P in the periaqueductal gray and dorsal raphe nucleus. J. Comp. Neurol. 447, 82–97. Commons, K. G., Aicher, S. A., Kow, L. M., and Pfaff, D. W. 2000. Presynaptic and postsynaptic relations of mu-opioid receptors to gamma-aminobutyric acid-immunoreactive and medullary-projecting periaqueductal gray neurons. J. Comp. Neurol. 419, 532–542. Commons, K. G., Beck, S. G., Rudoy, C., and Van Bockstaele, E. J. 2001. Anatomical evidence for presynaptic modulation by the delta opioid receptor in the ventrolateral periaqueductal gray of the rat. J. Comp. Neurol. 430, 200–208. Connor, M. and Christie, M. J. 1998. Modulation of Ca2þ channel currents of acutely dissociated rat periaqueductal grey neurons. J. Physiol. 509, 47–58. Coutinho, S. V., Urban, M. O., and Gebhart, G. F. 1998. Role of glutamate receptors and nitric oxide in the rostral ventromedial medulla in visceral hyperalgesia. Pain 78, 59–69. Crown, E. D., Grau, J. W., and Meagher, M. W. 2004. Pain in a balance: noxious events engage opposing processes that concurrently modulate nociceptive reactivity. Behav. Neurosci. 118, 1418–1426. da Costa Gomez, T. M. and Behbehani, M. M. 1995. An electrophysiological characterization of the projection from the central nucleus of the amygdala to the periaqueductal gray of the rat: the role of opioid receptors. Brain Res. 689, 21–31. da Costa Gomez, T. M., Chandler, S. D., and Behbehani, M. M. 1996. The role of the basolateral nucleus of the amygdala in the pathway between the amygdala and the midbrain periaqueductal gray in the rat. Neurosci. Lett. 214, 5–8. Davis, M. 1992a. The Role of the Amygdala in Conditioned Fear. In: The Amygdala: Neurobiological Aspects of Emotion, Memory and Mental Dysfunction (eds. J. P. Aggleton), pp. 255–305. Wiley–Liss. Davis, M. 1992b. The role of the amygdala in fear and anxiety. Annu. Rev. Neurosci. 15, 353–375. Davis, K. D., Hutchison, W. D., Lozano, A. M., and Dostrovsky, J. O. 1994. Altered pain and temperature perception following cingulotomy and capsulotomy in a patient with schizoaffective disorder. Pain 59, 189–199.

Depaulis, A., Keay, K. A., and Bandler, R. 1994. Quiescence and hyporeactivity evoked by activation of cell bodies in the ventrolateral midbrain periaqueductal gray of the rat. Exp. Brain Res. 99, 75–83. Depaulis, A., Morgan, M. M., and Liebeskind, J. C. 1987. Gabaergic modulation of the analgesic effects of morphine microinjected in the ventral periaqueductal gray matter of the rat. Brain Res. 436, 223–228. Dickenson, A. H., Oliveras, J. L., and Besson, J. M. 1979. Role of the nucleus raphe magnus in opiate analgesia as studied by the microinjection technique in the rat. Brain Res. 170, 95–111. Dielenberg, R. A., Leman, S., and Carrive, P. 2004. Effect of dorsal periaqueductal gray lesions on cardiovascular and behavioral responses to cat odor exposure in rats. Behav. Brain Res. 153, 487–496. Donahue, R. R., LaGraize, S. C., and Fuchs, P. N. 2001. Electrolytic lesion of the anterior cingulate cortex decreases inflammatory, but not neuropathic nociceptive behavior in rats. Brain Res. 897, 131–138. Drew, G. M., Mitchell, V. A., and Vaughan, C. W. 2005. Postsynaptic actions of substance P on rat periaqueductal grey neurons in vitro. Neuropharmacology 49, 587–595. Drower, E. J. and Hammond, D. L. 1988. Gabaergic modulation of nociceptive threshold: effects of thip and bicuculline microinjected in the ventral medulla of the rat. Brain Res. 450, 316–324. Ellrich, J., Ulucan, C., and Schnell, C. 2000. Are ‘neutral cells’ in the rostral ventro-medial medulla subtypes of on- and offcells? Neurosci. Res. 38, 419–423. Ellrich, J., Ulucan, C., and Schnell, C. 2001. Is the response pattern of on- and off-cells in the rostral ventromedial medulla to noxious stimulation independent of stimulation site? Exp. Brain Res. 136, 394–399. Fang, F. G., Haws, C. M., Drasner, K., Williamson, A., and Fields, H. L. 1989. Opioid peptides (dago-enkephalin, dynorphin a (1–13), bam 22p) microinjected into the rat brainstem: comparison of their antinociceptive effect and their effect on neuronal firing in the rostral ventromedial medulla. Brain Res. 501, 116–128. Fanselow, M. S. 1985. Odors released by stressed rats produce opioid analgesia in unstressed rats. Behav. Neurosci. 99, 589–592. Fanselow, M. S. 1986. Conditioned fear-induced opiate analgesia: a competing motivational state theory of stress analgesia. Ann. N. Y. Acad. Sci. 467, 40–54. Fanselow, M. S. 1991. The Midbrain Periaqueductal Gray as a Coordinator of Action in Response to Fear and Anxiety. In: The Midbrain Periaqueductal Gray Matter (eds. A. DePaulis and R. Bandler), pp. 151–173. Plenum. Fanselow, M. S. and Helmstetter, F. J. 1988. Conditional analgesia, defensive freezing, and benzodiazepines. Behav. Neurosci. 102, 233–243. Fanselow, M. S. and Kim, J. J. 1992. The benzodiazepine inverse agonist dmcm as an unconditional stimulus for fearinduced analgesia: implications for the role of gabaa receptors in fear-related behavior. Behav. Neurosci. 106, 336–344. Farook, J. M., Wang, Q., Moochhala, S. M., Zhu, Z. Y., Lee, L., and Wong, P. T. 2004. Distinct regions of periaqueductal gray (PAG) are involved in freezing behavior in hooded pvg rats on the cat-freezing test apparatus. Neurosci. Lett. 354, 139–142. Fields, H. L. and Heinricher, M. M. 1985. Anatomy and physiology of a nociceptive modulatory system. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 308, 361–374. Fields, H. L., Basbaum, A. I., and Heinricher, M. M. 2005. Central nervous system mechanisms of pain modulation. In: Wall and Melzack’s textbook of pain, 5th ed. (ed. McMahon, S. and Koltzenburg, M. Elsevier.

The Brainstem and Nociceptive Modulation Fields, H. L., Bry, J., Hentall, I., and Zorman, G. 1983a. The activity of neurons in the rostral medulla of the rat during withdrawal from noxious heat. J. Neurosci. 3, 2545–2552. Fields, H. L., Malick, A., and Burstein, R. 1995. Dorsal horn projection targets of ON and OFF cells in the rostral ventromedial medulla. J. Neurophysiol. 74, 1742–1759. Fields, H. L., Vanegas, H., Hentall, I. D., and Zorman, G. 1983b. Evidence that disinhibition of brain stem neurones contributes to morphine analgesia. Nature 306, 684–686. Floyd, N. S., Price, J. L., Ferry, A. T., Keay, K. A., and Bandler, R. 2000. Orbitomedial prefrontal cortical projections to distinct longitudinal columns of the periaqueductal gray in the rat. J. Comp. Neurol. 422, 556–578. Foltz, E. L. and Lowell, E. W. 1962. Pain ‘‘relief’’ by frontal cingulumotomy. J. Neurosurg. 19, 89–100. Foo, H. and Helmstetter, F. J. 2000. Activation of kappa opioid receptors in the rostral ventromedial medulla blocks stressinduced antinociception. Neuroreport 11, 3349–3352. Foo, H. and Mason, P. 2003. Discharge of raphe magnus ON and OFF cells is predictive of the motor facilitation evoked by repeated laser stimulation. J. Neurosci. 23, 1933–1940. Foo, H. and Mason, P. 2005. Movement-related discharge of ventromedial medullary neurons. J. Neurophysiol. 93, 873–883. Fox, R. J. and Sorenson, C. A. 1994. Bilateral lesions of the amygdala attenuate analgesia induced by diverse environmental challenges. Brain Res. 648, 215–221. Friederich, M. W. and Walker, J. M. 1990. The effect of footshock on the noxious-evoked activity of neurons in the rostral ventral medulla. Brain Res. Bull. 24, 605–608. Friedrich, A. E. and Gebhart, G. F. 2003. Modulation of visceral hyperalgesia by morphine and cholecystokinin from the rat rostroventral medial medulla. Pain 104, 93–101. Fuchs, P. N., Balinsky, M., and Melzack, R. 1996. Electrical stimulation of the cingulum bundle and surrounding cortical tissue reduces formalin-test pain in the rat. Brain Res. 743, 116–123. Gao, K., Chen, D. O., Genzen, J. R., and Mason, P. 1998. Activation of serotonergic neurons in the raphe magnus is not necessary for morphine analgesia. J. Neurosci. 18, 1860–1868. Gao, K., Kim, Y. H., and Mason, P. 1997. Serotonergic pontomedullary neurons are not activated by antinociceptive stimulation in the periaqueductal gray. J. Neurosci. 17, 3285–3292. Gauriau, C. and Bernard, J. F. 2004. A comparative reappraisal of projections from the superficial laminae of the dorsal horn in the rat: the forebrain. J. Comp. Neurol. 468, 24–56. Gebhart, G. F. 1982. Opiate and opioid peptide effects on brain stem neurons: relevance to nociception and antinociceptive mechanisms. Pain 12, 93–140. Gilbert, A. and Franklin, K. 2002. The role of descending fibers from the rostral ventromedial medulla in opioid analgesia in rats. Eur. J. Pharmacol. 449, 75. Gilbert, A. K. and Franklin, K. B. 2001. GABAergic modulation of descending inhibitory systems from the rostral ventromedial medulla (RVM). Dose-response analysis of nociception and neurological deficits. Pain 90, 25–36. Grau, J. W., Hyson, R. L., Maier, S. F., Madden, J. T., and Barchas, J. D. 1981. Long-term stress-induced analgesia and activation of the opiate system. Science 213, 1409–1411. Guilbaud, G., Peschanski, M., Gautron, M., and Binder, D. 1980. Responses of neurons of the nucleus raphe magnus to noxious stimuli. Neurosci. Lett. 17, 149–154. Gutstein, H. B., Mansour, A., Watson, S. J., Akil, H., and Fields, H. L. 1998. Mu and kappa opioid receptors in periaqueductal gray and rostral ventromedial medulla. Neuroreport 9, 1777–1781.

619

Hack, S. P., Vaughan, C. W., and Christie, M. J. 2003. Modulation of GABA release during morphine withdrawal in midbrain neurons in vitro. Neuropharmacology 45, 575–584. Hajnik, T., Lai, Y. Y., and Siegel, J. M. 2000. Atonia-related regions in the rodent pons and medulla. J. Neurophysiol. 84, 1942–1948. Hammond, D. L. and Yaksh, T. L. 1984. Antagonism of stimulation-produced antinociception by intrathecal administration of methysergide or phentolamine. Brain Res. 298, 329–337. Harasawa, I., Fields, H. L., and Meng, I. D. 2000. Delta opioid receptor mediated actions in the rostral ventromedial medulla on tail flick latency and nociceptive modulatory neurons. Pain 85, 255–262. Hardy, S. G. 1985. Analgesia elicited by prefrontal stimulation. Brain Res. 339, 281–284. Harris, J. A. and Westbrook, R. F. 1995. Effects of benzodiazepine microinjection into the amygdala or periaqueductal gray on the expression of conditioned fear and hypoalgesia in rats. Behav. Neurosci. 109, 295–304. Harris, J. A., Westbrook, R. F., Duffield, T. Q., and Bentivoglio, M. 1995. Fos expression in the spinal cord is suppressed in rats displaying conditioned hypoalgesia. Behav. Neurosci. 109, 320–328. Haws, C. M., Heinricher, M. M., and Fields, H. L. 1990. Alphaadrenergic receptor agonists, but not antagonists, alter the tail-flick latency when microinjected into the rostral ventromedial medulla of the lightly anesthetized rat. Brain Res. 533, 192–195. Hayes, R. L., Dubner, R., and Hoffman, D. S. 1981. Neuronal activity in medullary dorsal horn of awake monkeys trained in a thermal discrimination task. Ii. Behavioral modulation of responses to thermal and mechanical stimuli. J. Neurophysiol. 46, 428–443. Heinricher, M. M. 2005. Nociceptin/orphanin FQ: pain, stress and neural circuits. Life Sci. 77(25), 3127–3132. Heinricher, M. M. and Fields, H. L. 2003. The Delta Opioid Receptor and Brain Pain-Modulating Circuits. In: The Delta Receptor: Molecular and Effect of Delta Opioid Compounds (eds. K. J. Chang, F. Porreca, and J. Woods), pp. 467–480. Marcel Dekker. Heinricher, M. M. and Kaplan, H. J. 1991. GABA-mediated inhibition in rostral ventromedial medulla: role in nociceptive modulation in the lightly anesthetized rat. Pain 47, 105–113. Heinricher, M. M. and McGaraughty, S. 1998. Analysis of excitatory amino acid transmission within the rostral ventromedial medulla: implications for circuitry. Pain 75, 247–255. Heinricher, M. M. and Morgan, M. M. 1999. Supraspinal Mechanisms of Opioid Analgesia. In: Opioids and Pain Control (ed. C. Stein), pp. 46–69. Cambridge University Press. Heinricher, M. M. and Neubert, M. J. 2004. Neural basis for the hyperalgesic action of cholecystokinin in the rostral ventromedial medulla. J. Neurophysiol. 92, 1982–1989. Heinricher, M. M. and Rosenfeld, J. P. 1985. Microinjection of morphine into nucleus reticularis paragigantocellularis of the rat: suppression of noxious-evoked activity of nucleus raphe magnus neurons. Brain Res. 359, 388–391. Heinricher, M. M. and Roychowdhury, S. 1997. Reflex-related activation of putative pain facilitating neurons in rostral ventromedial medulla (RVM) depends upon excitatory amino acid transmission. Neuroscience 78, 1159–1165. Heinricher, M. M. and Tortorici, V. 1994. Interference with GABA transmission in the rostral ventromedial medulla: disinhibition of off-cells as a central mechanism in nociceptive modulation. Neuroscience 63, 533–546. Heinricher, M. M., Barbaro, N. M., and Fields, H. L. 1989. Putative nociceptive modulating neurons in the rostral ventromedial medulla of the rat: firing of on- and off-cells is

620 The Brainstem and Nociceptive Modulation related to nociceptive responsiveness. Somatosens. Mot. Res. 6, 427–439. Heinricher, M. M., Haws, C. M., and Fields, H. L. 1988. Opposing Actions of Norepinephrine and Clonidine on Single Pain-Modulating Neurons in Rostral Ventromedial Medulla. In: Pain Research and Clinical Management (eds. R. Dubner, G. F. Gebhart, and M. R. Bond), pp. 590–594. Elsevier. Heinricher, M. M., Haws, C. M., and Fields, H. L. 1991. Evidence for GABA-mediated control of putative nociceptive modulating neurons in the rostral ventromedial medulla: iontophoresis of bicuculline eliminates the off-cell pause. Somatosens. Mot. Res. 8, 215–22. Heinricher, M. M., Martenson, M. E., and Neubert, M. J. 2004a. Prostaglandin E2 in the midbrain periaqueductal gray produces hyperalgesia and activates pain-modulating circuitry in the rostral ventromedial medulla. Pain 110, 419–426. Heinricher, M. M., McGaraughty, S., and Farr, D. A. 1999. The role of excitatory amino acid transmission within the rostral ventromedial medulla in the antinociceptive actions of systemically administered morphine. Pain 81, 57–65. Heinricher, M. M., McGaraughty, S., and Grandy, D. K. 1997. Circuitry underlying antiopioid actions of orphanin FQ in the rostral ventromedial medulla. J. Neurophysiol. 78, 3351–3358. Heinricher, M. M., McGaraughty, S., and Tortorici, V. 2001a. Circuitry underlying antiopioid actions of cholecystokinin within the rostral ventromedial medulla. J. Neurophysiol. 85, 280–286. Heinricher, M. M., Morgan, M. M., and Fields, H. L. 1992. Direct and indirect actions of morphine on medullary neurons that modulate nociception. Neuroscience 48, 533–543. Heinricher, M. M., Morgan, M. M., Tortorici, V., and Fields, H. L. 1994. Disinhibition of off-cells and antinociception produced by an opioid action within the rostral ventromedial medulla. Neuroscience 63, 279–288. Heinricher, M. M., Neubert, M. J., Martenson, M. E., and Gonc¸alves, L. 2004b. Prostaglandin E2 in the medial preoptic area produces hyperalgesia and activates pain-modulating circuitry in the rostral ventromedial medulla. Neuroscience 128, 389–398. Heinricher, M. M., Pertovaara, A., and Ossipov, M. H. 2003. Descending Modulation after Injury. In: Progress in Pain Research and Management, Vol. 24 (eds. J. O. Dostrovsky, D. B. Carr, and M. Koltzenburg), pp. 251–260. IASP Press. Heinricher, M. M., Schouten, J. C., and Jobst, E. E. 2001b. Activation of brainstem n-methyl-D-aspartate receptors is required for the analgesic actions of morphine given systemically. Pain 92, 129–138. Helmstetter, F. J. 1992. The amygdala is essential for the expression of conditional hypoalgesia. Behav. Neurosci. 106, 518–528. Helmstetter, F. J. and Bellgowan, P. S. 1993. Lesions of the amygdala block conditional hypoalgesia on the tail flick test. Brain Res. 612, 253–257. Helmstetter, F. J. and Bellgowan, P. S. 1994. Hypoalgesia in response to sensitization during acute noise stress. Behav. Neurosci. 108, 177–185. Helmstetter, F. J. and Landeira-Fernandez, J. 1990. Conditional hypoalgesia is attenuated by naltrexone applied to the periaqueductal gray. Brain Res. 537, 88–92. Helmstetter, F. J. and Tershner, S. A. 1994. Lesions of the periaqueductal gray and rostral ventromedial medulla disrupt antinociceptive but not cardiovascular aversive conditional responses. J. Neurosci. 14, 7099–7108. Helmstetter, F. J., Calcagnetti, D. J., and Fanselow, M. S. 1990. The beta-carboline dmcm produces hypoalgesia after central administration. Psychobiology 18, 293–297.

Helmstetter, F. J., Tershner, S. A., Poore, L. H., and Bellgowan, P. S. 1998. Antinociception following opioid stimulation of the basolateral amygdala is expressed through the periaqueductal gray and rostral ventromedial medulla. Brain Res. 779, 104–118. Herbert, H. and Saper, C. B. 1992. Organization of medullary adrenergic and noradrenergic projections to the periaqueductal gray matter in the rat. J. Comp. Neurol. 315, 34–52. Herkenham, M., Lynn, A. B., Johnson, M. R., Melvin, L. S., de Costa, B. R., and Rice, K. C. 1991. Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J. Neurosci. 11, 563–583. Hermann, D. M., Luppi, P. H., Peyron, C., Hinckel, P., and Jouvet, M. 1996. Forebrain projections of the rostral nucleus raphe magnus shown by iontophoretic application of choleratoxin b in rats. Neurosci. Lett. 216, 151–154. Hermann, D. M., Luppi, P. H., Peyron, C., Hinckel, P., and Jouvet, M. 1997. Afferent projections to the rat nuclei raphe magnus, raphe pallidus and reticularis gigantocellularis pars alpha demonstrated by iontophoretic application of choleratoxin (subunit b). J. Chem. Neuroanat. 13, 1–21. Hernandez, N., Lopez, Y., and Vanegas, H. 1989. Medullary onand off-cell responses precede both segmental and thalamic responses to tail heating. Pain 39, 221–230. Hicks, T. P. 1983. Antagonism of synaptic transmission in vivo: contributions of microiontophoresis. Brain Behav. Evol. 22, 1–12. Hirakawa, N., Tershner, S. A., Fields, H. L., and Manning, B. H. 2000. Bi-directional changes in affective state elicited by manipulation of medullary pain-modulatory circuitry. Neuroscience 100, 861–871. Hofer, M. A. 1970. Cardiac and respiratory function during sudden prolonged immobility in wild rodents. Psychosom. Med. 32, 633–647. Hohmann, A. G., Suplita, R. L., Bolton, N. M., Neely, M. H., Fegley, D., Mangieri, R., Krey, J. F., Walker, J. M., Holmes, P. V., Crystal, J. D., Duranti, A., Tontini, A., Mor, M., Tarzia, G., and Piomelli, D. 2005. An endocannabinoid mechanism for stress-induced analgesia. Nature 435, 1108–1112. Hosoi, M., Oka, T., and Hori, T. 1997. Prostaglandin e receptor ep3 subtype is involved in thermal hyperalgesia through its actions in the preoptic hypothalamus and the diagonal band of broca in rats. Pain 71, 303–311. Hough, L. B., Nalwalk, J. W., Stadel, R., Timmerman, H., Leurs, R., Paria, B. C., Wang, X., and Dey, S. K. 2002. Inhibition of improgan antinociception by the cannabinoid (cb)1 antagonist n- (piperidin-1-yl)-5- (4-chlorophenyl)-1(2,4-dichlorophenyl)-4-methyl-1h-p yrazole-3-carboxamide (sr141716a): lack of obligatory role for endocannabinoids acting at cb (1) receptors. J. Pharmacol. Exp. Ther. 303, 314–322. Hurley, R. W. and Hammond, D. L. 2000. The analgesic effects of supraspinal  and  opioid receptor agonists are potentiated during persistent inflammation. J. Neurosci. 20, 1249–1259. Hurley, R. W. and Hammond, D. L. 2001. Contribution of endogenous enkephalins to the enhanced analgesic effects of supraspinal  opioid receptor agonists after inflammatory injury. J. Neurosci 21, 2536–2545. Hutchison, W. D., Harfa, L., and Dostrovsky, J. O. 1996. Ventrolateral orbital cortex and periaqueductal gray stimulation-induced effects on on- and off-cells in the rostral ventromedial medulla in the rat. Neuroscience 70, 391–407. Ingram, S. L., Fossum, E., and Morgan, M. M. 2007. Behavioral and electrophysiological evidence for opioid tolerance in adolescent rats. Neuropsychopharmacology 32, 600–606.

The Brainstem and Nociceptive Modulation Ingram, S. L., Vaughan, C. W., Bagley, E. E., Connor, M., and Christie, M. J. 1998. Enhanced opioid efficacy in opioid dependence is caused by an altered signal transduction pathway. J. Neurosci. 18, 10269–10276. Iversen, L. and Chapman, V. 2002. Cannabinoids: a real prospect for pain relief? Curr. Opin. Pharmacol. 2, 50–55. Jacquet, Y. F. and Lajtha, A. 1976. The periaqueductal gray: site of morphine analgesia and tolerance as shown by 2-way cross tolerance between systemic and intracerebral injections. Brain Res. 103, 501–513. Jinks, S. L., Carstens, E., and Antognini, J. F. 2004a. Isoflurane differentially modulates medullary on and off neurons while suppressing hind-limb motor withdrawals. Anesthesiology 100, 1224–1234. Jinks, S. L., Carstens, E., and Antognini, J. F. 2004b. Medullary on-cells facilitate multilimb movements elicited by intense noxious stimulation. Abstract Viewer/Itinerary Planner. Society for Neuroscience, Online, Program 296.297. Kalmari, J. and Pertovaara, A. 2004. Colorectal distensioninduced suppression of a nociceptive somatic reflex response in the rat: modulation by tissue injury or inflammation. Brain Res. 1018, 106–110. Kalra, A., Urban, M. O., and Sluka, K. A. 2001. Blockade of opioid receptors in rostral ventral medulla prevents antihyperalgesia produced by transcutaneous electrical nerve stimulation (tens). J. Pharmacol. Exp. Ther. 298, 257–263. Kalyuzhny, A. E. and Wessendorf, M. W. 1998. Relationship of - and -opioid receptors to GABAergic neurons in the central nervous system, including antinociceptive brainstem circuits. J. Comp. Neurol. 392, 528–547. Kalyuzhny, A. E. and Wessendorf, M. W. 1999. Serotonergic and GABaergic neurons in the medial rostral ventral medulla express kappa-opioid receptor immunoreactivity. Neuroscience 90, 229–234. Kalyuzhny, A. E., Arvidsson, U., Wu, W., and Wessendorf, M. W. 1996. M-opioid and -opioid receptors are expressed in brainstem antinociceptive circuits: studies using immunocytochemistry and retrograde tract-tracing. J. Neurosci. 16, 6490–6503. Kaplan, H. and Fields, H. L. 1991. Hyperalgesia during acute opioid abstinence: evidence for a nociceptive facilitating function of the rostral ventromedial medulla. J. Neurosci. 11, 1433–1439. Kavaliers, M. 1988. Brief exposure to a natural predator, the short-tailed weasel, induces benzodiazepine-sensitive analgesia in white-footed mice. Physiol. Behav. 43, 187–193. Keay, K. A. and Bandler, R. 2001. Parallel circuits mediating distinct emotional coping reactions to different types of stress. Neurosci. Biobehav. Rev. 25, 669–678. Kiefel, J. M., Rossi, G. C., and Bodnar, R. J. 1993. Medullary mu and delta opioid receptors modulate mesencephalic morphine analgesia in rats. Brain Res. 624, 151–161. Kincaid, W., Neubert, M. J., Xu, M., Kim, C.-J., and Heinricher, M. M. 2006. Role for medullary pain facilitating neurons in secondary thermal hyperalgesia. J. Neurophysiol. 95, 33–41. Kinscheck, I. B., Watkins, L. R., and Mayer, D. J. 1984. Fear is not critical to classically conditioned analgesia: the effects of periaqueductal gray lesions and administration of chlordiazepoxide. Brain Res. 298, 33–44. Kiser, R. S., Lebovitz, R. M., and German, D. C. 1978. Anatomic and pharmacologic differences between two types of aversive midbrain stimulation. Brain Res. 155, 331–342. Kovelowski, C. J., Ossipov, M. H., Sun, H., Lai, J., Malan, T. P., and Porreca, F. 2000. Supraspinal cholecystokinin may drive tonic descending facilitation mechanisms to maintain neuropathic pain in the rat. Pain 87, 265–273.

621

Krettek, J. E. and Price, J. L. 1978. Amygdaloid projections to subcortical structures within the basal forebrain and brainstem in the rat and cat. J. Comp. Neurol. 178, 225–254. Kshatri, A. M., Baghdoyan, H. A., and Lydic, R. 1998. Cholinomimetics, but not morphine, increase antinociceptive behavior from pontine reticular regions regulating rapid-eye-movement sleep. Sleep 21, 677–685. Lagraize, S. C., Borzan, J., Peng, Y. B., and Fuchs, P. N. 2006. Selective regulation of pain affect following activation of the opioid anterior cingulate cortex system. Exp. Neurol. 197(1), 22–30. LaGraize, S. C., Borzan, J., Rinker, M. M., Kopp, J. L., and Fuchs, P. N. 2004a. Behavioral evidence for competing motivational drives of nociception and hunger. Neurosci. Lett. 372, 30–34. LaGraize, S. C., Labuda, C. J., Rutledge, M. A., Jackson, R. L., and Fuchs, P. N. 2004b. Differential effect of anterior cingulate cortex lesion on mechanical hypersensitivity and escape/avoidance behavior in an animal model of neuropathic pain. Exp. Neurol. 188, 139–148. Lane, D. A., Patel, P. A., and Morgan, M. M. 2005. Evidence for an intrinsic mechanism of antinociceptive tolerance within the ventrolateral periaqueductal gray of rats. Neuroscience 135, 227–234. Lane, D. A., Tortorici, V., and Morgan, M. M. 2004. Behavioral and electrophysiological evidence for tolerance to continuous morphine administration into the ventrolateral periaqueductal gray. Neuroscience 125, 63–69. Le Bars, D. 1988. Serotonin and Pain. In: Neuronal Serotonin (eds. N. N. Osborne and M. Hamon), pp. 171–226. Wiley. Le Bars, D. 2002. The whole body receptive field of dorsal horn multireceptive neurones. Brain Res. Rev. 40, 29–44. Leman, S., Dielenberg, R. A., and Carrive, P. 2003. Effect of dorsal periaqueductal gray lesion on cardiovascular and behavioural responses to contextual conditioned fear in rats. Behav. Brain Res. 143, 169–176. Lester, L. S. and Fanselow, M. S. 1985. Exposure to a cat produces opioid analgesia in rats. Behav. Neurosci. 99, 756–759. Leung, C. G. and Mason, P. 1995. Effects of isoflurane concentration on the activity of pontomedullary raphe and medial reticular neurons in the rat. Brain Res. 699, 71–82. Leung, C. G. and Mason, P. 1998. Physiological survey of medullary raphe and magnocellular reticular neurons in the anesthetized rat. J. Neurophysiol. 80, 1630–1646. Leung, C. G. and Mason, P. 1999. Physiological properties of raphe magnus neurons during sleep and waking. J. Neurophysiol. 81, 584–595. Lewis, J. W., Cannon, J. T., and Liebeskind, J. C. 1980. Opioid and nonopioid mechanisms of stress analgesia. Science 208, 623–625. Lichtman, A. H. and Fanselow, M. S. 1990. Cats produce analgesia in rats on the tail-flick test: naltrexone sensitivity is determined by the nociceptive test stimulus. Brain Res. 533, 91–94. Lovick, T. A. 1993. Integrated activity of cardiovascular and pain regulatory systems: role in adaptive behavioural responses. Prog. Neurobiol. 40, 631–644. Lumb, B. M., Parry, D. M., Semenenko, F. M., McMullan, S., and Simpson, D. A. 2002. C-nociceptor activation of hypothalamic neurones and the columnar organisation of their projections to the periaqueductal grey in the rat. Exp. Physiol. 87, 123–128. Madden, C. J. and Morrison, S. F. 2003. Excitatory amino acid receptor activation in the raphe pallidus area mediates prostaglandin-evoked thermogenesis. Neuroscience 122, 5–15. Maier, S. F. 1986. Stressor controllability and stress-induced analgesia. Ann. N. Y. Acad. Sci. 467, 55–72.

622 The Brainstem and Nociceptive Modulation Manning, B. H. and Mayer, D. J. 1995. The central nucleus of the amygdala contributes to the production of morphine antinociception in the formalin test. Pain 63, 141–152. Mansikka, H. and Pertovaara, A. 1997. Supraspinal influence on hindlimb withdrawal thresholds and mustard oil-induced secondary allodynia in rats. Brain Res. Bull. 42, 359–365. Mansour, A., Fox, C. A., Akil, H., and Watson, S. J. 1995. Opioidreceptor mRNA expression in the rat CNS: anatomical and functional implications. Trends Neurosci. 18, 22–29. Mantyh, P. W. and Hunt, S. P. 1984. Evidence for cholecystokinin-like immunoreactive neurons in the rat medulla oblongata which project to the spinal cord. Brain Res. 291, 49–54. Marinelli, S., Connor, M., Schnell, S. A., Christie, M. J., Wessendorf, M. W., and Vaughan, C. W. 2005. -opioid receptor-mediated actions on rostral ventromedial medulla neurons. Neuroscience 132, 239–244. Marinelli, S., Vaughan, C. W., Schnell, S. A., Wessendorf, M. W., and Christie, M. J. 2002. Rostral ventromedial medulla neurons that project to the spinal cord express multiple opioid receptor phenotypes. J. Neurosci. 22, 10847–10855. Martin, W. J., Tsou, K., and Walker, J. M. 1998. Cannabinoid receptor-mediated inhibition of the rat tail-flick reflex after microinjection into the rostral ventromedial medulla. Neurosci. Lett. 242, 33–36. Mason, P. 1997. Physiological identification of pontomedullary serotonergic neurons in the rat. J. Neurophysiol. 77, 1087–1098. Mason, P. 2001. Contributions of the medullary raphe and ventromedial reticular region to pain modulation and other homeostatic functions. Annu. Rev. Neurosci. 24, 737–777. Mason, P., Escobedo, I., Burgin, C., Bergan, J., Lee, J. H., Last, E. J., and Holub, A. L. 2001. Nociceptive responsiveness during slow-wave sleep and waking in the rat. Sleep 24, 32–38. Matsumoto, S., Levendusky, M. C., Longhurst, P. A., Levin, R. M., and Millington, W. R. 2004. Activation of mu opioid receptors in the ventrolateral periaqueductal gray inhibits reflex micturition in anesthetized rats. Neurosci. Lett. 363, 116–119. McCleane, G. J. 1998. The cholecystokinin antagonist proglumide enhances the analgesic efficacy of morphine in humans with chronic benign pain. Anesth. Analg. 87, 1117–1120. McGaraughty, S. and Heinricher, M. M. 2002. Microinjection of morphine into various amygdaloid nuclei differentially affects nociceptive responsiveness and RVM neuronal activity. Pain 96, 153–162. McGaraughty, S. and Heinricher, M. M. 2004. Lesions of the periaqueductal gray disrupt input to the rostral ventromedial medulla following microinjections into the medial or basolateral nuclei of the amygdala. Brain Res. 1009, 223–227. McGaraughty, S., Chu, K. L., Bitner, R. S., Martino, B., Kouhen, R. E., Han, P., Nikkel, A. L., Burgard, E. C., Faltynek, C. R., and Jarvis, M. F. 2003. Capsaicin infused into the PAG affects rat tail flick responses to noxious heat and alters neuronal firing in the RVM. J. Neurophysiol. 90, 2702–2710. McLemore, S., Crown, E. D., Meagher, M. W., and Grau, J. W. 1999. Shock-induced hyperalgesia: Ii. Role of the dorsolateral periaqueductal gray. Behav. Neurosci. 113, 539–549. Melzack, R., Wall, P. D., and Ty, T. C. 1982. Acute pain in an emergency clinic: latency of onset and descriptor patterns related to different injuries. Pain 14, 33–43. Menetrey, D. and Basbaum, A. I. 1987. The distribution of substance p-, enkephalin- and dynorphin-immunoreactive neurons in the medulla of the rat and their contribution to bulbospinal pathways. Neuroscience 23, 173–187.

Menetrey, D., Chaouch, A., Binder, D., and Besson, J. M. 1982. The origin of the spinomesencephalic tract in the rat: an anatomical study using the retrograde transport of horseradish peroxidase. J. Comp. Neurol. 206, 193–207. Meng, I. D. and Johansen, J. P. 2004. Antinociception and modulation of rostral ventromedial medulla neuronal activity by local microinfusion of a cannabinoid receptor agonist. Neuroscience 124, 685–693. Meng, I. D., Johansen, J. P., Harasawa, I., and Fields, H. L. 2005. Kappa opioids inhibit physiologically identified medullary pain modulating neurons and reduce morphine antinociception. J. Neurophysiol. 93, 1138–1144. Meng, I. D., Manning, B. H., Martin, W. J., and Fields, H. L. 1998. An analgesia circuit activated by cannabinoids. Nature 395, 381–383. Miki, K., Zhou, Q. Q., Guo, W., Guan, Y., Terayama, R., Dubner, R., and Ren, K. 2002. Changes in gene expression and neuronal phenotype in brain stem pain modulatory circuitry after inflammation. J. Neurophysiol. 87, 750–760. Millan, M. J. 2002. Descending control of pain. Prog. Neurobiol. 66, 355–474. Miller, K. K., Hoffer, A., Svoboda, K. R., and Lupica, C. R. 1997. Cholecystokinin increases GABA release by inhibiting a resting Kþ conductance in hippocampal interneurons. J. Neurosci. 17, 4994–5003. Millhorn, D. E., Hokfelt, T., Seroogy, K., Oertel, W., Verhofstad, A. A., and Wu, J. Y. 1987a. Immunohistochemical evidence for colocalization of gamma-aminobutyric acid and serotonin in neurons of the ventral medulla oblongata projecting to the spinal cord. Brain Res. 410, 179–185. Millhorn, D. E., Hokfelt, T., Verhofstad, A. A., and Terenius, L. 1989. Individual cells in the raphe nuclei of the medulla oblongata in rat that contain immunoreactivities for both serotonin and enkephalin project to the spinal cord. Exp. Brain Res. 75, 536–542. Millhorn, D. E., Seroogy, K., Ho¨kfelt, T., Schmued, L. C., Terenius, L., Buchan, A., and Brown, J. C. 1987b. Neurons of the ventral medulla oblongata that contain both somatostatin and enkephalin immunoreactivities project to nucleus tractus solitarii and spinal cord. Brain Res. 424, 99–108. Mitchell, J. M., Lowe, D., and Fields, H. L. 1998. The contribution of the rostral ventromedial medulla to the antinociceptive effects of systemic morphine in restrained and unrestrained rats. Neuroscience 87, 123–133. Monhemius, R., Azami, J., Green, D. L., and Roberts, M. H. 2001. CB1 receptor mediated analgesia from the nucleus reticularis gigantocellularis pars alpha is activated in an animal model of neuropathic pain. Brain Res. 908, 67–74. Moreau, J. L. and Fields, H. L. 1986. Evidence for GABA involvement in midbrain control of medullary neurons that modulate nociceptive transmission. Brain Res. 397, 37–46. Morgan, M. M. 1991. Differences in Antinociception Evoked from Dorsal and Ventral Regions of the Caudal Periaqueductal Gray Matter. In: The Midbrain Periaqueductal Gray Matter (eds. A. DePaulis and R. Bandler), pp. 139–150. Plenum. Morgan, M. M. and Carrive, P. 2001. Activation of the ventrolateral periaqueductal gray reduces locomotion but not mean arterial pressure in awake, freely moving rats. Neuroscience 102, 905–910. Morgan, M. M. and Clayton, C. C. 2005. Defensive behaviors evoked from the ventrolateral periaqueductal gray of the rat: comparison of opioid and GABA disinhibition. Behav. Brain Res. 164, 61–66. Morgan, M. M. and Fields, H. L. 1994. Pronounced changes in the activity of nociceptive modulatory neurons in the rostral ventromedial medulla in response to prolonged thermal noxious stimuli. J. Neurophysiol. 72, 1161–1170.

The Brainstem and Nociceptive Modulation Morgan, M. M. and Whitney, P. K. 2000. Immobility accompanies the antinociception mediated by the rostral ventromedial medulla of the rat. Brain Res. 872, 276–281. Morgan, M. M., Clayton, C. C., and Boyer-Quick, J. S. 2005. Differential susceptibility of the PAG and RVM to tolerance to the antinociceptive effect of morphine in the rat. Pain 113, 91–98. Morgan, M. M., Clayton, C. C., and Lane, D. A. 2003. Behavioral evidence linking opioid-sensitive gabaergic neurons in the ventrolateral periaqueductal gray to morphine tolerance. Neuroscience 118, 227–232. Morgan, M. M., Heinricher, M. M., and Fields, H. L. 1992. Circuitry linking opioid-sensitive nociceptive modulatory systems in periaqueductal gray and spinal cord with rostral ventromedial medulla. Neuroscience 47, 863–871. Morgan, M. M., Heinricher, M. M., and Fields, H. L. 1994. Inhibition and facilitation of different nocifensor reflexes by spatially remote noxious stimuli. J. Neurophysiol. 72, 1152–1160. Nakamura, K., Matsumura, K., Kaneko, T., Kobayashi, S., Katoh, H., and Negishi, M. 2002. The rostral raphe pallidus nucleus mediates pyrogenic transmission from the preoptic area. J. Neurosci. 22, 4600–4610. Narita, M., Mizoguchi, H., Narita, M., Dun, N. J., Hwang, B. H., Endoh, T., Suzuki, T., Nagase, H., Suzuki, T., and Tseng, L. F. 2000. G protein activation by endomorphins in the mouse periaqueductal gray matter. J. Biomed. Sci. 7, 221–225. Nashold, B. S., Wilson, W. P., and Slaughter, D. G. 1969. Sensations evoked by stimulation in the midbrain in man. J. Neurosurg. 30, 14–24. Nason, M. W., Jr. and Mason, P. 2004. Modulation of sympathetic and somatomotor function by the ventromedial medulla. J. Neurophysiol. 92, 510–522. Neubert, M. J., Kincaid, W., and Heinricher, M. M. 2004. Nociceptive facilitating neurons in the rostral ventromedial medulla. Pain 110, 158–165. Ogawa, S., Kow, L. M., and Pfaff, D. W. 1992. Effects of lordosisrelevant neuropeptides on midbrain periaqueductal gray neuronal activity in vitro. Peptides 13, 965–975. Oka, T., Aou, S., and Hori, T. 1994. Intracerebroventricular injection of prostaglandin E2 induces thermal hyperalgesia in rats: the possible involvement of ep3 receptors. Brain Res. 663, 287–292. Oliveras, J. L., Martin, G., and Montagne-Clavel, J. 1991a. Drastic changes of ventromedial medulla neuronal properties induced by barbiturate anesthesia. Ii. Modifications of the single-unit activity produced by brevital, a short-acting barbiturate in the awake, freely moving rat. Brain Res. 563, 251–260. Oliveras, J. L., Martin, G., Montagne, J., and Vos, B. 1990. Single unit activity at ventromedial medulla level in the awake, freely moving rat: effects of noxious heat and light tactile stimuli onto convergent neurons. Brain Res. 506, 19–30. Oliveras, J. L., Montagne-Clavel, J., and Martin, G. 1991b. Drastic changes of ventromedial medulla neuronal properties induced by barbiturate anesthesia. I. Comparison of the single-unit types in the same awake and pentobarbital-treated rats. Brain Res. 563, 241–250. Ongur, D. and Price, J. L. 2000. The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Cereb Cortex 10, 206–219. Osborne, P. B., Vaughan, C. W., Wilson, H. I., and Christie, M. J. 1996. Opioid inhibition of rat periaqueductal grey neurones with identified projections to rostral ventromedial medulla in vitro. J. Physiol. 490, 383–389. Ossipov, M. H., Kovelowski, C. J., Nichols, M. L., Hruby, V. J., and Porreca, F. 1995. Characterization of supraspinal antinociceptive actions of opioid delta agonists in the rat. Pain 62, 287–293.

623

Palkovits, M. and Horvath, S. 1994. Galanin immunoreactive neurons in the medulla oblongata of rats. Acta Biol. Hung. 45, 399–417. Pan, Z. Z. and Fields, H. L. 1996. Endogenous opioid-mediated inhibition of putative pain-modulating neurons in rat rostral ventromedial medulla. Neuroscience 74, 855–862. Pan, Z. Z., Grudt, T. J., and Williams, J. T. 1994. Alpha 1-adrenoceptors in rat dorsal raphe neurons: regulation of two potassium conductances. J. Physiol. 478 Pt 3, 437–447. Pan, Z., Hirakawa, N., and Fields, H. L. 2000. A cellular mechanism for the bidirectional pain-modulating actions of orphanin FQ/nociceptin. Neuron 26, 515–522. Pan, Z. Z., Tershner, S. A., and Fields, H. L. 1997. Cellular mechanism for anti-analgesic action of agonists of the kappa- opioid receptor. Nature 389, 382–385. Pan, Z. Z., Williams, J. T., and Osborne, P. B. 1990. Opioid actions on single nucleus raphe magnus neurons from rat and guinea-pig in vitro. J. Physiol. 427, 519–532. Parry, D. M., Semenenko, F. M., Conley, R. K., and Lumb, B. M. 2002. Noxious somatic inputs to hypothalamic-midbrain projection neurones: a comparison of the columnar organisation of somatic and visceral inputs to the periaqueductal grey in the rat. Exp. Physiol. 87, 117–122. Pastoriza, L. N., Morrow, T. J., and Casey, K. L. 1996. Medial frontal cortex lesions selectively attenuate the hot plate response: possible nocifensive apraxia in the rat. Pain 64, 11–17. Pavlovic, Z. W., Cooper, M. L., and Bodnar, R. J. 1996. Opioid antagonists in the periaqueductal gray inhibit morphine and beta-endorphin analgesia elicited from the amygdala of rats. Brain Res. 741, 13–26. Pertovaara, A. and Kalmari, J. 2002. Neuropathy reduces viscero-somatic inhibition via segmental mechanisms in rats. Neuroreport 13, 1047–1050. Pertovaara, A., Wei, H., and Hamalainen, M. M. 1996. Lidocaine in the rostroventromedial medulla and the periaqueductal gray attenuates allodynia in neuropathic rats. Neurosci. Lett. 218, 127–130. Petrovic, P., Kalso, E., Petersson, K. M., and Ingvar, M. 2002. Placebo and opioid analgesia – imaging a shared neuronal network. Science 295, 1737–1740. Porreca, F., Burgess, S. E., Gardell, L. R., Vanderah, T. W., Malan, T. P., Jr., Ossipov, M. H., Lappi, D. A., and Lai, J. 2001. Inhibition of neuropathic pain by selective ablation of brainstem medullary cells expressing the -opioid receptor. J. Neurosci. 21, 5281–5288. Porreca, F., Ossipov, M. H., and Gebhart, G. F. 2002. Chronic pain and medullary descending facilitation. Trends Neurosci. 25, 319–325. Potrebic, S. B., Fields, H. L., and Mason, P. 1994. Serotonin immunoreactivity is contained in one physiological cell class in the rat rostral ventromedial medulla. J. Neurosci. 14, 1655–1665. Price, J. L. and Amaral, D. G. 1981. An autoradiographic study of the projections of the central nucleus of the monkey amygdala. J. Neurosci. 1, 1242–1259. Price, D. D., Milling, L. S., Kirsch, I., Duff, A., Montgomery, G. H., and Nicholls, S. S. 1999. An analysis of factors that contribute to the magnitude of placebo analgesia in an experimental paradigm. Pain 83, 147–156. Price, D. D., von der Gruen, A., Miller, J., Rafii, A., and Price, C. 1985. Potentiation of systemic morphine analgesia in humans by proglumide, a cholecystokinin antagonist. Anesth. Analg. 64, 801–806. Prieto, G. J., Cannon, J. T., and Liebeskind, J. C. 1983. N. Raphe magnus lesions disrupt stimulation-produced analgesia from ventral but not dorsal midbrain areas in the rat. Brain Res. 261, 53–57.

624 The Brainstem and Nociceptive Modulation Proudfit, H. K. 1992. The Behavioural Pharmacology of the Noradrenergic System. In: Towards the Use of Noradrenergic Agonists for the Treatment of Pain (eds. J. M. Besson and G. Guilbaud), pp. 119–136. Elsevier. Ramirez, F. and Vanegas, H. 1989. Tooth pulp stimulation advances both medullary off-cell pause and tail flick. Neurosci. Lett. 100, 153–156. Ren, K. and Dubner, R. 1996. Enhanced descending modulation of nociception in rats with persistent hindpaw inflammation. J. Neurophysiol. 76, 3025–3037. Ren, K. and Dubner, R. 2002. Descending modulation in persistent pain: an update. Pain 100, 1–6. Rizvi, T. A., Ennis, M., Behbehani, M. M., and Shipley, M. T. 1991. Connections between the central nucleus of the amygdala and the midbrain periaqueductal gray: topography and reciprocity. J. Comp. Neurol. 303, 121–131. Rizvi, T. A., Ennis, M., and Shipley, M. T. 1992. Reciprocal connections between the medial preoptic area and the midbrain periaqueductal gray in rat: a WGA-HRP and PHA-L study. J. Comp. Neurol. 315, 1–15. Rizvi, T. A., Murphy, A. Z., Ennis, M., Behbehani, M. M., and Shipley, M. T. 1996. Medial preoptic area afferents to periaqueductal gray medullo-output neurons: a combined fos and tract tracing study. J. Neurosci. 16, 333–344. Rodgers, R. J. and Randall, J. I. 1988. Environmentally Induced Analgesia: Situational Factors, Mechanisms and Significance. In: Endorphins, Opiates and Behavioral Processes. (eds. R. J. Rodgers and S. J. Cooper), pp. 107–144. Wiley. Romanovsky, A. A., Kulchitsky, V. A., Akulich, N. V., Koulchitsky, S. V., Simons, C. T., Sessler, D. I., and Gourine, V. N. 1996. First and second phases of biphasic fever: two sequential stages of the sickness syndrome? Am. J. Physiol. 271, R244–253. Rosellini, R. A., Abrahamsen, G. C., Stock, H. S., and Caldarone, B. J. 1994. Modulation of hypoalgesia by morphine and number of shock trials: covariation of a measure of context fear and hypoalgesia. Physiol. Behav. 56, 183–188. Rosen, A., Zhang, Y. X., Lund, I., Lundeberg, T., and Yu, L. C. 2004. Substance p microinjected into the periaqueductal gray matter induces antinociception and is released following morphine administration. Brain Res. 1001, 87–94. Rossi, G. C., Pasternak, G. W., and Bodnar, R. J. 1994. Mu and delta opioid synergy between the periaqueductal gray and the rostro-ventral medulla. Brain Res. 665, 85–93. Roychowdhury, S. M. and Fields, H. L. 1996. Endogenous opioids acting at a medullary -opioid receptor contribute to the behavioral antinociception produced by GABA antagonism in the midbrain periaqueductal gray. Neuroscience 74, 863–872. Sagen, J. and Proudfit, H. K. 1981. Hypoalgesia induced by blockade of noradrenergic projections to the raphe magnus: reversal by blockade of noradrenergic projections to the spinal cord. Brain Res. 223, 391–396. Sagen, J. and Proudfit, H. K. 1985. Evidence for pain modulation by pre- and postsynaptic noradrenergic receptors in the medulla oblongata. Brain Res. 331, 285–293. Sandku¨hler, J. and Gebhart, G. F. 1984. Relative contributions of the nucleus raphe magnus and adjacent medullary reticular formation to the inhibition by stimulation in the periaqueductal gray of a spinal nociceptive reflex in the pentobarbital-anesthetized rat. Brain Res. 305, 77–87. Sandrew, B. B. and Poletti, C. E. 1984. Limbic influence on the periaqueductal gray: a single unit study in the awake squirrel monkey. Brain Res. 303, 77–86. Schreff, M., Schulz, S., Wiborny, D., and Hollt, V. 1998. Immunofluorescent identification of endomorphin-2-

containing nerve fibers and terminals in the rat brain and spinal cord. Neuroreport 9, 1031–1034. Semenenko, F. M. and Lumb, B. M. 1992. Projections of anterior hypothalamic neurones to the dorsal and ventral periaqueductal grey in the rat. Brain Res. 582, 237–245. Semenenko, F. M. and Lumb, B. M. 1999. Excitatory projections from the anterior hypothalamus to periaqueductal gray neurons that project to the medulla: a functional anatomical study. Neuroscience 94, 163–174. Shipley, M. T., Ennis, M., Rizvi, T. A., and Behbehani, M. M. 1991. Topographical Specificity of Forebrain Inputs to the Midbrain Periaqueductal Gray: Evidence for Discrete Longitudinally Organized Input Columns. In: The Midbrain Periaqueductal Gray (eds. A. Depaulis and R. Bandler), pp. 417–448. Plenum. Siuciak, J. A. and Advokat, C. 1987. Tolerance to morphine microinjections in the periaqueductal gray (PAG) induces tolerance to systemic, but not intrathecal morphine. Brain Res. 424, 311–319. Skinner, K., Basbaum, A. I., and Fields, H. L. 1997. Cholecystokinin and enkephalin in brain stem pain modulating circuits. Neuroreport 8, 2995–2998. Smith, D. J., Hawranko, A. A., Monroe, P. J., Gully, D., Urban, M. O., Craig, C. R., Smith, J. P., and Smith, D. L. 1997. Dose-dependent pain-facilitatory and -inhibitory actions of neurotensin are revealed by SR 48692, a nonpeptide neurotensin antagonist: influence on the antinociceptive effect of morphine. J. Pharmacol. Exp. Ther. 282, 899–908. Smith, D. J., Perrotti, J. M., Crisp, T., Cabral, M. E., Long, J. T., and Scalzitti, J. M. 1988. The mu opiate receptor is responsible for descending pain inhibition originating in the periaqueductal gray region of the rat brain. Eur. J. Pharmacol. 156, 47–54. Soja, P. J., Cairns, B. E., and Kristensen, M. P. 1999. Transmission through Ascending Trigeminal and Lumbar Sensory Pathways: Dependence on Behavioral State. In: Handbook of Behavioral State Control (eds. R. Lydic and H. A. Baghdoyan), pp. 521–544. CRC Press. Stanfa, L., Dickenson, A., Xu, X. J., and Wiesenfeld-Hallin, Z. 1994. Cholecystokinin and morphine analgesia: variations on a theme. Trends Pharmacol. Sci. 15, 65–66. Sugaya, K., Ogawa, Y., Hatano, T., Koyama, Y., Miyazato, T., and Oda, M. 1998. Evidence for involvement of the subcoeruleus nucleus and nucleus raphe magnus in urine storage and penile erection in decerebrate rats. J. Urol. 159, 2172–2176. Suzuki, R., Rygh, L. J., and Dickenson, A. H. 2004. Bad news from the brain: descending 5-HT pathways that control spinal pain processing. Trends Pharmacol. Sci. 25, 613–617. Talbot, J. D., Villemure, J. G., Bushnell, M. C., and Duncan, G. H. 1995. Evaluation of pain perception after anterior capsulotomy: a case report. Somatosens. Mot. Res. 12, 115–126. Terayama, R., Guan, Y., Dubner, R., and Ren, K. 2000. Activityinduced plasticity in brain stem pain modulatory circuitry after inflammation. Neuroreport 11, 1915–1919. Tershner, S. A., Mitchell, J. M., and Fields, H. L. 2000. Brainstem pain modulating circuitry is sexually dimorphic with respect to mu and kappa opioid receptor function. Pain 85, 153–159. Tortorici, V. and Morgan, M. M. 2002. Comparison of morphine and kainic acid microinjections into identical PAG sites on the activity of RVM neurons. J. Neurophysiol. 88, 1707–1715. Tortorici, V. and Vanegas, H. 1995. Anti-nociception induced by systemic or PAG-microinjected lysine–acetylsalicylate in rats. Effects on tail-flick related activity of medullary off- and on-cells. Eur. J. Neurosci. 7, 1857–1865.

The Brainstem and Nociceptive Modulation Tortorici, V., Morgan, M. M., and Vanegas, H. 2001. Tolerance to repeated microinjection of morphine into the periaqueductal gray is associated with changes in the behavior of off- and on-cells in the rostral ventromedial medulla of rats. Pain 89, 237–244. Tracey, I. 2005. Nociceptive processing in the human brain. Curr. Opin. Neurobiol. 15(4), 478–487. Tracey, I., Ploghaus, A., Gati, J. S., Clare, S., Smith, S., Menon, R. S., and Matthews, P. M. 2002. Imaging attentional modulation of pain in the periaqueductal gray in humans. J. Neurosci. 22, 2748–2752. Tsou, K., Brown, S., Sanudo-Pena, M. C., Mackie, K., and Walker, J. M. 1998. Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience 83, 393–411. Urban, M. O. and Gebhart, G. F. 1997. Characterization of biphasic modulation of spinal nociceptive transmission by neurotensin in the rat rostral ventromedial medulla. J. Neurophysiol. 78, 1550–1562. Urban, M. O. and Smith, D. J. 1993. Role of neurotensin in the nucleus raphe magnus in opioid-induced antinociception from the periaqueductal gray. J. Pharmacol. Exp. Ther. 265, 580–586. Urban, M. O., Coutinho, S. V., and Gebhart, G. F. 1999. Biphasic modulation of visceral nociception by neurotensin in rat rostral ventromedial medulla. J. Pharmacol. Exp. Ther. 290, 207–213. Urban, M. O., Jiang, M. C., and Gebhart, G. F. 1996. Participation of central descending nociceptive facilitatory systems in secondary hyperalgesia produced by mustard oil. Brain Res. 737, 83–91. Valet, M., Sprenger, T., Boecker, H., Willoch, F., Rummeny, E., Conrad, B., Erhard, P., and Tolle, T. R. 2004. Distraction modulates connectivity of the cingulo-frontal cortex and the midbrain during pain – an FMRI analysis. Pain 109, 399–408. Van Bockstaele, E. J., Aston-Jones, G., Pieribone, V. A., Ennis, M., and Shipley, M. T. 1991. Subregions of the periaqueductal gray topographically innervate the rostral ventral medulla in the rat. J. Comp. Neurol. 309, 305–327. Vanderah, T. W., Ossipov, M. H., Lai, J., Malan, T. P., and Porreca, F. 2001a. Mechanisms of opioid-induced pain and antinociceptive tolerance: descending facilitation and spinal dynorphin. Pain 92, 5–9. Vanderah, T. W., Suenaga, N. M., Ossipov, M. H., Malan, T. P., Jr., Lai, J., and Porreca, F. 2001b. Tonic descending facilitation from the rostral ventromedial medulla mediates opioid-induced abnormal pain and antinociceptive tolerance. J. Neurosci. 21, 279–286. Vanderhorst, V. G., Mouton, L. J., Blok, B. F., and Holstege, G. 1996. Distinct cell groups in the lumbosacral cord of the cat project to different areas in the periaqueductal gray. J. Comp. Neurol. 376, 361–385. Vanderhorst, V. G., Terasawa, E., and Ralston, H. J., 3rd 2002. Estrogen receptor-alpha immunoreactive neurons in the ventrolateral periaqueductal gray receive monosynaptic input from the lumbosacral cord in the rhesus monkey. J. Comp. Neurol. 443, 27–42. Vanegas, H. 2004. To the descending pain-control system in rats, inflammation-induced primary and secondary hyperalgesia are two different things. Neurosci. Lett. 361, 225–228. Vanegas, H. and Schaible, H.-G. 2004. Descending control of persistent pain: inhibitory or facilitatory? Brain Res. Rev. 46, 295–309. Vanegas, H. and Tortorici, V. 2002. Opioidergic effects of nonopioid analgesics on the central nervous system. Cell. Mol. Neurobiol. 22, 655–661. Vanegas, H., Barbaro, N. M., and Fields, H. L. 1984. Midbrain stimulation inhibits tail-flick only at currents

625

sufficient to excite rostral medullary neurons. Brain Res. 321, 127–133. Vaughan, C. W. 1998. Enhancement of opioid inhibition of GABAergic synaptic transmission by cyclo-oxygenase inhibitors in rat periaqueductal grey neurones. Br. J. Pharmacol. 123, 1479–1481. Vaughan, C. W. and Christie, M. J. 1997. Presynaptic inhibitory action of opioids on synaptic transmission in the rat periaqueductal grey in vitro. J. Physiol. 498, 463–472. Vaughan, C. W., Bagley, E. E., Drew, G. M., Schuller, A., Pintar, J. E., Hack, S. P., and Christie, M. J. 2003. Cellular actions of opioids on periaqueductal grey neurons from c57b16/j mice and mutant mice lacking mor-1. Br. J. Pharmacol. 139, 362–367. Vaughan, C. W., Bandler, R., and Christie, M. J. 1996. Differential responses of lateral and ventrolateral rat periaqueductal grey neurones to noradrenaline in vitro. J. Physiol. 490, 373–381. Vaughan, C. W., Connor, M., Bagley, E. E., and Christie, M. J. 2000. Actions of cannabinoids on membrane properties and synaptic transmission in rat periaqueductal gray neurons in vitro. Mol. Pharmacol. 57, 288–295. Vaughan, C. W., Ingram, S. L., Connor, M. A., and Christie, M. J. 1997. How opioids inhibit GABA-mediated neurotransmission. Nature 390, 611–614. Vaughan, C. W., McGregor, I. S., and Christie, M. J. 1999. Cannabinoid receptor activation inhibits GABAergic neurotransmission in rostral ventromedial medulla neurons in vitro. Br. J. Pharmacol. 127, 935–940. Vianna, D. M., Graeff, F. G., Brandao, M. L., and LandeiraFernandez, J. 2001. Defensive freezing evoked by electrical stimulation of the periaqueductal gray: comparison between dorsolateral and ventrolateral regions. Neuroreport 12, 4109–4112. Villemure, C. and Bushnell, M. C. 2002. Cognitive modulation of pain: How do attention and emotion influence pain processing? Pain 95, 195–199. Wager, T. D., Rilling, J. K., Smith, E. E., Sokolik, A., Casey, K. L., Davidson, R. J., Kosslyn, S. M., Rose, R. M., and Cohen, J. D. 2004. Placebo-induced changes in fMRI in the anticipation and experience of pain. Science 303, 1162–1167. Walker, P. and Carrive, P. 2003. Role of ventrolateral periaqueductal gray neurons in the behavioral and cardiovascular responses to contextual conditioned fear and poststress recovery. Neuroscience 116, 897–912. Walker, J. M. and Huang, S. M. 2002a. Cannabinoid analgesia. Pharmacol. Ther. 95, 127–135. Walker, J. M. and Huang, S. M. 2002b. Endocannabinoids in pain modulation. Prostaglandins Leukot. Essent. Fatty Acids 66, 235–242. Walker, J. M., Huang, S. M., Strangman, N. M., Tsou, K., and Sanudo-Pena, M. C. 1999. Pain modulation by release of the endogenous cannabinoid anandamide. Proc. Natl. Acad. Sci. U. S. A. 96, 12198–12203. Wall, P. D. 1979. On the relation of injury to pain. Pain 6, 253–264. Wang, H. and Wessendorf, M. W. 1999. Mu- and deltaopioid receptor mRNAs are expressed in spinally projecting serotonergic and nonserotonergic neurons of the rostral ventromedial medulla. J. Comp. Neurol. 404, 183–196. Waters, A. J. and Lumb, B. M. 1997. Inhibitory effects evoked from both the lateral and ventrolateral periaqueductal grey are selective for the nociceptive responses of rat dorsal horn neurones. Brain Res. 752, 239–249. Watkins, L. R. and Mayer, D. J. 1982. Organization of endogenous opiate and nonopiate pain control systems. Science 216, 1185–1192.

626 The Brainstem and Nociceptive Modulation Watkins, L. R., Cobelli, D. A., and Mayer, D. J. 1982. Opiate vs non-opiate footshock induced analgesia (FSIA): descending and intraspinal components. Brain Res. 245, 97–106. Watkins, L. R., Kinscheck, I. B., and Mayer, D. J. 1983a. The neural basis of footshock analgesia: the effect of periaqueductal gray lesions and decerebration. Brain Res. 276, 317–324. Watkins, L. R., Wiertelak, E. P., Goehler, L. E., MooneyHeiberger, K., Martinez, J., Furness, L., Smith, K. P., and Maier, S. F. 1994. Neurocircuitry of illness-induced hyperalgesia. Brain Res. 639, 283–299. Watkins, L. R., Wiertelak, E. P., and Maier, S. F. 1993. The amygdala is necessary for the expression of conditioned but not unconditioned analgesia. Behav. Neurosci. 107, 402–405. Watkins, L. R., Young, E. G., Kinscheck, I. B., and Mayer, D. J. 1983b. The neural basis of footshock analgesia: the role of specific ventral medullary nuclei. Brain Res. 276, 305–315. Wiberg, M., Westman, J., and Blomqvist, A. 1987. Somatosensory projection to the mesencephalon: an anatomical study in the monkey. J. Comp. Neurol. 264, 92–117. Wiertelak, E. P., Roemer, B., Maier, S. F., and Watkins, L. R. 1997. Comparison of the effects of nucleus tractus solitarius and ventral medial medulla lesions on illness-induced and subcutaneous formalin- induced hyperalgesias. Brain Res. 748, 143–150. Wiesenfeld-Hallin, Z., de Arauja Lucas, G., Alster, P., Xu, X. J., and Ho¨kfelt, T. 1999. Cholecystokinin/opioid interactions. Brain Res. 848, 78–89. Williams, F. G. and Beitz, A. J. 1990. Ultrastructural morphometric analysis of GABA-immunoreactive terminals in the ventrocaudal periaqueductal grey: analysis of the relationship of GABA terminals and the GABAa receptor to periaqueductal grey-raphe magnus projection neurons. J. Neurocytol. 19, 686–696. Williams, F. G., Mullet, M. A., and Beitz, A. J. 1995. Basal release of met-enkephalin and neurotensin in the ventrolateral periaqueductal gray matter of the rat: a microdialysis study of antinociceptive circuits. Brain Res. 690, 207–216. Williams, J. L., Worland, P. D., and Smith, M. G. 1990. Defeatinduced hypoalgesia in the rat: effects of conditioned odors, naltrexone, and extinction. J. Exp. Psychol. Anim. Behav. Proc. 16, 345–357. Williams, J. T., Christie, M. J., and Manzoni, O. 2001. Cellular and synaptic adaptations mediating opioid dependence. Physiol. Rev. 81, 299–343.

Xie, J. Y., Herman, D. S., Stiller, C. O., Gardell, L. R., Ossipov, M. H., Lai, J., Porreca, F., and Vanderah, T. W. 2005. Cholecystokinin in the rostral ventromedial medulla mediates opioid-induced hyperalgesia and antinociceptive tolerance. J. Neurosci. 25, 409–416. Xin, L., Geller, E. B., Liu-Chen, L. Y., Chen, C., and Adler, M. W. 1997. Substance p release in the rat periaqueductal gray and preoptic anterior hypothalamus after noxious cold stimulation: effect of selective mu and kappa opioid agonists. J. Pharmacol. Exp. Ther. 282, 1055–1063. Yezierski, R. P. 1988. Spinomesencephalic tract: projections from the lumbosacral spinal cord of the rat, cat, and monkey. J. Comp. Neurol. 267, 131–146. Yezierski, R. P. and Mendez, C. M. 1991. Spinal distribution and collateral projections of rat spinomesencephalic tract cells. Neuroscience 44, 113–130. Zadina, J. E., Hackler, L., Ge, L. J., and Kastin, A. J. 1997. A potent and selective endogenous agonist for the -opiate receptor. Nature 386, 499–502. Zagon, A., Totterdell, S., and Jones, R. S. 1994. Direct projections from the ventrolateral medulla oblongata to the limbic forebrain: anterograde and retrograde tract-tracing studies in the rat. J. Comp. Neurol. 340, 445–468. Zambreanu, L., Wise, R. G., Brooks, J. C., Iannetti, G. D., and Tracey, I. 2005. A role for the brainstem in central sensitisation in humans. Evidence from functional magnetic resonance imaging. Pain 114, 397–407. Zhang, L., Sykes, K. T., and Hammond, D. L. 2004. Peripheral inflammation increases the proportion of spinally projecting neurons that express functional opioid receptors in the rostral ventromedial medulla (RVM). Abstract Viewer/ Itinerary Planner. Society for Neuroscience. Online, Program 297.294. Zhang, Y. Q., Tang, J. S., Yuan, B., and Jia, H. 1997. Inhibitory effects of electrically evoked activation of ventrolateral orbital cortex on the tail-flick reflex are mediated by periaqueductal gray in rats. Pain 72, 127–135. Zhuo, M. and Gebhart, G. F. 1992. Characterization of descending facilitation and inhibition of spinal nociceptive transmission from the nuclei reticularis gigantocellularis and gigantocellularis pars alpha in the rat. J. Neurophysiol. 67, 1599–1614. Zhuo, M. and Gebhart, G. F. 1997. Biphasic modulation of spinal nociceptive transmission from the medullary raphe nuclei in the rat. J. Neurophysiol. 78, 746–758.

42 Emotional and Behavioral Significance of the Pain Signal and the Role of the Midbrain Periaqueductal Gray (PAG) K Keay and R Bandler, University of Sydney, Sydney, NSW, Australia ª 2009 Elsevier Inc. All rights reserved.

42.1 42.2 42.2.1 42.2.2 42.2.2.1 42.2.2.2 42.2.3 42.2.3.1 42.2.4 42.2.4.1 42.2.4.2 42.3 References

More than a Sensation? Coping with Pain Active versus Passive Emotional Coping Neural Representations of Active Emotional Coping Dorsolateral periaqueductal gray Lateral periaqueductal gray Neural Representation of Passive Emotional Coping Ventrolateral periaqueductal gray Outputs Mediating Active and Passive Emotional Coping Lateral periaqueductal gray and ventrolateral periaqueductal gray Dorsolateral periaqueductal gray Conclusion

42.1 More than a Sensation? In a provocative article entitled On the Relation of Injury to Pain, Wall P. D. (1979) suggested that ‘‘. . . pain is better classified as an awareness of a need state than as a sensation; that it has more in common with the phenomena of hunger and thirst than it has with seeing and hearing . . . .’’ He also observed, somewhat anecdotally, that as pain changed from acute to chronic the emotional coping reaction also changed. Livingston W. K. (1998) in his posthumously published book Pain and Suffering stated a similar belief that ‘‘. . . pain is not strictly a physical sensation that can be defined simply by its anatomical and physiological substrates.’’ Writing even earlier, Lewis T. (1942) observed that different emotional coping reactions were evoked by pain of different tissue origins, ‘‘. . . while painful sensations derived from the human skin are associated with brisk movements, with a rise of pulse rate and with a sense of invigoration . . . painful sensations derived from deeper structures are associated often with quiescence, with slowing of the pulse, falling of the blood pressure, sweating and nausea.’’ He went on to suggest that ‘‘. . . the difference in the quality of skin pain and of deep pain is so clear . . . that it would perhaps seem unsafe to class both together under the one unqualified term pain and concluded that ‘‘. . . we should bear in mind the possibly serious fallacy of regarding both types (of pain) as represented in a common centre.’’

627 627 627 628 628 630 630 630 630 630 630 633 633

It is striking that these eminent researchers although starting from different perspectives arrive at a shared view, namely, that in addition to knowledge of the anatomy and physiology of its ascending sensory pathways, understanding how pain is localized in the brain also requires knowledge of the neurobiology of the emotional coping strategies triggered by different classes of pain.

42.2 Coping with Pain 42.2.1 Active versus Passive Emotional Coping Animals (including humans) employ different strategies to cope with different classes of pain. Active emotional coping, which is characterized by engagement with the environment (i.e., fight or flight), is the usual response to escapable pain. Components of active coping include increased vigilance, hyperreactivity, increased somatomotor activity, and increased sympathetic activity. Passive emotional coping, is the antithesis of active coping. Instead of engagement with the environment, there is disengagement (e.g., conservation-withdrawal (Henry, J. P. and Stephens, P. M., 1977)). Components of passive coping include: decreased vigilance, hyporeactivity, quiescence, and falls in arterial pressure and heart rate. Passive 627

628 Emotional and Behavioral Significance of PAG

42.2.2.1

Dorsolateral periaqueductal gray The dlPAG is distinguished from the lPAG by the presence (e.g., nitric oxide synthase (NOS), cholecystokinin (CCK), acetylcholine (ACh), Met-enkephalin) or absence (e.g., cytochrome oxidase and Gly-2 transporter) of specific neurochemicals (for a review, see Keay, K. A. and Bandler, R., 2004). Anatomically, major descending inputs to dlPAG originate from medial prefrontal cortical (PFC) fields and select medial hypothalamic nuclei, but there is a striking absence of ascending afferents arising from either brainstem or spinal cord (Figure 2). The predominance of forebrain, primarily cortical inputs, led to the suggestion that when triggered by psychological (cortical) stimuli, active coping is mediated by the dlPAG (Bandler, R. et al., 2000). Consistent with this suggestion, the potential threat signaled by the presence of a cat (sight and/or odor, but without physical contact) triggers active coping and a selective increase in immediate early gene (c-fos) expression in the dlPAG of the rat (Figure 2) (Canteras, N. S. and Goto, M., 1999).

emotional coping is the usual response to inescapable pain, i.e., pain of deep origin (muscle, joint, viscera) or any persistent/chronic pain (Lewis, T., 1942; Wall, P. D., 1979; Bandler, R. et al., 2000; Keay, K. A. et al., 2001).

42.2.2 Neural Representations of Active Emotional Coping Research carried out in rats, cats, and primates has identified longitudinally oriented, neuronal columns within the midbrain periaqueductal gray (PAG) as critical substrates integrating active or passive emotional coping. As seen in Figure 1 active emotional coping responses (i.e., a coordinated reaction of freezing, fight or flight, hypertension, tachycardia, and a nonopioid-mediated analgesia) are evoked when excitatory amino acids are microinjected into either the dorsolateral (dlPAG) or lateral (lPAG) column. (Bandler, R. and Shipley, M. T., 1994). Anatomical and functional studies suggest, however, different neural circuits and triggers are involved.

Confrontational defense/threat hypertension and tachycardia nonopioid-mediated analgesia dl

Dorsolateral and lateral PAG: active emotional coping

dm

dl

Escape/flight hypertension and tachycardia nonopioid-mediated analgesia

dm

lat dl

dm

lat vl Ventrolateral PAG: passive emotional coping Quiescence and hyporeactivity hypotension and bradycardia opioid-mediated analgesia

dl

dm

lat

vl

Figure 1 Schematic illustration of the dorsomedial (dm), dorsolateral (dl), lateral (lat), and ventrolateral (vl) neuronal columns within the periaqueductal gray (PAG). Injections of excitatory amino acids (EAA) within the dorsolateral and lateral PAG evoke active emotional coping strategies, whereas passive emotional coping strategies are evoked from the ventrolateral PAG. Specifically, EAA injections made within the dlPAG and lPAG columns evoke defensive reactions (confrontation, threat, escape, flight), hypertension, tachycardia, and a non-opioid-mediated analgesia. In contrast, EAA injections made within the vlPAG evoke cessation of spontaneous activity (quiescence), decreased responsiveness to the environment (hyporeactivity), hypotension, bradycardia, and an opioid-mediated analgesia. Adapted from Bandler, R. and Shipley, M. T. 1994. Columnar organization in the midbrain periaqueductal gray: modules for emotional expression? Trends Neurosci. 17, 379–389.

Emotional and Behavioral Significance of PAG

629

Prefrontal cortex FPm

ACd

ACv

PL MO

IL

Hypothalamus

Dorsolateral PAG

PVN

f

dl

LHAa

lat

3V

AHA opt

III

dl lat

DHA DMH

3V vl

LHAm f

DR

dl

mt LHAp

3V PHA vl

f

cnf

3V

Rostral medulla

RVLM

Exposure to a cat –5.8

–6.8

–7.8

–8.8

Figure 2 Schematic illustration of the major afferent and efferent projections of the dorsolateral periaqueductal gray (dlPAG). Major forebrain inputs to the dlPAG arise from dorsal, medial prefrontal cortical fields, and medial hypothalamic regions. The dlPAG does not project directly to the medulla, but can influence the rostral ventrolateral medulla via the cuneiform nucleus (cnf). The lower panel illustrates the pattern of neural activation (c-fos expression) evoked by a psychological stressor (exposure, without physical contact, of a rat to a cat), which evokes active emotional coping. The shaded area indicates the dorsolateral PAG column. RVLM, rostral ventrolateral medulla ACd, dorsal anterior cingulate cortex; ACv, ventral anterior cingulate cortex; AId, dorsal agranular insular cortex; AIp, posterior agranular insular cortex; DLO, dorsolateral orbital cortex; FPm, medial frontal pole; IL, infralimbic cortex; MO, medial orbital cortex; PL, prelimbic cortex; PRh, perirhinal cortex; VLOm, ventrolateral orbital cortex, medial part; VO, ventral orbital cortex AHA, anterior hypothalamic area; DHA, dorsal hypothalamic area; DMH, dorsomedial hypothalamic area; LHAa, lateral hypothalamic area, anterior; LHAm, lateral hypothalamic area, medial; LHAp, lateral hypothalamic area, posterior; PHA, posterior hypothalamic area; PVN, periventricular hypothalamic nucleus; f, fornix; mt, mamillothalmic tract; opt, optic tract; 3V, third ventricle; dl, dorsolateral PAG; lat, lateral PAG; vl, ventrolateral PAG, DR, dorsal raphe. Exposure to a cat: Adapted from Canteras, N. S. and Goto, M. 1999. Fos-like immunoreactivity in the periaqueductal gray of rats exposed to a natural predator. Neuroreport 10, 413–418.

630 Emotional and Behavioral Significance of PAG

42.2.2.2

Lateral periaqueductal gray Although the boundary between the lPAG and dlPAG can be established on neurochemical grounds, the boundary between the lPAG and ventrolateral periaqueductal gray (vlPAG) rests on functional criteria (see Figure 1 and Section 42.2.3). Anatomically, the lPAG receives modest descending afferents of cortical and dorsal hypothalamic origins. However, in contrast to the dlPAG, the lPAG receives substantial and somatotopically organized ascending inputs from laminae I, II, IV, and V of the spinal cord, as well as the caudal, spinal trigeminal complex (Sp5) (Figure 3). The predominance of inputs arising from noci-responsive spinal and SpV regions suggests that active coping in response to physical stimuli (e.g., acute cutaneous pain) is mediated by the lPAG. In support of this hypothesis, brief applications of a noxious, cutaneous (thermal) stimulus evoked increased Fos expression within the lPAG, hypertension and active coping (Figure 3) (Keay, K. A. and Bandler, R. 1993; 2002).

42.2.3 Neural Representation of Passive Emotional Coping Passive coping (i.e., a coordinated, conservationwithdrawal reaction of quiescence, hyporeactivity, hypotension, bradycardia, and an opioid-mediated analgesia) is evoked by microinjection of excitatory amino acids into the vlPAG column (Figure 1) (Bandler, R. and Shipley, M. T., 1994; Keay, K. A. and Bandler, R., 2001). 42.2.3.1 gray

Ventrolateral periaqueductal

In common with the lPAG, substantial ascending inputs to the vlPAG originate from superficial and deep dorsal horn of spinal cord (and the transition zone between caudal and interpolar parts of Sp5, personal observations) (Keay, K. A. et al., 1997). Double-label anatomical tracing studies indicate, however, that vlPAG and lPAG projections arise from distinct and separate populations of spinal neurons (Clement, C. I. et al., 2000). Further, spinovlPAG projections are not somatotopically organized (Keay, K. A. et al., 1997). The vlPAG also receives substantial ascending inputs from nuclei of the solitary tract (NTS), as well as descending inputs from select orbital and insular cortical fields and the lateral hypothalamus (Figure 4). The convergence within the vlPAG of spinal, medullary, and forebrain

afferents suggests that passive coping, whether evoked by physical or psychological stimuli, is mediated by the vlPAG. In support of this view, Fos expression is strongly evoked in the vlPAG when passive coping is triggered either (1) as a primary response to a deep or persistent noxious stimulus (see Figure 4) (Clement, C. I. et al., 1996; Keay, K. A. et al., 1997; 2001; Keay, K. A. and Bandler, R., 2002) or (2) in order to promote recovery and healing, as a delayed response to acute injury (for a discussion, see Wall, P. D., 1979; Keay, K. A. and Bandler, R., 2004).

42.2.4 Outputs Mediating Active and Passive Emotional Coping 42.2.4.1 Lateral periaqueductal gray and ventrolateral periaqueductal gray

Although they mediate distinct emotional coping strategies, the same ventromedial and ventrolateral medullary regions are projected upon by lPAG and vlPAG (see Figures 3 and 4) (Keay, K. A. and Bandler, R., 2001). Consistent with the opposing functional roles of lPAG and vlPAG, electrophysiological studies reveal opposite effects on medullary target neurons. For example, presympathetic rostral ventrolateral medulla (RVLM) vasopressor neurons are excited by lPAG stimulation, but inhibited by vlPAG stimulation (Verberne, A. J. and Boudier, H. R. S., 1991; Lovick, T. A., 1992a; 1992b; Verberne, A. and Guyenet, P., 1992). In contrast to shared descending targets, there exist distinct ascending projections to specific hypothalamic and midline and intralaminar thalamic fields (Floyd, N. S. et al., 1996; 2000; Krout, K. E. and Loewy, A. D., 2000; Floyd, N. S. et al., 2001).

42.2.4.2 gray

Dorsolateral periaqueductal

Although it integrates an identical emotional coping strategy to the lPAG, the dlPAG has few direct medullary outputs. Its influence on the ventrolateral medulla is likely mediated indirectly, in part via a substantial projection to the cuneiform region (see Figure 2) (Redgrave, P. et al., 1988; Mitchell, I. J. et al., 1988a; 1988b). The dlPAG also projects to distinct thalamic and hypothalamic fields (Floyd, N. S. et al., 1996; 2000; Krout, K. E. and Loewy, A. D., 2000; Floyd, N. S. et al., 2001).

Emotional and Behavioral Significance of PAG

631

Prefrontal cortex DLO

AId

FPm

ACd PL

VO/VLO m MO

MO

IL

Lateral PAG dl

Hypothalamus

Medullary dorsal horn

lat

PVN

f

III

LHAa AHA

Sp5

3V dl

opt

lat DHA 3V

vl

DMH

LHAm

DR

f

Spinal cord dl

mt 3V PHA

LHAp f

3V vl

RM RVLM CMM

CVLM

Medulla

Intermittent (acute) cutaneous pain (Keay, K. A. and Bandler, R. 1993) –5.8

–6.8

–7.8

–8.8

Figure 3 Schematic illustration of the major afferent and efferent projections of the lateral periaqueductal gray (lPAG). Major inputs to lPAG arise from spinal cord and the medullary dorsal horn (spinal trigeminal complex (SpV)). In addition, more modest inputs arise from a restricted part of medial prefrontal cortex as well as dorsal hypothalamic regions. The lPAG projects directly to both the rostral and caudal ventrolateral medulla (RVLM, CVLM), as well as the rostral and caudal ventromedial medulla (RM, CMM). The panel in the lower part of the figure shows the pattern of neural activation (c-fos expression) evoked by an acute cutaneous noxious stimulus (intermittent radiant heat), which evokes active emotional coping. The shaded area indicates the lPAG column. For abbreviations see caption to Figure 2.

632 Emotional and Behavioral Significance of PAG

Prefrontal cortex DLO AId FPm

ACd

ACv

PL

VO/VLO m MO

MO

IL

Ventrolateral PAG Hypothalamus

dl

Nucleus of the solitary tract lat

PVN

f

Sol

LHAa AHA

3V

vl

opt

DR

DHA

DMH

LHAm

3V

dl

Spinal cord

f

vl mt LHAp

3V PHA

f

3V

RM RVLM CMM

Medulla

CVLM

Muscle pain (Keay, K. A. et al., 2001)

Persistent cutaneous pain

–5.8

–6.8

–7.8

–8.8

(Keay, K. A. et al., 2001)

Figure 4 Schematic illustration of the major afferent and efferent projections of the ventrolateral periaqueductal gray (vlPAG). Major inputs to vlPAG arise from spinal cord and the nucleus of the solitary tract. In addition, significant inputs arise also from ventromedial prefrontal cortex and orbital/insular cortices. As well, substantial inputs arise from lateral hypothalamic fields. The vlPAG projects directly to both rostral and caudal ventrolateral medulla (RVLM, CVLM), as well as the rostral and caudal ventromedial medulla (RM, CMM). The panel in the lower part of the figure shows the patterns of neural activation (c-fos expression) evoked by an acute deep noxious stimulus (muscle pain: i.m. formalin) and a persistent cutaneous noxious stimulus (clip applied to dorsum of neck), each of which evoke passive emotional coping. The shaded area indicates the vlPAG column. For abbreviations see caption to Figure 2.

Emotional and Behavioral Significance of PAG

42.3 Conclusion Animals (including humans) share the capacity to respond to escapable or inescapable pain with different emotional coping strategies. It has been established that the PAG is divisible into distinct longitudinal neuronal columns, which mediate distinct coping strategies (dlPAG/lPAG: active emotional coping; vlPAG: passive emotional coping). Further, each PAG column lies embedded within parallel, but distinct circuits, which extend rostrally to include specific PFC and hypothalamic regions (Bernard, J. F. and Bandler, J. F., 1998; Keay, K. A. and Bandler, R., 2001). On the output side, each PAG column projects either directly (lPAG/vlPAG) or indirectly (dlPAG) onto ventrolateral and ventromedial medullary regions containing (1) somatic and autonomic premotor neurons and (2) neurons mediating antinociception. A substantial body of evidence supports the view that the different PAG columns, and, their associated circuits, play critical roles in integrating the somatic, autonomic and antinociceptive components which characterize the distinct emotional coping reactions evoked by pain of different tissue origins and/or durations.

References Bandler, R. and Shipley, M. T. 1994. Columnar organization in the midbrain periaqueductal gray: modules for emotional expression? Trends Neurosci. 17, 379–389. Bandler, R., Keay, K. A., Floyd, N., and Price, J. 2000. Central circuits mediating patterned autonomic activity during active vs. passive emotional coping. Brain Res. Bull. 53, 95–104. Bandler, R., Price, J. L., and Keay, K. A. 2000. Brain mediation of active and passive emotional coping. Progr. Brain Res. 122, 333–349. Bernard, J. F. and Bandler, R. 1998. Parallel circuits for emotional coping behaviour: new pieces in the puzzle. J. Comp. Neurol. 401, 429–436. Canteras, N. S. and Goto, M. 1999. Fos-like immunoreactivity in the periaqueductal gray of rats exposed to a natural predator. Neuroreport 10, 413–418. Clement, C. I., Keay, K. A., Owler, B. K., and Bandler, R. 1996. Common patterns of increased and decreased fos expression in midbrain and pons evoked by noxious deep somatic and noxious visceral manipulations in the rat. J. Comp. Neurol. 366, 495–515. Clement, C. I., Keay, K. A., Podzebenko, K., Gordon, B. D., and Bandler, R. 2000. Spinal sources of noxious visceral and noxious deep somatic afferent drive onto the ventrolateral periaqueductal gray of the rat. J. Comp. Neurol. 425, 323–344. Floyd, N. S., Keay, K. A., and Bandler, R. 1996. A calbindin immunoreactive ‘‘deep pain’’ recipient thalamic nucleus in the rat. Neuroreport 7, 622–626.

633

Floyd, N. S., Price, J. L., Ferry, A. T., Keay, K. A., and Bandler, R. 2000. Orbitomedial prefrontal cortical projections to distinct longitudinal columns of the periaqueductal gray in the rat. J. Comp. Neurol. 422, 556–578. Floyd, N. S., Price, J. L., Ferry, A. T., Keay, K. A., and Bandler, R. 2001. Orbitomedial prefrontal cortical projections to hypothalamus in the rat. J. Comp. Neurol. 432, 307–328. Henry, J. P. and Stephens, P. M. 1977. Stress Health and the Social Environment: A Sociobiological Approach to Medicine. Springer. Keay, K. A. and Bandler, R. 1993. Deep and superficial noxious stimulation increases fos-like immunoreactivity in different regions of the midbrain periaqueductal grey of the rat. Neurosci. Lett. 154, 23–26. Keay, K. A. and Bandler, R. 2001. Parallel circuits mediating distinct emotional coping reactions to different types of stress. Neurosci. Biobehav. Rev. 25, 669–678. Keay, K. A. and Bandler, R. 2002. Distinct central representations of inescapable and escapable pain: observations and speculation. Exp. Physiol. 87, 275–279. Keay, K. A. and Bandler, R. 2004. Periaqueductal Gray. In: The Rat Nervous System, 3rd edn. (ed. G. Paxinos), pp. 243–257. Elsevier. Keay, K. A., Clement, C. I., Depaulis, A., and Bandler, R. 2001. Different representations of inescapable noxious stimuli in the periaqueductal gray and upper cervical spinal cord of freely moving rats. Neurosci. Lett. 313, 17–20. Keay, K. A., Clement, C. I., Owler, B., Depaulis, A., and Bandler, R. 1994. Convergence of deep somatic and visceral nociceptive information onto a discrete ventrolateral midbrain periaqueductal gray region. Neuroscience 61, 727–732. Keay, K. A., Feil, K., Gordon, B. D., Herbert, H., and Bandler, R. 1997. Spinal afferents to functionally distinct periaqueductal gray columns in the rat: an anterograde and retrograde tracing study. J. Comp. Neurol. 385, 207–229. Krout, K. E. and Loewy, A. D. 2000. Periaqueductal gray matter projections to midline and intralaminar thalamic nuclei of the rat. J. Comp. Neurol. 424, 111–141. Lewis, T. 1942. Pain. MacMillan. Livingston, W. K. 1998. Pain and Suffering. IASP Press. Lovick, T. A. 1992a. Inhibitory modulation of the cardiovascular defence response by the ventrolateral periaqueductal grey matter in rats. Exp. Brain Res. 89, 133–139. Lovick, T. A. 1992b. Midbrain influences on ventrolateral medullo-spinal neurones in the rat. Exp. Brain Res. 90, 147–152. Mitchell, I. J., Dean, P., and Redgrave, P. 1988a. The projection from superior colliculus to cuneiform area in the rat. Ii. Defence-like responses to stimulation with glutamate in cuneiform nucleus and surrounding structures. Exp. Brain Res. 72, 626–639. Mitchell, I. J., Redgrave, P., and Dean, P. 1988b. Plasticity of behavioural response to repeated injection of glutamate in cuneiform area of rat. Brain Res. 460, 394–397. Redgrave, P., Dean, P., Mitchell, I. J., Odekunle, A., and Clark, A. 1988. The projection from superior colliculus to cuneiform area in the rat. I. Anatomical studies. Exp. Brain Res. 72, 611–625. Verberne, A. and Guyenet, P. 1992. Midbrain central gray: influence on medullary sympathoexcitatory neurons and the baroreflex in rats. Am. J. Physiol. 263, R24–R33. Verberne, A. J. and Boudier, H. R. S. 1991. Midbrain central grey: regional heamodynamic control and excitatory amino acidergic mechanisms. Brain Res. 550, 86–94. Wall, P. D. 1979. On the relation of injury to pain. Pain 6, 253–264.

634 Emotional and Behavioral Significance of PAG

Further Reading Bandler, R. and Keay, K. A. 1996. Columnar organization in the midbrain periaqueductal gray and the integration of emotional expression. Progr. Brain Res. 107, 285–300. Keay, K. A., Clement, C. I., Matar, W. M., Heslop, D. J., Henderson, L. A., and Bandler, R. 1997. Noxious activation

of spinal or vagal afferents evoked distinct patterns of fos-like immunoreactivity in the ventrolateral periaqueductal grey of unanaesthetised rats. Brain Res. 948, 122–130. Lovick, T. and Bandler, R. 2005. The organization of the Midbrain Periaqueductal Grey and the Integration of Pain Behaviour. In: The Neurobiology of Pain (eds. S. Hunt and M. Koltzenburg), pp. 267–287. Oxford University Press.

43 The Thalamus and Nociceptive Processing J O Dostrovsky, University of Toronto, Toronto, ON, Canada A D Craig, Barrow Neurological Institute, Phoenix, AZ, USA ª 2009 Elsevier Inc. All rights reserved.

43.1 43.2 43.2.1 43.2.1.1 43.2.1.2 43.2.1.3 43.2.1.4 43.2.1.5 43.2.1.6 43.2.1.7 43.2.2 43.3 43.3.1 43.3.2 43.3.3 43.3.4 43.3.5 43.4 43.4.1 43.4.2 43.4.3 43.5 43.5.1 43.5.2 43.5.3 43.5.4 43.6 References

Introduction Comparative Anatomical Findings Thalamic Nuclei Receiving Direct Spinothalamic Tract Inputs Ventroposterior nuclei Posterior part of the ventromedial nucleus Ventral lateral nucleus Parafascicular nucleus Medial dorsal nucleus Central lateral nucleus Nucleus submedius Indirect Nociceptive Pathways to the Thalamus Comparative Physiological Findings Ventroposterior Nuclei Ventroposterior Inferior Nucleus Posterior Thalamus and Posterior Part of the Ventromedial Nucleus Intralaminar Nuclei Medial Dorsal Nucleus Direct Physiological Evidence in Humans Nociceptive Neurons Innocuous Cooling-Responsive Neurons Stimulation-Induced Pain and Temperature Sensations The Thalamus and Central Neuropathic Pain Physiological Observations in Central Pain Patients Thalamic Bursting Activity Effects of Thalamic Lesions on Pain The Thalamic Pain Syndrome Pharmacology

43.1 Introduction The thalamus has been recognized to play a very important role in the higher-level processing of nociceptive inputs ever since the clinical observations by Dejerine J. and Roussy G. (1906) and Head H. and Holmes G. (1911) of pain resulting from strokes affecting the lateral thalamus. Modern-day anatomical and electrophysiological techniques have provided a wealth of information regarding the processing of nociceptive information at the thalamic level. The concept that medial thalamus is involved in the affective/motivational aspect of pain and the lateral thalamus in the sensory/discriminative aspect of pain

635 635 636 636 636 637 638 638 638 638 638 639 639 640 640 642 643 643 644 644 645 647 647 647 647 648 649 650

originated with the comprehensive analysis of 23 thalamic pain patients by Head and Holmes, and it was emphasized particularly by Melzack R. and Casey K. L. (1968). For many years, the available anatomical and physiological evidence suggested that these functions be ascribed to indirect spinoreticulothalamic (paleospinothalamic) input to medial thalamus and direct (neospinothalamic) spinothalamic tract (STT)mediated input to somatosensory lateral thalamus, which was most prominent in humans. However, the recent evidence summarized below indicates that lamina I STT input to distinct portions of medial and lateral thalamus can be directly associated with these functions. 635

636 The Thalamus and Nociceptive Processing

This chapter will review the major findings relating to the anatomy, physiology, and pharmacology of thalamus with respect to understanding its role in the mediation of acute and chronic pain. The chapter will start with an overview of thalamic anatomy and the termination sites of ascending somatosensory pathways focusing on the STT in the primate. Then the physiological findings in animals will be summarized, followed by discussions of findings in humans and a summary of thalamic pharmacology.

43.2 Comparative Anatomical Findings In contrast to spinal cord, there are significant species differences in the anatomy of the pathways and the nuclei mediating nociception at the thalamic level. This chapter will focus on findings from primates including humans and will commence with a description of the thalamic termination sites of ascending pathways involved in the transmission of nociceptive information. The major pathway involved in the relay of nociceptive and thermoreceptive information is the STT and the functionally equivalent component of the trigeminothalamic tract (TTT) that originates in the medullary dorsal horn (subnucleus caudalis of the trigeminal spinal tract nucleus, also termed the medullary dorsal horn). Although the STT is frequently described as a single tract, this chapter will describe separately the terminations of its two components, the lateral and the ventral. The lateral STT originates largely from lamina I of the superficial dorsal horn and contains many neurons responding specifically to noxious stimuli and innocuous thermoreceptive neurons. In contrast, the ventral STT originates largely from neurons in deeper layers, most of which respond to innocuous tactile and proprioceptive inputs in addition to nociceptive inputs (Craig, A. D. and Dostrovsky, J. O., 1999; Craig, A. D., 2003). 43.2.1 Thalamic Nuclei Receiving Direct Spinothalamic Tract Inputs There are six major regions of termination of the STT and TTT within the primate thalamus: the ventroposterior nucleus (VP), the posterior portion of the ventromedial nucleus (VMpo), the ventrolateral nucleus (VL), the central lateral nucleus (CL), the parafascicular nucleus (Pf), and the

ventrocaudal portion of the medial dorsal nucleus (MDvc) (Mehler, W. R., 1969; Boivie, J., 1979; Berkley, K. J., 1980; Craig, A. D., 2003; 2004). Each of these is described in more detail below.

43.2.1.1

Ventroposterior nuclei The VP that comprises the ventroposterior lateral (VPL) and ventroposterior medial (VPM) nuclei receives its major ascending afferent input from the medial lemniscus and is the main relay nucleus for tactile and kinesthetic information. This nucleus is also frequently termed the ventrobasal complex and in the human, the ventrocaudal nucleus (Vc) (Hassler, R., 1959; Mehler, W. R., 1966; Jones, E. G., 1990). However, it is well established that the STT and TTT also have terminations in this region. The STT terminations in VP form clusters (also referred to as archipelago), which are especially dense along its caudal border with the posterior group and pulvinar and along its rostral border with the VL and near the laminae that occur within VP (Stepniewska, I. et al., 2003). The terminations are roughly in register with the detailed somatotopic organization of the low-threshold mechanoreceptive (LTM) lemniscal terminations and thalamocortical neurons, with craniofacial inputs to VPM, arm/forelimb inputs to medial VPL, and leg/hindlimb inputs to lateral VPL. Some of the STT axons terminating in VP also send a collateral into the CL (Applebaum, A. E. et al., 1979; Giesler, G. J. Jr. et al., 1981). The main source of STT and TTT terminations in VP is from the neurons in the deep dorsal horn (laminae IV and V) as shown in Figure 1(b). Interestingly, these terminations appear directed to VP neurons that are immunopositive for calbindin in contrast to the lemniscal afferents from the dorsal column nuclei (DCN) and principal trigeminal nucleus, which terminate in the vicinity of neurons that are immunopositive for parvalbumin (Rausell, E. and Jones, E. G., 1991). Furthermore, the calbindinimmunopositive neurons project to the superficial layers of cortex, whereas the parvalbumin neurons project to the middle layers (Gingold, S. I. et al., 1991; Rausell, E. and Jones, E. G., 1991). Another difference between spinothalamic and lemniscal terminations is that the latter but not the former form triadic synapses with GABAergic presynaptic dendrites (Ralston, H. J., III and Ralston, D. D., 1994). These differences suggest that the spinothalamic nociceptive inputs are processed differently than the innocuous mechanoreceptive inputs in VP.

The Thalamus and Nociceptive Processing

(a)

637

(b)

Area 24c

le apsu nal c Inter

le apsu nal c Inter Lenticular nucleus

S1

Area 3a Dorsal posterior insula

MDvc Thalamus

VPI

S2

Lenticular nucleus

CL Thalamus

VMpo Midbrain Pons

VPL VPI

S2

Midbrain

PAG

Pons

PB

??

A6/A7 Medulla

Medulla A1/C1/A5 Lamina V

Lamina 1 COLD HPC

SRD

Lateral STT

NS

WDR LT Anterior STT

Figure 1 A schematic summary diagram of the ascending projections from the spinal cord to the thalamus and on to the cortex. (a) The lateral spinothalamic tract arising from nociceptive (HPC and NS) and innocuous thermoreceptive (COLD) neurons in lamina I. The major thalamic termination sites are in the posterior part of the ventromedial nucleus (VMpo), ventroposterior inferior nucleus (VPI), and the ventrocaudal part of the medial dorsal nucleus (MDvc). Also shown are the brainstem terminations in the ventrolateral medulla (A1/C1/A5), the dorsolateral pons (A6/A7), the parabrachial nucleus (PB), the periaqueductal gray (PAG), and the cortical projections of the thalamic sites receiving the lamina I inputs. (b) The ascending projections of lamina IV–V cells, primarily wide dynamic range (WDR) neurons and low-threshold mechanoreceptive (LTM) neurons, via the ventral spinothalamic tract (STT) to the VPI, ventroposterior lateral nucleus (VPL), ventrolateral nucleus (VL), and central lateral nucleus (CL). Terminations also occur in the brainstem in the subnucleus reticularis dorsalis (SRD) and other sites, probably including the reticular core. Adapted with permission from Craig, A. D. and Dostrovsky, J.O. 1999. Medulla to Thalamus. In: Textbook of Pain (eds. P. D. Wall and R. Melzack), pp. 183–214. Churchill-Livingstone.

Immediately ventral to VPL and VPM lies the ventroposterior inferior nucleus (VPI; roughly equivalent to the parvicellular part of the ventrocaudal nucleus (Vcpc) in humans). Curiously, this nucleus receives STT and TTT inputs from neurons located not only in laminae IV and V but also in lamina I, as well as from vestibular afferents (Ralston, H. J., III and Ralston, D. D., 1992). The VPI projects to secondary somatosensory cortex (SII) and retroinsular (vestibular) cortex (Friedman, D. P. and Murray, E. A., 1986; Stevens, R. T. et al., 1993). Species differences . In the rat, there are STT and TTT terminations throughout VP (Mehler, W. R., 1969; Peschanski, M., 1984), which originate from both superficial and deep layers of the dorsal horn. In contrast, in the cat, the STT and TTT terminate along the ventral aspect of VPL (and VPI and the basal part of the ventromedial nucleus (VMb)) and there are

almost no terminals within VP (Berkley, K. J., 1980; Craig, A. D. and Burton, H., 1985). 43.2.1.2 Posterior part of the ventromedial nucleus

Recent studies in the monkey have revealed that there is a very prominent and dense projection from STT and TTT neurons in lamina I to a region that has been termed the posterior ventromedial nucleus (VMpo), which lies immediately posterior and inferior to VP and is contiguous rostrally with the VMb (Craig, A. D., 2004). Of particular interest and importance are the findings that the STT and TTT terminations are topographically organized (Craig, A. D., 2003; 2004) and that the VMpo neurons project in a topographic manner to the dorsal posterior insula, a region that is consistently activated by thermal and nociceptive stimuli. The VMpo is the

638 The Thalamus and Nociceptive Processing

major projection target of the lamina I neurons in the primate, which comprise its almost exclusive ascending sensory input (Figure 1(a)). The trigeminal inputs terminate anteriorly and lumbar inputs most posteriorly. This anteroposterior topographic arrangement contrasts with the mediolateral topography of the VP. The dense lamina I STT and TTT terminations in VMpo are clearly delineated with the use of immunohistochemical labeling for calbindin. A region of calbindin-positive terminal labeling has been observed in a comparable location in the human thalamus (Blomqvist, A. et al., 2000) and corresponds with the area of dense STT terminations observed in thalamus following cordotomies performed to alleviate pain (Mehler, W. R., 1966). This region can also be delineated in monkeys and humans based on its different cytoarchitecture. Electron microscopy has revealed that the glutamatergic STT and TTT terminations form triadic synapses with the VMpo relay cell dendrites and GABAergic presynaptic dendrites (Beggs, J. et al., 2003). This is similar to the termination of lemniscal afferents in VP but contrasts with the STT terminations in VP. The triadic contacts are believed to provide high synaptic security and temporal fidelity. VMpo was not specifically identified in earlier anatomical studies, but the region was included in the caudal VP (Mehler, W. R., 1966), the Vc portae (Hassler, R., 1970), and the posterior complex (Po) ( Jones, E. G., 1990). Species differences. In the cat, there is a sparse lamina I terminal field in the ventral VMb, and this may constitute a primordial homologue of the primate VMpo. In support of this notion is the fact that lesions to this part of VMb in the cat disrupt discriminative thermal sensation (Norrsell, U. and Craig, A. D., 1999) and that it projects to insular cortex (Clasca, F. et al., 1997). A homologous region does not appear to exist in the rat. 43.2.1.3

Ventral lateral nucleus Moderately dense STT terminations are observed extending rostrally from VP into caudal VL in cats and monkeys that overlap with inputs from the cerebellum (Berkley, K. J., 1980; Stepniewska, I. et al., 2003). These inputs probably originate from neurons in the deep dorsal horn and ventral horn (laminae V and VII). VL projects to the motor cortex (Jones, E. G., 1985), and this STT component is most likely related with sensorimotor integration rather than nociception.

43.2.1.4

Parafascicular nucleus The centre´ median (CM) and Pf regions are frequently cited as playing a major role in nociception. However, there is only a weak STT projection to Pf that originates from lamina I and V cells, and more recent anatomical studies fail to confirm earlier reports of STT terminations in CM. The Pf and CM nuclei appear to be involved in motor-related processing as their main connections are with the basal ganglia, substantia nigra, and motor cortex (Jones, E. G., 1985; Royce, G. J. et al., 1989; Sadikot, A. F. et al., 1992). 43.2.1.5

Medial dorsal nucleus Recent studies in the monkey reveal moderately dense STT and TTT projections to the MDvc. The terminals are topographically organized along an anteroposterior axis, with trigeminal input located most posteriorly. The cells of origin of this projection are in lamina I of the spinal and medullary dorsal horn (Ganchrow, D., 1978; Craig, A. D., 2004). Cells in MDvc project to area 24c in the cortex at the fundus of the anterior cingulate sulcus (limbic motor cortex), rather than to the orbitofrontal and prefrontal cortex where the remainder of medial dorsal nucleus (MD) projects (Ray, J. P. and Price, J. L., 1993; Craig, A. D., 2003). It is likely that this region of MD plays an important role in mediating the affective/motivational aspect of pain. There appears to be no homologous region in the cat or rat (see Section 43.2.1.7). 43.2.1.6

Central lateral nucleus Dense STT terminations are observed in the caudal part of CL and in some other portions of the nucleus. The cells of origin are located in laminae V and VII (Applebaum, A. E. et al., 1979; Giesler, G. J., Jr. et al., 1981; Craig, A. D., Jr. et al., 1989). Projections from different regions of the spinal cord terminate in different cell clusters but do not appear to be topographically organized (Craig, A. D. and Burton, H., 1985). This nucleus also receives projections from the cerebellum, tectum, substantia nigra, and globus pallidus. Most of the neurons in this region project to the basal ganglia, but there are also projections to the superficial and deep layers of posterior parietal and motor cortices (Jones, E. G., 1985; Royce, G. J. et al., 1989). The function of the STT input to this nucleus is unknown, but one can speculate that it may be involved in motor set, attention, and orientation. Similar STT terminations have been observed in cats, rats, and other vertebrates.

The Thalamus and Nociceptive Processing

43.2.1.7

Nucleus submedius In the cat, there are dense and topographically organized terminations of the TTT and STT arising from spinal and medullary dorsal horn lamina I neurons in the medial thalamic nucleus submedius (Sm). Although Sm originates developmentally from the pronucleus of MD, it projects to the ventrolateral orbital cortex rather than to the cingulate cortex and thus constitutes a major phylogenetic difference from the lamina I projection to MDvc in the primate (Craig, A. D., Jr. et al., 1982; Coffield, J. A. et al., 1992). In the cat, the spinal input to the anterior cingulate relays in the ventral VP (Musil, S. Y. and Olson, C. R., 1988; Yasui, Y. et al., 1988) and also indirectly by way of the parabrachial nucleus (PB) (Devinsky, O. et al., 1995). In the rat, input to Sm originates primarily from trigeminal cells at the junction of the caudalis and interpolaris subnuclei of the trigeminal spinal tract nucleus and from trigeminal and cervical lamina I cells, as well as other cells in the spinal cord (Dado, R. J. and Giesler, G. J., Jr., 1990; Yoshida, A. et al., 1992).

43.2.2 Indirect Nociceptive Pathways to the Thalamus In addition to the STT, there are several polysynaptic pathways that may be involved in relaying nociceptive signals to the thalamus. First, the postsynaptic dorsal column pathway comprises dorsal horn neurons located primarily in laminae IV–VI and X whose axons ascend ipsilaterally in the superficial dorsolateral funiculus and deep dorsal columns and terminate in the ventral and rostral portions of the DCN (gracile and cuneate nuclei). These portions of the DCN have projections to motorrelated regions of the brainstem rather than to VP (Brodal, A., 1982; Willis, W. D., 1985; Berkley, K. J. et al., 1986). Although most of the neurons in this pathway respond only to nonnoxious cutaneous mechanical stimuli, some respond also to noxious stimuli. Some of the nociceptive neurons in this pathway convey visceral activity in the rat and possibly also in the primate (Al-Chaer, E. D. et al., 1998; see also Villanueva, L. and Nathan, P., 2000). However, functional imaging studies of visceral pain in humans reveal a pattern of activation that does not appear consistent with the hypothesis that this pathway is important for visceral pain in humans (e.g., Strigo, I. A. et al., 2003). Second, the spinocervicothalamic tract comprises dorsal horn neurons whose axons ascend ipsilaterally in the

639

dorsolateral funiculus and terminate in the lateral cervical nucleus that is located at the level of C1-2 just lateral to the superficial dorsal horn (Boivie, J., 1983). The neurons of the lateral cervical nucleus project to the contralateral VP via the medial lemniscus. This pathway is prominent in the cat and raccoon but very small in the primate. Some of the neurons in this pathway respond to nociceptive stimuli although most respond only to innocuous stimuli (Kajander, K. C. and Giesler, G. J., Jr., 1987; Downie, J. W. et al., 1988). Third, evidence obtained in the rat indicates that spinal input to a dorsal reticular region in the caudal medulla is relayed by way of a portion of the ventromedial nucleus to layer 1 of widespread regions of the frontal cortex (Desbois, C. et al., 1999; Desbois, C. and Villanueva, L., 2001). This region also has a descending projection to the deep dorsal horn of the spinal cord. Modulation of activity, such as those associated with alerting responses, is suggested as a potential function, but whether this pathway exists in primates and humans is unknown. Fourth, a spinoreticulothalamic pathway (paleospinothalamic tract) was hypothesized long ago to accommodate clinical observations made in patients with thalamic pain syndrome (see below). Modern evidence indicates that spinal terminations in the brainstem reticular formation do not overlap with the locations of cells that project to thalamus, except within the PB (Blomqvist, A. and Berkley, K. J., 1992). The PB receives contralateral spinal input and ipsilateral trigeminal input that originates mainly from lamina I but also from lamina V cells. There is only a crude topography, and although there is considerable anatomical overlap with ascending homeostatic afferent input from the nucleus of the solitary tract, evidence in the rat indicates that nociceptive neurons are mainly modality selective (Bernard, J. F. and Besson, J. M., 1990). In primates, PB projects mainly to VMb in the thalamus, as well as to hypothalamus and amygdala, but in rats, it projects more broadly within medial thalamus and to various cortical regions associated with autonomic control.

43.3 Comparative Physiological Findings The previous section described the pathways and thalamic termination sites of spinal and trigeminal neurons that include nociceptive neurons. On this basis, one would expect to find neurons in the

640 The Thalamus and Nociceptive Processing

thalamic termination sites that would also respond to noxious inputs, and this is particularly the case for the regions receiving inputs from lamina I. There have indeed been many reports of nociceptive neurons in lateral, posterior, and medial areas of the thalamus. However, it should be kept in mind that the existence of neurons responding to noxious stimuli in a given region of thalamus does not necessarily signify that the region is involved in mediating the sensations of pain that would be expected to be elicited by noxious stimuli giving rise to the noxious responses. For example, the responses could be related to arousal, attentional, and motor consequences of the noxious stimulus. The following section will summarize the physiological findings reported for each of the main thalamic regions receiving nociceptive inputs. 43.3.1

Ventroposterior Nuclei

As mentioned earlier, the VPL and VPM are the main thalamic targets for innocuous tactile information ascending via the medial lemniscus from the DCN and principal trigeminal nucleus. It is thus not surprising that most of the neurons in this region respond exclusively to innocuous low-threshold mechanical cutaneous inputs. These neurons are organized in a high-resolution somatotopic fashion and project primarily to areas 3b and 1 of primary somatosensory (SI) cortex. There is an anterior and dorsally located shell that contains neurons responding to deep, muscle and joint afferent inputs, and this proprioceptive information is relayed to areas 3a and 2 of SI cortex (Kaas, J. H. et al., 1984; Jones, E. G., 1990). It is generally considered that VP is the main relay nucleus for nociceptive inputs involved in mediating the sensory aspects of pain (localization and intensity discrimination) (Melzack, R. and Casey, K. L., 1968; Willis, W. D., 1985), since it receives STT inputs (primates and rodents, but not carnivores) and projects to the somatotopically organized SI cortex. Indeed, there have been many reports of nociceptive neurons within VP in the primate and rodent. In the monkey, about 10% of the neurons are nociceptive and most of these are of the wide dynamic range (WDR – responding to both LTM inputs and nociceptive inputs) type (Figure 2) (Willis, W. D., 1985; Apkarian, A. V. and Shi, T., 1994; Willis, W. D. and Westlund, K. N., 1997). They usually have moderately large receptive fields (e.g., more than half of the face or arm), and these are organized in a crude somatotopic manner roughly corresponding to the somatotopy of the intermingled

LTM neurons (Willis, W. D. and Westlund, K. N., 1997). In the monkey, these neurons are concentrated in the posterior part of VP and near the major fiber laminae, consistent with the predominant location of the terminations of the STT and TTT axons of lamina V neurons (Applebaum, A. E. et al., 1979; Boivie, J., 1979; Kenshalo, D. R., Jr. et al., 1980; Casey, K. L. and Morrow, T. J., 1983; Gingold, S. I. et al., 1991; Bushnell, M. C. et al., 1993). Anatomical studies have provided evidence suggesting that the nociceptive neurons project to areas 3b and 1 of SI cortex. Interestingly, these studies suggest that the cortical terminations of these nociceptive neurons are in the most superficial layers of cortex in contrast to the VP LTM neurons whose axons terminate in the middle layer of cortex (Rausell, E. et al., 1992; Shi, T. et al., 1993), indicating a possible modulatory role for these nociceptive inputs. Electrophysiological studies have confirmed that some of these WDR neurons within VP can be antidromically activated from areas 3b and 1 of SI (Kenshalo, D. R., Jr. et al., 1980). Curiously, visceral noxious stimuli activate not only VP WDR neurons but also LTM neurons and do not appear to be somatotopically organized (Chandler, M. J. et al., 1992; Al-Chaer, E. D. et al., 1998). Species differences: In the rat, nociceptive-specific (NS) and WDR nociceptive cells have been reported throughout VP intermixed in a roughly topographic manner with the LTM neurons (Guilbaud, G. et al., 1980). The receptive fields of these nociceptive neurons are generally quite large and often bilateral. Some receive convergent visceral input. In rats with experimentally induced arthritis or neuropathies, increased numbers of WDR VP cells that project to the sensorimotor cortex have been reported (Guilbaud, G. et al., 1990). In contrast to the primate and rodent, in the cat, there are virtually no nociceptive cells within VP proper. However, NS and WDR nociceptive neurons in this species can be found in the dorsal and ventral aspects of VP, the ventral aspect of VMb and VPI. These are the regions where STT and TTT terminations occur (see above). The nociceptive neurons within this shell-like region are organized in a crude mediolateral topographic pattern in parallel (but not in register) with the somatotopy of the adjacent VP. A portion of these neurons receive convergent input from skin, muscle, viscera, tooth pulp, or cranial vasculature (Davis, K. D. and Dostrovsky, J. O., 1988; Bruggemann, J. et al., 1994). Some of these neurons have been shown to project to area 3a of SI, SII, and/or anterior cingulate cortex (Yasui, Y. et al., 1988; Craig, A. D. and Dostrovsky, J. O., 2001).

(a)

641

Squeeze

120

140

(c)

160

The Thalamus and Nociceptive Processing

(b)

Impulses s–1 60 80 100

Pinch

LD LP

Press.

MD Brush

40

CL

20

VPLC CM–Pf

0

P 0

20

40

60 80 Time (s)

100

120

1 mm

(d) 35 °C

(e) 50 °C

(f)

35

50 °C

1 ms 5s

Figure 2 Example of responses of a wide-dynamic-range (WDR) neuron in ventroposterior nuclei (VP). The receptive field on the leg is shown in (a). The location of the recording site in VPLc (VP) is indicated in (b). The histogram (c) shows the responses to graded intensities of mechanical stimulation. This neuron also responded to noxious thermal stimulation (d, e, and f). Modified with kind permission from Kenshalo, D. R., Jr., Giesler, G. J., Jr., Leonard, R. B., and Willis, W. D. 1980. Responses of neurons in primate ventral posterior lateral nucleus to noxious stimuli. J. Neurophysiol. 43, 1594–1614.

43.3.2

Ventroposterior Inferior Nucleus

The neurons in the region located immediately inferior (ventral) to VPL and VPM (VPI) project to SII (Krubitzer, L. et al., 1995) and to retroinsular (vestibular) cortex. Some of the neurons in this region are excited by nociceptive inputs (Figure 3). These WDR and NS neurons are arranged in a topographic representation within this region in the monkey (Apkarian, A. V. and Shi, T., 1994).

43.3.3 Posterior Thalamus and Posterior Part of the Ventromedial Nucleus The posterior thalamus has frequently been implicated in pain processing and has been shown in

various species to contain nociceptive neurons (Albe-Fessard, D. et al., 1985; Willis, W. D., 1985; Willis, W. D., Jr., 1997). Although it was formerly regarded as undifferentiated, more detailed and recent observations in monkeys and humans have described a distinct nucleus that has been termed VMpo. The VMpo has been shown to be the recipient of a major projection from lamina I STT and TTT neurons. In accordance with its lamina I inputs, it has been shown to contain NS and thermoreceptive neurons (Craig, A. D. et al., 1994). Their responses are similar to those of lamina I STT and TTT neurons, and they have small receptive fields that are topographically organized in a rostrocaudal axis, in correspondence with the topographically organized terminations of the afferent inputs (Figure 4).

642 The Thalamus and Nociceptive Processing

Spikes s–1

(a)

80

Brush press. pinch VPL

40 VPM VPl

0 0

Spikes s–1

(b)

180

60 Time (s)

120

Brush press. pinch VPL

90 VPM VPl

0 0

Spikes s–1

(c)

120

60 Time (s)

120

Brush press. pinch Pulo

VPL

60 Po MG

0 0

60 Time (s)

120

Figure 3 Example of responses of nociceptive neurons in ventroposterior inferior nucleus (VPI) and posterior complex (Po). Reproduced with kind permission from Apkarian, A. V. and Shi, T. 1994. Squirrel monkey lateral thalamus. I. Somatic nociresponsive neurons and their relation to spinothalamic terminals. J. Neurosci. 14, 6779–6795.

Neuronal recordings in awake monkeys in the presumed VMpo (originally assumed to be in VPM but subsequently re-interpreted from the original histology to be in VMpo (Craig, unpublished observations) revealed strong correlation between the neuronal activity and the behavioral detection of noxious and innocuous thermal stimuli applied to the face. Furthermore, lidocaine-induced block of activity in this region reduced the monkey’s behavioral responses to these stimuli (Bushnell, M. C. et al., 1993; Duncan, G. H. et al., 1993). Further support for the critical role of VMpo in relaying nociceptive and thermoreceptive information for perception of pain and temperature is the finding that it has a strong and topographic projection to the dorsal margin of the posterior insula (Craig, A. D., 2003), where preliminary fMRI observations in monkeys show strong activation with noxious stimuli (Craig, A. D., 2002). Furthermore, human imaging

studies have consistently found this region of insular cortex to be activated by noxious and thermal stimuli. This rostrocaudally organized topography is distinct from the mediolateral topography observed in SII and in the adjacent parietal operculum (Disbrow, E. et al., 2000). There is also a minor projection from VMpo to area 3a of SI cortex. Species differences. In the cat and rat where there is no clearly differentiated nociceptive and thermoreceptive relay site in the Po, there are nevertheless nociceptive neurons, but they tend to have very large receptive fields and are not arranged in a clear somatotopic fashion (Poggio, G. F. and Mountcastle, V. B., 1960; Carstens, E. and Yokota, T., 1980). This region does receive some lamina I inputs in the cat. In the rat, there is convergent STT input from laminae I and V to the posterior triangular nucleus, which projects to the region of SII and to the amygdala. It is possible that in the rat, nociceptive inputs also arise

The Thalamus and Nociceptive Processing

643

Noceptive single unit

125

Spikes s–1

100 75 50 25 0 0

34

100

39

200 Time (s)

300

43 46 Temperature (°C)

50

400

54

Figure 4 Example of the responses of a posterior part of the ventromedial (VMpo) nociceptive neuron. The histogram shows the graded responses of a single nociceptive-specific neuron to noxious heat pulses applied with a thermode applied to the receptive field on the contralateral ulnar hand. Adapted with kind permission from Craig, A. D., Bushnell, M. C., Zhang, E. -T., and Blomqvist, A. 1994. A thalamic nucleus specific for pain and temperature sensation. Nature 372, 770–773.

via a descending corticothalamic route (Diamond, M. E. et al., 1992; Berkley, K. J. et al., 1993). Furthermore, there is no direct projection to the portion of insular cortex homologous to that targeted by VMpo in the primate. The part of Po dorsal to VP in the cat, where some nociceptive neurons have been reported (Hutchison, W. D. et al., 1992; Bruggemann, J. et al., 1994), projects to area 5a (Jones, E. G., 1985). Nevertheless, in both the cat and the rat, there exists a narrow region along the ventral aspect of VMb that contains nociceptive and visceroceptive neurons and projects to the insular cortex adjacent to the gustatory cortex (Yasui, Y. et al., 1991; Clasca, F. et al., 1997; Norrsell, U. and Craig, A. D., 1999).

43.3.4

Intralaminar Nuclei

As described earlier, several regions in medial thalamus receive direct inputs from the spinal cord and the trigeminal nucleus, but there are also indirect inputs to these regions from the brainstem, and in particular from the PB. Neurons responding to noxious electrical, mechanical, or heat stimuli have been recorded throughout the intralaminar thalamus, in particular in CL and CM–Pf. Most of these recordings have been obtained in anesthetized rats and cats although some recordings have been performed in monkeys (Albe-Fessard, D. et al., 1985; Bushnell, M. C. et al., 1993; Bruggemann, J. et al., 1994). Most of the

nociceptive neurons in this region have large receptive fields that can be bilateral. Studies employing graded natural stimuli have revealed that some of the cells can code for stimulus intensity. Although natural stimulation was used in only some studies, cells with graded responses to noxious heat have been observed. In particular, a study in the awake monkey by Bushnell M. C. and Duncan G. H. (1989) reported the existence of nociceptive neurons in the CM–Pf and CL region that responded in a graded fashion to noxious thermal stimuli applied to the face (Figure 5). It is possible that the responses of at least some of these neurons may be related to attention and arousal rather than to perception of pain. It is interesting that many intralaminar neurons have been shown to respond to eye movements (Schlag, J. and Schlag-Rey, M., 1986), which is consistent with the termination of ascending inputs from the cerebellum and the superior colliculus. Indeed, it has been proposed that this region plays a role in gaze orientation (Jones, E. G., 1985).

43.3.5

Medial Dorsal Nucleus

As mentioned earlier, Craig and colleagues have recently described a direct lamina I input to the MDvc in the monkey. A particular interesting feature of this projection is that the MDvc contains neurons that project to the anterior cingulate cortex (Craig, A. D. and Zhang, E.-T., 1996), a region

644 The Thalamus and Nociceptive Processing

(b) 40

80 47 °C

35

60 Spikes s–1

Mean spikes s–1( ± SE)

(a)

30

47.2 °C + 47.4 °C

40 20

25 0 20

0 46

47 °C

48

49

0

2 T2

s

4 RE

Figure 5 Responses of a neuron in posteromedial thalamus of an awake monkey to noxious thermal stimuli to the face. (a) The mean firing rate to increasing temperatures. (b) A peristimulus histogram with associated dot raster display showing increased firing when the temperature increased from 47  C to 47.2  C or 47.4  C. In this particular example, the monkey did not respond until the end of the trial (RE button release). Adapted with kind permission from Bushnell, M. C. and Duncan, G. H. 1989. Sensory and affective aspects of pain perception: is medial thalamus restricted to emotional issues. Exp. Brain Res. 78, 415–418.

frequently implicated in pain. There is only very limited information regarding the properties of the neurons in MDvc; however, preliminary studies in anesthetized monkeys indicate that it contains a discrete group of NS neurons with large, sometimes bilateral receptive fields (Craig, A. D., 2003). Furthermore, this study reports that their spontaneous firing can be inhibited by innocuous thermal (cool, warm) stimuli. This phenomenon could provide an explanation for the well-known cold-induced inhibition of pain and the thermal grill illusion of pain (see below). It is possible that some of the recordings of nociceptive neurons in medial thalamus in the study of Bushnell M. C. and Duncan G. H. (1989) mentioned above may also have included neurons located in MDvc. Species differences. Whereas in the monkey (and presumably the human), the STT and the TTT project to MDvc, in the cat and the rat, there is a projection that originates mainly in lamina I to the developmentally related Sm. Several studies have reported the existence of NS neurons in Sm in the rat (Dostrovsky, J. O. and Guilbaud, G., 1988; Coffield, J. A. and Miletic, V., 1993; Kawakita, K. et al., 1993). Receptive fields are generally quite large and some have inputs from deep tissues. In the Freund’s adjuvant-induced arthritic rat, many Sm cells were found to respond to joint movements, which are normally not effective in activating the Sm neurons

(Dostrovsky, J. O. and Guilbaud, G., 1988). Various studies in the rat that have examined the effects of lesioning or electrically and chemically induced excitation of Sm have provided evidence for a role of Sm and its cortical target VLO in the activation of descending antinociceptive pathways by way of the periaqueductal gray (PAG) (Roberts, V. J. and Dong, W. K., 1994; Zhang, S. et al., 1998). Although it has been shown in the cat that there is also a projection from innocuous thermoreceptive cool lamina I STT neurons in addition to the NS neurons (Craig, A. D. and Dostrovsky, J. O., 2001), neurons excited by cooling stimuli have not been found. It is possible, however, that inputs from these neurons may provide a basis for the cold-induced inhibition of nociceptive processing, similar to MDvc of the primate (Ericson, A. C. et al., 1996).

43.4 Direct Physiological Evidence in Humans Functional stereotactic surgery for the treatment of chronic pain or tremor provides a unique opportunity to record and stimulate in the thalamus of awake patients. There have been several studies that have provided information of interest in terms of furthering our understanding of the role of thalamus in pain and these are described below.

The Thalamus and Nociceptive Processing

43.4.1

Nociceptive Neurons

thalamus. It is difficult to evaluate these old reports since few details were provided and more recent studies have not been able to confirm the findings (Lenz, F. A. et al., 1997). However, there have been very few opportunities to record from neurons in medial thalamus, and the number of neurons that can be tested with noxious stimuli in the awake patient is limited, and this may account for the lack of definitive evidence.

Lenz and colleagues have searched for neurons in VP (often termed Vc in humans) and the immediately adjacent posterior and inferior region of thalamus. Although most of the neurons in Vc respond only to nonnoxious mechanical stimulation of the skin (LTM neurons), they reported that some neurons also had an increased response to noxious mechanical stimuli and some responded weakly to noxious or innocuous thermal stimuli in addition to innocuous tactile stimuli (i.e., WDR neurons) (for review, see Lenz, F. A. and Dougherty, P. M., 1997; Lee J. et al., 1999). These WDR neurons were primarily located in the posteroinferior portion of VP. In the adjoining posteroinferior area, which includes VMpo (Blomqvist, A. et al., 2000), they found NS neurons that responded to noxious heat but no LTM neurons (Lenz, F. A. et al., 1993a). Although nociceptive neurons have frequently been reported in medial thalamus of anesthetized animals, there have only been a few old reports of neurons responding to noxious stimuli in awake human medial

43.4.2 Innocuous Cooling-Responsive Neurons Neurons responding selectively to innocuous cooling of the skin have been found in the human thalamic region located medial and posteroinferior to VP, which likely corresponds to VMpo (Davis, K. D. et al., 1999). These neurons had discrete receptive fields on the contralateral body and responses similar to those of lamina I spinal and trigeminal neurons (Figure 6(a)). This finding is consistent with the findings in animals, where cooling-specific neurons have only been found

(a1)

(b)

30

10

20 10

8

8 Cool rating

Spikes 100 ms–1 Temperature (°C)

645

6 4 2 0

6

4

10 s (a2)

2

35° 10° 0 0

2

4

6

20 30 40 50 8 10 12 14 Stimulus intensity (μA)

1s Figure 6 (a1) Recording from a single neuron in the presumed posterior ventromedial nucleus (VMpo) region in an awake patient showing responses to cooling stimuli applied to receptive field on the fifth digit. The top trace shows the temperature of the thermode with increasing cooling steps. The bottom trace is a histogram of the neuronal firing showing graded responses to the increasing cooling steps. (a2) Segment of raw trace of neuronal recording from (a1) showing response to first part of a cooling step. (b) Thalamic stimulation evoked cool sensations. Verbal ratings (0–10 scale) of the innocuous cool sensations evoked by threshold and suprathreshold intensities of thalamic microstimulation obtained in eight patients. Figurines adjacent to each line depict the location of the thalamic stimulation-evoked sensation at threshold. Reprinted with kind permission from Davis, K. D., Lozano, R. M., Manduch, M., Tasker, R. R., Kiss, Z. H., and Dostrovsky, J. O. 1999. Thalamic relay site for cold perception in humans. J. Neurophysiol. 81, 1970–1973.

646 The Thalamus and Nociceptive Processing

in the cat medial VPM and in the monkey VMpo. Animal studies have also shown that cooling-specific neurons are found only in lamina I of the trigeminal medullary dorsal horn (nucleus caudalis) and spinal dorsal horn. Thus, the existence of cooling-specific neurons in the human VMpo is consistent with the evidence cited above that this region receives a major input from lamina I neurons. The close association of pain and temperature further supports an important role of VMpo in the relay of pain signals in the human. 43.4.3 Stimulation-Induced Pain and Temperature Sensations The electrophysiological studies in human patients during stereotactic surgery provide a unique

RF

Depth (mm)

lntensity PF (μA)

2.0 P 5

1.5 P 6

opportunity to determine the sensations evoked by electrical stimulation within the brain, since these are performed with the patient awake. As might be expected, electrical stimulation (1 s trains of 100–300 Hz) within VP and adjacent regions of the thalamus usually evokes innocuous paresthesia. These sensations, which can be elicited by low stimulus intensities (e.g., 2 mA), are perceived as originating from a small region of the contralateral side of the body (Figure 7). The projected fields are usually in register with the receptive fields of the neurons recorded at the stimulation site. Increasing the intensity of stimulation results in an increase in the perceived intensity of sensation and usually also with an increase in the projected field size, but although the sensation can be very

0 P 5

P 12

P 24

P 48

1.3

1.0 P 10

–0.6 P 12

–1.0 N 14 –1.2 N 3

0.6

Deep

0.3 P 8

–1.4 N 5 –1.6 P 9

P 16

P 10

P, N 20

N 24

Sharp jabbing

Sharp jabbing Sharp

N 10 Sharp jabbing, deep N 12

Sharp

Quick and sharp

–1.8 P 7

N = pain P = paresthesia Figure 7 Stimulation-evoked pain in a chronic pain patient (causalgia left arm). The diagram shows a reconstruction of an electrode track through the ventrocaudal nucleus and on into the posteroinferior region, showing the locations of the receptive fields (RF) of the low-threshold mechanoreceptive neurons recorded at sites along the electrode track on the left of the vertical line and the projected fields (PF) induced by stimulation on the right side. The electrode track has been broken down into two contiguous segments. Depths of recordings are indicated in millimeters to the left of the line at each recording/stimulation site. While the electrode was in ventrocaudal nucleus (Vc), as evidenced by the low-threshold mechanoreceptive fields, stimulation induced nonpainful paresthesia (P). However, at the bottom of the Vc (0) and at deeper sites, stimulation induced painful sensations (N).

The Thalamus and Nociceptive Processing

intense, it is not usually reported as painful. Nevertheless, stimulation at some sites in some patients is reported as eliciting a distinct painful and/or temperature sensation even at the threshold for sensation (Hassler, R. and Riechert, T., 1959; Halliday, A. M. and Logue, V., 1972; Tasker, R. R., 1984; Lenz, F. A. et al., 1993b; Davis, K. D. et al., 1996; Dostrovsky, J. O. et al., 2000). These sites are generally located near the posterior–inferior border of VP and extend several millimeters posterior, inferior, and medial to it (Figure 7). The incidence of sites where pain and/or thermal sensations can be evoked is much higher in the posteroinferior region than within VP (except in poststroke pain patients – see below). The sensations are always on the contralateral side of the body and can arise from a small region. The sensations are reported as being quite natural in contrast to the paresthesia (tingling or shock-like) sensations evoked within VP. There have been reports of cases where thalamic stimulation evoked pain arising from deep or visceral sites although these are rare (Lenz, F. A. et al., 1994; Davis, K. D. et al., 1995). Interestingly, Lenz and colleagues found that microstimulation within VP at sites where WDR neurons responding to noxious mechanical stimuli were found rarely elicited pain or temperature sensations, whereas at the sites in the region posteroinferior to VP where stimulation evoked pain, there was a high likelihood of finding nociceptive neurons (Lenz, F. A. and Dougherty, P. M., 1997). It seems likely that the sites in the region posteroinferior to VP where stimulation evokes pain and temperature are close to or in VMpo. It is also notable that at the sites where neurons responding selectively to cooling stimuli were found, microstimulation evoked cooling sensations arising from the same area of skin where the receptive fields of the neurons were located (Figure 6(b)). Increasing the stimulus intensity at such sites increased the intensity of the cold sensation (i.e., it felt colder). There have been few studies of the effects of stimulation in medial thalamus. A few studies reported that stimulation in the posterior aspect of medial thalamus can evoke pain (Sano, K., 1979; Jeanmonod, D. et al., 1994). However, in most cases the stimuli were delivered from large-tipped electrodes and the sensations were only elicited at high current intensities, so current spread (e.g., to the STT) is an issue. Several more recent studies have failed to replicate these findings.

647

43.5 The Thalamus and Central Neuropathic Pain 43.5.1 Physiological Observations in Central Pain Patients There have been many studies that have demonstrated the marked plasticity of the brain and in particular the alterations in neuronal properties and somatotopic organization at all levels of the somatosensory system subsequent to peripheral or central damage to the ascending pathways (Wall, J. T. et al., 2002). Although much less is known about the plasticity of the pain system, especially at the thalamic and cortical levels, it is reasonable to expect that marked changes will occur following damage to ascending nociceptive pathways. Indeed, there have been several animal studies that examined the effects of STT damage on thalamic physiology (Weng, H. R. et al., 2000; 2003). Studies in patients who have sustained deafferentation due, for example, to amputation or spinal cord injury provide evidence for plasticity (Lenz, F. A. et al., 1994; Davis, K. D. et al., 1998). For example, there is evidence suggesting expansion of the representation of intact regions into deafferented regions of VP thalamus. Micro-stimulation in such regions was found to evoke sensations arising from the phantom limb in amputees or to the deafferented body region in spinal injury patients (Lenz, F. A. et al., 1994; Davis, K. D. et al., 1998). Although these stimuli usually resulted in nonpainful paresthesia rather than pain, these types of changes may be involved in the development of chronic pain in these types of patients. Of particular interest have been the findings of two studies that found changes in the stimulation-evoked sensations in poststroke pain and some other types of chronic central pain patients. The incidence of stimulation sites in VP where stimulation evoked sensations in such patients was markedly elevated (Lenz, F. A. et al., 1998; Dostrovsky, J. O. et al., 2000). In addition, there was an increase in the number of sites in the posteroinferior region where pain sensations were evoked and a decrease in sites where innocuous thermal stimuli were evoked (Figure 8). These findings provide further evidence suggesting that there have been alterations in the thalamic and cortical processing of somatosensory inputs leading to increased perception of pain. It is interesting, however, that deep brain stimulation within thalamus (Siegfried, J., 1987; Kupers, R. C. and Gybels, J. M., 1993) can alleviate the pain in some of these chronic pain patients, possibly by disrupting the pathological patterns and balance of activity in these regions.

648 The Thalamus and Nociceptive Processing

(a)

(b) 25

25 P < 0.0001

20

Motor (n = 345) NSP (n = 156) PSP (n = 73)

P < 0.0001

15 10 5

% of total stimulation sites in postero inferior region

% of total stimulation sites in Vc nucleus

30

Motor (n = 1642) NSP (n = 790) PSP (n = 388)

20

15

P < 0.0001 P < 0.001

P < 0.001

10 P < 0.001

5

0

0 Pain

Temperature

Pain

Temperature

Figure 8 Bar graphs showing the incidence of sites in the ventrocaudal nucleus (a) and the posteroinferior region (b) where stimulation evoked sensations of pain or innocuous temperature in movement disorder patients (Motor), chronic nonpoststroke pain patients (NSP), and poststroke pain patients (PSP). Reprinted with kind permission from Dostrovsky, J. O., Manduch, M., Davis, K. D., Tasker, R. R., Lozano, A. M. 2000. Thalamic Stimulation-Evoked Pain and Temperature Sites in Pain and Non-pain Patients. In: Proceedings of the 9th World Congress on Pain (eds. M. Devor, M. C. Rowbotham, and Z. Wiesenfeld-Hallin), pp. 419–425. IASP Press.

43.5.2

Thalamic Bursting Activity

Thalamic neurons switch to a bursting mode when they are hyperpolarized. This bursting activity is generated by activation of low-threshold T-type calcium channels that give rise to a calcium spike and a burst of sodium channel-generated action potentials (so-called LTS bursting). This bursting activity is generally only observed during sleep. However, recordings in medial and lateral thalamus of chronic pain patients during the awake state revealed the existence of neurons firing in typical calcium spike-mediated bursts (Lenz, F. A. et al., 1989; Jeanmonod, D. et al., 1993; Lenz, F. A. et al., 1994). It was proposed that this activity may be related to the patients’ chronic pain and in fact may mediate the spontaneous pain in these patients (Lenz, F. A. and Dougherty, P. M., 1997; Llinas, R. R. et al., 1999). However, similar LTS firing in similar regions of thalamus can also be observed in patients without pain and thus is not specific to pain ( Jeanmonod, D. et al., 1996; Radhakrishnan, V. et al., 1999). More recently, Llinas R. R. et al. (1999) have proposed that LTS bursting in thalamus may be the cause of many different neurological diseases including chronic pain and have termed this condition thalamic dysrhythmia. Nevertheless, the role of LTS bursting in chronic central pain remains unclear. It has been proposed that central neuropathic pain may be mediated by reduced GABAergic inhibition in the thalamus (Roberts, V. J. and Dong, W. K.,

1994). Studies in the primate have found that following chronic cervical rhizotomy there is a downregulation of thalamic GABAA receptors (Rausell, E. et al., 1992), providing some support for this suggestion. On the other hand, several positron emission tomography (PET) studies have obtained evidence suggesting that chronic neuropathic pain is associated with decreased blood flow, suggesting decreased activity (Apkarian, A. V. et al., 2005).

43.5.3 Effects of Thalamic Lesions on Pain There have been many studies since the original pioneering studies of Dejerine and Roussy and Head and Holmes which have documented that strokes affecting the lateral thalamus can lead to central pain (poststroke pain and thalamic pain syndrome) (Pagni, C. A., 1998). In addition, infarcts and lesions that involve the posteroinferior region can also result in analgesia and thermanesthesia (Head, H. and Holmes, G., 1911; Hassler, R. and Riechert, T., 1959; Hassler, R., 1970; Tasker, R. R., 1984). Lesions have been purposefully made in medial thalamus of chronic pain patients for relief of their pain (Gybels, J. M. and Sweet, W. H., 1989). However, such procedures are rarely undertaken at the present time as most neurosurgeons do not believe that they are effective. It is possible, however, that in some of

The Thalamus and Nociceptive Processing

the reported successes the lesions may have included MDvc and/or VMpo (Jeanmonod, D. et al., 1994; Lenz, F. A. and Dougherty, P. M., 1997). Interestingly, lesions in medial thalamus that spare the lateral thalamus and STT do not appear to cause central pain (Bogousslavsky, J. et al., 1988). 43.5.4

The Thalamic Pain Syndrome

The poststroke central (thalamic) pain (CPSP) syndrome was first recognized by Dejerine and Roussy, and it has been comprehensively analyzed clinically by Head H. and Holmes G. (1911), Riddoch G. and Critchley Mc. D. (1937), Schott B. et al. (1986), Boivie J. (1994), Pagni C. A. (1998), and others. The first patients had lesions confined to the thalamus, and so the syndrome was first called thalamic pain. However, patients with central pain have lesions that interrupt the ascending lateral STT – lamina I – spinothalamocortical pathway by way of VMpo to the dorsal posterior insula at any level (Schmahmann, J. D. and Leifer, D., 1992; Pagni, C. A., 1998; Craig, A. D., 2003). Such lesions produce loss of pain and temperature sensation, but in about half of such cases, this disruption results, immediately or after a variable delay, in the paradoxical appearance of ongoing pain in the deafferented region. Head and Holmes inferred that this meant that pain sensation occurred in the thalamus, but we now know that the thalamus serves mainly as a relay for activity ascending to the cortex. This syndrome likely results from disruption of the interactions at cortical and subcortical levels between components of the pain processing network. One such interaction is the inhibition caused by cooling on pain, and it has been suggested that interruption of this interaction could cause central pain by disinhibition (Craig, A. D., 1998). The suggestion is based on similarities with the thermal grill illusion of pain, in which reduced activity in coolingspecific lamina I STT neurons can unmask the coldactivated burning pain elicited by polymodal nociceptive lamina I STT neurons (HPC) in the anterior cingulate cortex. A study of thermal sensation in a central pain patient directly supports that hypothesis (Morin, C. et al., 2002). A recent imaging study of a central pain patient suggested that the posterolateral thalamic lesion did not involve VMpo but that conclusion was incompatible with the patient’s loss of thermal sensation (cf. Craig, A. D. et al., 2000; Montes, C. et al., 2005). The indirect ascending nociceptive input to the medial thalamus by way of the PB may also play a role in central pain.

649

43.6 Pharmacology The pharmacology of thalamic nociceptive neurons has not been extensively studied. However, it is reasonable to assume that they share many common features with those of other thalamic neurons about which much more is known. The two most important transmitters are glutamate and GABA (McCormick, D. A., 1992; Steriade, M. et al., 1997; Sherman, S. M. and Guillery, R. W., 2001). Glutamate is released by the ascending axons of medial lemniscal and STT and TTT pathways to excite thalamocortical neurons. The released glutamate acts at both NMDA and non-NMDA (AMPA and/ or kainate) ionotropic glutamate receptors. In the cat and primate, there are also many interneurons within the thalamus and these also receive glutamatergic inputs from these afferents that activate in addition to the ionotropic receptors and metabotropic glutamate receptors (Jones, E. G., 1985; Magnusson, K. R. et al., 1987; Ericson, A. C. et al., 1995; Blomqvist, A. et al., 1996; Sherman, S. M. and Guillery, R. W., 2001). The thalamocortical neurons also receive a massive glutamatergic projection from layer 6 of the cortex, which activates both ionotropic and metabotropic receptors (Rustioni, A. et al., 1983; Jones, E. G., 1987; Deschenes, M. and Hu, B., 1990; Eaton, S. A. and Salt, T. E., 1990; 1996; Salt, T. E. and Eaton, S. A., 1996). The thalamocortical neurons release glutamate at their cortical terminals (Kharazia, V. N. and Weinberg, R. J., 1994; Pirot, S. et al., 1994). GABA is the major inhibitory neurotransmitter in the thalamus, and the major source of these inputs is from the thalamic reticular nucleus (TRN). The TRN GABAergic neurons are topographically organized and receive excitatory inputs from collaterals of thalamocortical and corticothalamic neurons. In cats and primates, but not rats, there are also GABAergic interneurons within the thalamus (Houser, C. R. et al., 1980; Rustioni, A. et al., 1983; Jones, E. G., 1985; Steriade, M. et al., 1997). The TRN produces both short- and long-latency inhibitory responses; the short-latency IPSPs are mediated by GABAA receptors, whereas the long-latency responses are mediated by the GABAB metabotropic receptors (Lee, S. M. et al., 1994). Interestingly, activation of presynaptic glutamate metabotropic receptors reduces the release of GABA from the TRN receptors (Salt, T. E. and Eaton, S. A., 1995). Most of the studies of thalamic GABAergic

650 The Thalamus and Nociceptive Processing

mechanisms have involved nonnociceptive neurons; however, studies in Pf have shown that thalamic nociceptive neurons receive inhibitory inputs from the TRN and are inhibited by GABA (ReyesVazquez, C. and Dafny, N., 1983; Jia, H. et al., 2004), and microinjection of the GABAA antagonist bicuculline or agonist muscimol into Sm enhanced or depressed, respectively, the antinociception induced by the prior microinjection of morphine into the rat Sm (Jia, H. et al., 2004). There is also recent evidence for modulation of GABAB receptors in VP and Po by noxious inputs (inflammation) (Ferreira-Gomes, J. et al., 2004). The thalamic relay neurons as well as the TRN and inhibitory interneurons also receive projections from serotoninergic neurons in the dorsal raphe nucleus, and norardrenergic and cholinergic neurons in the peribrachial region (see reviews by McCormick, D. A., 1992; Steriade, M. et al., 1997). Their role in nociception is, however, unclear. There have been recent studies in the rat that have demonstrated an involvement of serotoninergic mechanisms in modulation of transmission through the Sm, and these may play a role in a pain modulatory system proposed to relay in Sm (Xiao, D. Q. et al., 2005). There is also evidence that 5HT modulates nociceptive processing in the rat Pf (Harte, S. E. et al., 2005). Several neuropeptides have also been identified in thalamic afferents and neurons. For example, tachykinins, cholecystokinin, and enkephalins have been identified in spinothalamic fibers ending in the rat and human thalamus and are presumably coreleased with glutamate, but their function is not known (Coffield, J. A. and Miletic, V., 1987; Gall, C. et al., 1987; Hirai, T. and Jones, E. G., 1989; Battaglia, G. et al., 1992; Nishiyama, K. et al., 1995). It is usually assumed that the analgesia produced by opiates results from an action at the spinal and brainstem levels. However, there is increasing evidence for a role of opioids also at thalamic and cortical levels, and thus, a direct depressant effect of opioids on thalamic and cortical nociceptive neurons may contribute to the opioid-induced analgesia. Opioid receptors and enkephalinergic terminals have been identified in the thalamus (Mansour, A. et al., 1987; Miletic, V. and Coffield, J. A., 1988). Systemic morphine inhibits thalamic nociceptive neurons (e.g., Benoist, J. M. et al., 1983), but this does not prove that effect is due to an action at the thalamic level. However, there have been studies that have shown that local application of opioid agents

can depress the responses of thalamic nociceptive neurons (He, L. F. et al., 1991; Coffield, J. A. and Miletic, V., 1993) and produce antinociception when microinjected into Sm (Yang, Z. J. et al., 2002). Furthermore, the use of radiolabeled -opioid agonists with PET has shown high opiate receptor levels in the human thalamus (see review in Apkarian, A. V. et al., 2005), and evidence for their involvement in endogenous pain modulation.

References Al-Chaer, E. D., Feng, Y., and Willis, W. D. 1998. A role for the dorsal column in nociceptive visceral input into the thalamus of primates. J. Neurophysiol. 79, 3143–3150. Albe-Fessard, D., Berkley, K. J., Kruger, L., Ralston, H. J., III, and Willis, W. D., Jr. 1985. Diencephalic mechanisms of pain sensation. Brain Res. 356, 217–296. Apkarian, A. V. and Shi, T. 1994. Squirrel monkey lateral thalamus. I. Somatic nociresponsive neurons and their relation to spinothalamic terminals. J. Neurosci. 14, 6779–6795. Apkarian, A. V., Bushnell, M. C., Treede, R. D., and Zubieta, J. K. 2005. Human brain mechanisms of pain perception and regulation in health and disease. Eur. J. Pain 9, 463–484. Applebaum, A. E., Leonard, R. B., Kenshalo, D. R., Jr., Martin, R. F., and Willis, W. D. 1979. Nuclei in which functionally identified spinothalamic tract neurons terminate. J. Comp. Neurol. 188, 575–585. Battaglia, G., Spreafico, R., and Rustioni, A. 1992. Substance P innervation of the rat and cat thalamus. I. Distribution and relation to ascending spinal pathways. J. Comp. Neurol. 315, 457–472. Beggs, J., Jordan, S., Ericson, A. C., Blomqvist, A., and Craig, A. D. 2003. Synaptology of trigemino- and spinothalamic lamina I terminations in the posterior ventral medial nucleus of the macaque. J. Comp. Neurol. 459, 334–354. Benoist, J. M., Kayser, V., Gautron, M., and Guilbaud, G. 1983. Low dose of morphine strongly depresses responses of specific nociceptive neurones in the ventrobasal complex of the rat. Pain 15, 333–344. Berkley, K. J. 1980. Spatial relationships between the terminations of somatic sensory and motor pathways in the rostral brainstem of cats and monkeys. I. Ascending somatic sensory inputs to lateral diencephalon. J. Comp. Neurol. 193, 283–317. Berkley, K. J., Budell, R. J., Blomqvist, A., and Bull, M. 1986. Output systems of the dorsal column nuclei in the cat. Brain Res. Bull. 11, 199–225. Berkley, K. J., Guilbaud, G., Benoist, J. M., and Gautron, M. 1993. Responses of neurons in and near the thalamic ventrobasal complex of the rat to stimulation of uterus, cervix, vagina, colon, and skin. J. Neurophysiol. 69, 557–568. Bernard, J. F. and Besson, J. M. 1990. The spino(trigemino)pontoamygdaloid pathway: electrophysiological evidence for an involvement in pain processes. J. Neurophysiol. 63, 473–490. Blomqvist, A. and Berkley, K. J. 1992. A re-examination of the spino-reticulo-diencephalic pathway in the cat. Brain Res. 579, 17–31.

The Thalamus and Nociceptive Processing Blomqvist, A., Ericson, A. C., Craig, A. D., and Broman, J. 1996. Evidence for glutamate as a neurotransmitter in spinothalamic tract terminals in the posterior region of owl monkeys. Exp. Brain Res. 108, 33–44. Blomqvist, A., Zhang, E. T., and Craig, A. D. 2000. Cytoarchitectonic and immunohistochemical characterization of a specific pain and temperature relay, the posterior portion of the ventral medial nucleus, in the human thalamus. Brain 123 (Pt 3), 601–619. Bogousslavsky, J., Regli, F., and Uske, A. 1988. Thalamic infarcts: clinical syndromes, etiology, and prognosis. Neurology 38, 837–848. Boivie, J. 1979. An anatomical reinvestigation of the termination of the spinothalamic tract in the monkey. J. Comp. Neurol. 186, 343–370. Boivie, J. 1983. Anatomic and Physiologic Features of the Spino-cervico-thalamic Pathway. In: Somatosensory Integration in the Thalamus (eds. G. Macchi, A. Rustioni, and R. Spreafico), pp. 63–106. Elsevier. Boivie, J. 1994. Central Pain. In: Texbook of Pain (ed. P. D. Wall), pp. 871–902. Churchill Livingstone. Brodal, A. 1982. Neurological Anatomy. Oxford. Bruggemann, J., Vahle-Hinz, C., and Kniffki, K. D. 1994. Projections from the pelvic nerve to the periphery of the cat’s thalamic ventral posterolateral nucleus and adjacent regions of the posterior complex. J. Neurophysiol. 72, 2237–2245. Bushnell, M. C. and Duncan, G. H. 1989. Sensory and affective aspects of pain perception: is medial thalamus restricted to emotional issues. Exp. Brain Res. 78, 415–418. Bushnell, M. C., Duncan, G. H., and Tremblay, N. 1993. Thalamic VPM nucleus in the behaving monkey. I. Multimodal and discriminative properties of thermosensitive neurons. J. Neurophysiol. 69, 739–752. Carstens, E. and Yokota, T. 1980. Viscerosomatic convergence and responses to intestinal distension of neurons at the junction of midbrain and posterior thalamus in the cat. Exp. Neurol. 70, 392–402. Casey, K. L. and Morrow, T. J. 1983. Ventral posterior thalamic neurons differentially responsive to noxious stimulation of the awake monkey. Science 221, 675–677. Chandler, M. J., Hobbs, S. F., Fu, Q. G., Kenshalo, D. R., Jr., Blair, R. W., and Foreman, R. D. 1992. Responses of neurons in ventroposterolateral nucleus of primate thalamus to urinary bladder distension. Brain Res. 571, 26–34. Clasca, F., Llamas, A., and Reinoso-Suarez, F. 1997. Insular cortex and neighboring fields in the cat: a redefinition based on cortical microarchitecture and connections with the thalamus. J. Comp. Neurol. 384, 456–482. Coffield, J. A. and Miletic, V. 1987. Immunoreactive enkephalin is contained within some trigeminal and spinal neurons projecting to the rat medial thalamus. Brain Res. 425, 380–383. Coffield, J. A. and Miletic, V. 1993. Responses of rat nucleus submedius neurons to enkephalins applied with micropressure. Brain Res. 630, 252–261. Coffield, J. A., Bowen, K. K., and Miletic, V. 1992. Retrograde tracing of projections between the nucleus submedius, the ventrolateral orbital cortex, and the midbrain in the rat. J. Comp. Neurol. 321, 488–499. Craig, A. D. 1998. A new version of the thalamic disinhibition hypothesis of central pain. Pain Forum 7, 1–14. Craig, A. D. 2002. New and Old Thoughts on the Mechanisms of Pain Following Spinal Cord Injury. In: Spinal Cord Injury Pain: Assessment, Mechanisms, and Treatment (eds. R. P. Yezierski and K. J. Burchiel), pp. 237–261. IASP Press. Craig, A. D. 2003. Pain mechanisms: labeled lines versus convergence in central processing. Annu. Rev. Neurosci. 26, 1–30.

651

Craig, A. D. 2004. Distribution of trigeminothalamic and spinothalamic lamina I terminations in the macaque monkey. J. Comp. Neurol. 477, 119–148. Craig, A. D. and Burton, H. 1985. The distribution and topographical organization in the thalamus of anterogradelytransported horseradish peroxidase after spinal injections in cat and raccoon. Exp. Brain Res. 58, 227–254. Craig, A. D., Chen, K., Bandy, D., and Reiman, E. M. 2000. Thermosensory activation of insular cortex. Nat. Neurosci. 3, 184–190. Craig, A. D. and Dostrovsky, J. O. 1999. Medulla to Thalamus. In: Textbook of Pain (eds. P. D. Wall and R. Melzack), pp. 183–214. Churchill-Livingstone. Craig, A. D. and Dostrovsky, J. O. 2001. Differential projections of thermoreceptive and nociceptive lamina I trigeminothalamic and spinothalamic neurons in the cat. J. Neurophysiol. 86, 856–870. Craig, A. D. and Zhang, E.-T. 1996 Anterior cingulate projection from MDvc (a lamina I spinothalamic target in the medial thalamus of the monkey). Soc. Neurosci. Abstr. 22, 111. Craig, A. D., Bushnell, M. C., Zhang, E.-T., and Blomqvist A. 1994. A thalamic nucleus specific for pain and temperature sensation. Nature 372, 770–773. Craig, A. D., Jr., Linington, A. J., and Kniffki, K. D. 1989. Cells of origin of spinothalamic tract projections to the medial and lateral thalamus in the cat. J. Comp. Neurol. 289, 568–585. Craig, A. D., Jr., Wiegand, S. J., and Price, J. L. 1982. The thalamo-cortical projection of the nucleus submedius in the cat. J. Comp. Neurol. 206, 28–48. Dado, R. J. and Giesler, G. J., Jr. 1990. Afferent input to nucleus submedius in rats: retrograde labeling of neurons in the spinal cord and caudal medulla. J. Neurosci. 10, 2672–2686. Davis, K. D. and Dostrovsky, J. O. 1988. Responses of feline trigeminal spinal tract nucleus neurons to stimulation of the middle meningeal artery and sagittal sinus. J. Neurophysiol. 59, 648–666. Davis, K. D., Kiss, Z. H. T., Luo, L., Tasker, R. R., Lozano, A. M., and Dostrovsky, J. O. 1998. Phantom sensations generated by thalamic microstimulation. Nature 391, 385–387. Davis, K. D., Kiss, Z. H. T., Tasker, R. R., and Dostrovsky, J. O. 1996. Thalamic stimulation-evoked sensations in chronic pain patients and in nonpain (movement disorder) patients. J. Neurophysiol. 75, 1026–1037. Davis, K. D., Lozano, R. M., Manduch, M., Tasker, R. R., Kiss, Z. H., and Dostrovsky, J. O. 1999. Thalamic relay site for cold perception in humans. J. Neurophysiol. 81, 1970–1973. Davis, K. D., Tasker, R. R., Kiss, Z. H., Hutchison, W. D., and Dostrovsky, J. O. 1995. Visceral pain evoked by thalamic microstimulation in humans. Neuroreport 6, 369–374. Dejerine, J. and Roussy, G. 1906. La syndrome thalamique. Rev. Neurol. 14, 521–532. Desbois, C. and Villanueva, L. 2001. The organization of lateral ventromedial thalamic connections in the rat: a link for the distribution of nociceptive signals to widespread cortical regions. Neuroscience 102, 885–898. Desbois, C., Le, B. D., and Villanueva, L. 1999. Organization of cortical projections to the medullary subnucleus reticularis dorsalis: a retrograde and anterograde tracing study in the rat. J. Comp. Neurol. 410, 178–196. Deschenes, M. and Hu, B. 1990. Electrophysiology and pharmacology of the corticothalamic input to lateral thalamic nuclei: an intracellular study in the cat. Eur. J. Neurosci. 2, 140–152. Devinsky, O., Morrell, M. J., and Vogt, B. A. 1995. Contributions of anterior cingulate cortex to behaviour. Brain 118(Pt 1), 279–306. Diamond, M. E., Armstrong-James, M., Budway, M. J., and Ebner, F. F. 1992. Somatic sensory responses in the rostral

652 The Thalamus and Nociceptive Processing sector of the posterior group (POm) and in the ventral posterior medial nucleus (VPM) of the rat thalamus: dependence on the barrel field cortex. J. Comp. Neurol. 319, 66–84. Disbrow, E., Roberts, T., and Krubitzer, L. 2000. Somatotopic organization of cortical fields in the lateral sulcus of Homo sapiens: evidence for SII and PV. J. Comp. Neurol. 418, 1–21. Dostrovsky, J. O. and Guilbaud, G. 1988. Noxious stimuli excite neurons in nucleus submedius of the normal and arthritic rat. Brain Res. 460, 269–280. Dostrovsky, J. O., Manduch, M., Davis, K. D., Tasker, R. R., and Lozano, A. M. 2000. Thalamic Stimulation-Evoked Pain and Temperature Sites in Pain and Non-Pain Patients. In: Proceedings of the 9th World Congress on Pain (eds. M. Devor, M. C. Rowbotham, and Z. Wiesenfeld-Hallin), pp. 419–425. IASP Press. Downie, J. W., Ferrington, D. G., Sorkin, L. S., and Willis, W. D., Jr. 1988. The primate spinocervicothalamic pathway: responses of cells of the lateral cervical nucleus and spinocervical tract to innocuous and noxious stimuli. J. Neurophysiol. 59, 861–885. Duncan, G. H., Bushnell, M. C., Oliveras, J. L., Bastrash, N., and Tremblay, N. 1993. Thalamic VPM nucleus in the behaving monkey. III. Effects of reversible inactivation by lidocaine on thermal and mechanical discrimination. J. Neurophysiol. 70, 2086–2096. Eaton, S. A. and Salt, T. E. 1990. Thalamic NMDA receptors and nociceptive sensory synaptic transmission. Neurosci. Lett. 110, 297–302. Eaton, S. A. and Salt, T. E. 1996. Role of N-methyl-D-aspartate and metabotropic glutamate receptors in corticothalamic excitatory postsynaptic potentials in vivo. Neuroscience 73, 1–5. Ericson, A. C., Blomqvist, A., Craig, A. D., Ottersen, O. P., and Broman, J. 1995. Evidence for glutamate as neurotransmitter in trigemino-and spinothalamic tract terminals in the nucleus submedius of cats. Eur. J. Neurosci. 7, 305–317. Ericson, A. C., Blomqvist, A., Krout, K., and Craig, A. D. 1996. Fine structural organization of spinothalamic and trigeminothalamic lamina I terminations in the nucleus submedius of the cat. J. Comp. Neurol. 371, 497–512. Ferreira-Gomes, J., Neto, F. L., and Castro-Lopes, J. M. 2004. Differential expression of GABA(B(1b)) receptor mRNA in the thalamus of normal and monoarthritic animals. Biochem. Pharmacol. 68, 1603–1611. Friedman, D. P. and Murray, E. A. 1986. Thalamic connectivity of the second somatosensory area and neighboring somatosensory fields of the lateral sulcus of the macaque. J. Comp. Neurol. 252, 348–373. Gall, C., Lauterborn, J., Burks, D., and Seroogy, K. 1987. Colocalization of enkephalin and cholecystokinin in discrete areas of rat brain. Brain Res. 403, 403–408. Ganchrow, D. 1978. Intratrigeminal and thalamic projections of nucleus caudalis in the squirrel monkey (Saimiri sciureus): a degeneration and autoradiographic study. J. Comp. Neurol. 178, 281–312. Giesler, G. J., Jr., Yezierski, R. P., Gerhart, K. D., and Willis, W. D. 1981. Spinothalamic tract neurons that project to medial and/or lateral thalamic nuclei: evidence for a physiologically novel population of spinal cord neurons. J. Neurophysiol. 46, 1285–1308. Gingold, S. I., Greenspan, J. D., and Apkarian, A. V. 1991. Anatomic evidence of nociceptive inputs to primary somatosensory cortex: relationship between spinothalamic terminals and thalamocortical cells in squirrel monkeys. J. Comp. Neurol. 308, 467–490. Guilbaud, G., Benoist, J. M., Jazat, F., and Gautron, M. 1990. Neuronal responsiveness in the ventrobasal thalamic complex of rats with an experimental peripheral mononeuropathy. J. Neurophysiol. 64, 1537–1554.

Guilbaud, G., Peschanski, M., Gautron, M., and Binder, D. 1980. Neurones responding to noxious stimulation in VB complex and caudal adjacent regions in the thalamus of the rat. Pain 8, 303–318. Gybels, J. M. and Sweet, W. H. 1989. Neurosurgical Treatment of Persistent Pain. Physiological and Pathological Mechanisms of Human Pain. Pain and Headache, Vol. 11. Karger. Halliday, A. M. and Logue, V. 1972. Painful Sensations Evoked by Electrical Stimulation in the Thalamus. In: Neurophysiology Studied in Man (ed. G. G. Somjen), pp. 221–230. Excerpts Medica. Harte, S. E., Kender, R. G., and Borszcz, G. S. 2005. Activation of 5-HT1A and 5-HT7 receptors in the parafascicular nucleus suppresses the affective reaction of rats to noxious stimulation. Pain 113, 405–415. Hassler, R. 1959. Architechtronic Organization of the Thalamic Nuclei. In: An Introduction to Stereotaxis with an Atlas of the Human Brain (eds. G. Schaltenbrand and P. Bailey), pp. 142–180. Thieme. Hassler, R. 1970. Dichotomy of Facial Pain Conduction in the Diencephalon. In: Trigeminal Neuralgia (eds. R. Hassler and A. E. Walker), pp. 123–138. Sanders. Hassler, R. and Riechert, T. 1959. Klinische und anatomische Befunde bei stereotaktischen Schmerzoperationen im thalamus. Arch. Psychiatr. 200, 93–122. He, L. F., Dong, W. Q., and Wang, M. Z. 1991. Effects of iontophoretic etorphine and naloxone, and electroacupuncture on nociceptive responses from thalamic neurones in rabbits. Pain 44, 89–95. Head, H. and Holmes, G. 1911. Sensory disturbances from cerebral lesions. Brain 34, 102–254. Hirai, T. and Jones, E. G. 1989. A new parcellation of the human thalamus on the basis of histochemical staining. Brain Res. Brain Res. Rev. 14, 1–34. Houser, C. R., Vaughn, J. E., Barber, R. P., and Roberts, E. 1980. GABA neurons are the major cell type of the nucleus reticularis thalami. Brain Res. 200, 341–354. Hutchison, W. D., Luhn, M. A., and Schmidt, R. F. 1992. Knee joint input into the peripheral region of the ventral posterior lateral nucleus of cat thalamus. J. Neurophysiol. 67, 1092–1104. Jeanmonod, D., Magnin, M., and Morel, A. 1993. Thalamus and neurogenic pain: physiological, anatomical and clinical data. Neuroreport 4, 475–478. Jeanmonod, D., Magnin, M., and Morel, A. 1994. A thalamic concept of neurogenic pain. Proc. 7th Cong. Pain 2, 767–787. Jeanmonod, D., Magnin, M., and Morel, A. 1996. Low-threshold calcium spike bursts in the human thalamus. Common physiopathology for sensory, motor and limbic positive symptoms. Brain 119(Pt 2), 363–375. Jia, H., Xie, Y. F., Xiao, D. Q., and Tang, J. S. 2004. Involvement of GABAergic modulation of the nucleus submedius (Sm) morphine-induced antinociception. Pain 108, 28–35. Jones, E. G. 1985. The Thalamus. Plenum. Jones, E. G. 1987. Immunocytochemical Studies on Thalamic Afferent Transmitters. In: Thalamus and Pain (eds. J. M. Besson, G. Guilbaud, and M. Peschanski), pp. 83–109. Excerpta Medica. Jones, E. G. 1990. Correlation and revised nomenclature of ventral nuclei in the thalamus of human and monkey. Stereotact. Funct. Neurosurg. 54–55, 1–20. Kaas, J. H., Nelson, R. J., Sur, M., Dykes, R. W., and Merzenich, M. M. 1984. The somatotopic organization of the ventroposterior thalamus of the squirrel monkey, Saimiri sciureus. J. Comp. Neurol. 226, 111–140. Kajander, K. C. and Giesler, G. J., Jr. 1987. Responses of neurons in the lateral cervical nucleus of the cat to noxious cutaneous stimulation. J. Neurophysiol. 57, 1686–1704.

The Thalamus and Nociceptive Processing Kawakita, K., Dostrovsky, J. O., Tang, J. S., and Chiang, C. Y. 1993. Responses of neurons in the rat thalamic nucleus submedius to cutaneous, muscle and visceral nociceptive stimuli. Pain 55, 327–338. Kenshalo, D. R., Jr., Giesler, G. J., Jr., Leonard, R. B., and Willis, W. D. 1980. Responses of neurons in primate ventral posterior lateral nucleus to noxious stimuli. J. Neurophysiol. 43, 1594–1614. Kharazia, V. N. and Weinberg, R. J. 1994. Glutamate in thalamic fibers terminating in layer IV of primary sensory cortex. J. Neurosci. 14, 6021–6032. Krubitzer, L., Clarey, J., Tweedale, R., Elston, G., and Calford, M. 1995. A redefinition of somatosensory areas in the lateral sulcus of macaque monkeys. J. Neurosci. 15, 3821–3839. Kupers, R. C. and Gybels, J. M. 1993. Electrical stimulation of the ventroposterolateral thalamic nucleus (VPL) reduces mechanical allodynia in a rat model of neuropathic pain. Neurosci. Lett. 150, 95–98. Lee, J., Dougherty, P. M., Antezana, D., and Lenz, F. A. 1999. Responses of neurons in the region of human thalamic principal somatic sensory nucleus to mechanical and thermal stimuli graded into the painful range. J. Comp. Neurol. 410, 541–555. Lee, S. M., Friedberg, M. H., and Ebner, F. F. 1994. The role of GABA-mediated inhibition in the rat ventral posterior medial thalamus. II. Differential effects of GABAA and GABAB receptor antagonists on responses of VPM neurons. J. Neurophysiol. 71, 1716–1726. Lenz, F. A. and Dougherty, P. M. 1997. Pain Processing in the Human Thalamus. In: Thalamus, Volume II, Experimental and Clincal Aspects (eds. M. Steriade, E. G. Jones, and D. McCormick), pp. 617–651. Elsevier. Lenz, F. A., Gracely, R. H., Baker, F. H., Richardson, R. T., and Dougherty, P. M. 1998. Reorganization of sensory modalities evoked by microstimulation in region of the thalamic principal sensory nucleus in patients with pain due to nervous system injury. J. Comp. Neurol. 399, 125–138. Lenz, F. A., Kwan, H. C., Dostrovsky, J. O., and Tasker, R. R. 1989. Characteristics of the bursting pattern of action potentials that occurs in the thalamus of patients with central pain. Brain Res. 496, 357–360. Lenz, F. A., Kwan, H. C., Martin, R., Tasker, R., Richardson, R. T., and Dostrovsky, J. O. 1994. Characteristics of somatotopic organization and spontaneous neuronal activity in the region of the thalamic principal sensory nucleus in patients with spinal cord transection. J. Neurophysiol. 72, 1570–1587. Lenz, F. A., Seike, M., Lin, Y. C., Baker, F. H., Rowland, L. H., Gracely, R. H., and Richardson, R. T. 1993a. Neurons in the area of human thalamic nucleus ventralis caudalis respond to painful heat stimuli. Brain Res. 623, 235–240. Lenz, F. A., Seike, M., Richardson, R. T., Lin, Y. C., Baker, F. H., Khoja, I., Jaeger, C. J., and Gracely, R. H. 1993b. Thermal and pain sensations evoked by microstimulation in the area of human ventrocaudal nucleus. J. Neurophysiol. 70, 200–212. Llinas, R. R., Ribary, U., Jeanmonod, D., Kronberg, E., and Mitra, P. P. 1999. Thalamocortical dysrhythmia: a neurological and neuropsychiatric syndrome characterized by magnetoencephalography. Proc. Natl. Acad. Sci. U. S. A. 96, 15222–15227. Magnusson, K. R., Clements, J. R., Larson, A. A., Madl, J. E., and Beitz, A. J. 1987. Localization of glutamate in trigeminothalamic projection neurons: a combined retrograde transport-immunohistochemical study. Somatosens. Res. 4, 177–190. Mansour, A., Khachaturian, H., Lewis, M. E., Akil, H., and Watson, S. J. 1987. Autoradiographic differentiation of mu,

653

delta, and kappa opioid receptors in the rat forebrain and midbrain. J. Neurosci. 7, 2445–2464. McCormick, D. A. 1992. Neurotransmitter actions in the thalamus and cerebral cortex and their role in neuromodulation of thalamocortical activity. Prog. Neurobiol. 39, 337–388. Mehler, W. R. 1966. The posterior thalamic region in man. Confin. Neurol. 27, 18–29. Mehler, W. R. 1969. Some neurological species differences – a posteriori. Ann. N. Y. Acad. Sci. 167, 424–468. Melzack, R. and Casey, K. L. 1968. Sensory, Motivational, and Central Control Determinants of Pain. In: The Skin Senses (ed. D. R. Kenshalo), pp. 423–443. Thomas. Miletic, V. and Coffield, J. A. 1988. Enkephalin-like immunoreactivity in the nucleus submedius of the cat and rat thalamus. Somatosens. Res. 5, 325–334. Morin, C., Bushnell, M. C., Luskin, M. B., and Craig, A. D. 2002. Disruption of thermal perception in a multiple sclerosis patient with central pain. Clin. J. Pain 18, 191–195. Montes, C., Magnin, M., Maarrow, J., Frot, M., Convers, P., Mauguie´re, F., and Garcia-Larrea, L. 2005. Thalamic thermoalgesic transimission: ventral posterior (VP) complex versus VMpo in the light of a thalamic in farct with central pain. Pain 113, 223–232. Musil, S. Y. and Olson, C. R. 1988. Organization of cortical and subcortical projections to anterior cingulate cortex in the cat. J. Comp. Neurol. 272, 203–218. Nishiyama, K., Kwak, S., Murayama, S., and Kanazawa, I. 1995. Substance P is a possible neurotransmitter in the rat spinothalamic tract. Neurosci. Res. 21, 261–266. Norrsell, U. and Craig, A. D. 1999. Behavioral thermosensitivity after lesions of thalamic target areas of a thermosensory spinothalamic pathway in the cat. J. Neurophysiol. 82, 611–625. Pagni, C. A. 1998. Central Pain: A Neurosurgical Challenge. Edizioni Minerva Medica. Peschanski, M. 1984. Trigeminal afferents to the diencephalon in the rat. Neuroscience 12, 465–487. Pirot, S., Jay, T. M., Glowinski, J., and Thierry, A. M. 1994. Anatomical and electrophysiological evidence for an excitatory amino acid pathway from the thalamic mediodorsal nucleus to the prefrontal cortex in the rat. Eur. J. Neurosci. 6, 1225–1234. Poggio, G. F. and Mountcastle, V. B. 1960. A study of the functional contributions of the lemniscal and spinothalamic systems to somatic sensibility. Bull. Johns Hopkins Hosp. 106, 266–316. Radhakrishnan, V., Tsoukatos, J., Davis, K. D., Tasker, R. R., Lozano, A. M., and Dostrovsky, J. O. 1999. A comparison of the burst activity of lateral thalamic neurons in chronic pain and non-pain patients. Pain 80, 567–575. Ralston, H. J., III and Ralston, D. D. 1992. The primate dorsal spinothalamic tract: evidence for a specific termination in the posterior nuclei (Po/SG) of the thalamus. Pain 48, 107–118. Ralston, H. J., III, and Ralston, D. D. 1994. Medial lemniscal and spinal projections to the macaque thalamus: an electron microscopic study of differing GABAergic circuitry serving thalamic somatosensory mechanisms. J. Neurosci. 14, 2485–2502. Rausell, E. and Jones, E. G. 1991. Histochemical and immunocytochemical compartments of the thalamic VPM nucleus in monkeys and their relationship to the representational map. J. Neurosci. 11, 210–225. Rausell, E., Bae, C. S., Vinuela, A., Huntley, G. W., and Jones, E. G. 1992. Calbindin and parvalbumin cells in monkey VPL thalamic nucleus: distribution, laminar cortical projections, and relations to spinothalamic terminations. J. Neurosci. 12, 4088–4111.

654 The Thalamus and Nociceptive Processing Ray, J. P. and Price, J. L. 1993. The organization of projections from the mediodorsal nucleus of the thalamus to orbital and medial prefrontal cortex in macaque monkeys. J. Comp. Neurol. 337, 1–31. Reyes-Vazquez, C. and Dafny, N. 1983. Microiontophoretically applied THIP effects upon nociceptive responses of neurons in medial thalamus. Appl. Neurophysiol. 46, 254–260. Riddoch, G. and Critchley, Mc.D. 1937. La physiopatholgie de la douleru d9oriinge centrale. Rev. Neurol. 68, 77–104. Roberts, V. J. and Dong, W. K. 1994. The effect of thalamic nucleus submedius lesions on nociceptive responding in rats. Pain 57, 341–349. Royce, G. J., Bromley, S., Gracco, C., and Beckstead, R. M. 1989. Thalamocortical connections of the rostral intralaminar nuclei: an autoradiographic analysis in the cat. J. Comp. Neurol. 288, 555–582. Rustioni, A., Schmechel, D. E., Spreafico, R., Cheema, S., and Cuenod, M. 1983. Excitatory and Inhibitory Amino Acid Putative Neurotransmitters in the Ventralis Posterior Complex: An Autoradiographic and Immunocytochemical Study in Rats and Cats. In: Somatosensory Integration in the Thalamus (eds. G. Machhi, A. Rustioni, and R. Spreafico), pp. 365–383. Elsevier. Sadikot, A. F., Parent, A., and Franc¸ois, C. 1992. Efferent connections of the centromedian and parafascicular thalamic nuclei in the squirrel monkey: a PHA-L study of subcortical projections. J. Comp. Neurol. 315, 137–159. Salt, T. E. and Eaton, S. A. 1995. Distinct presynaptic metabotropic receptors for L-AP4 and CCG1 on GABAergic terminals: pharmacological evidence using novel alphamethyl derivative mGluR antagonists, MAP4 and MCCG, in the rat thalamus in vivo. Neuroscience 65, 5–13. Salt, T. E. and Eaton, S. A. 1996. Functions of ionotropic and metabotropic glutamate receptors in sensory transmission in the mammalian thalamus. Prog. Neurobiol. 48, 55–72. Sano, K. 1979. Stereotaxic Thalamolaminotomy and Posteromedial Hypothalamotomy for the Relief of Intractable Pain. In: Advances in Pain Research and Therapy (eds. J. J. Bonica and V. Ventafridda), pp. 475–485. Raven Press. Schlag, J. and Schlag-Rey, M. 1986. Role of the central thalamus in gaze control. Prog. Brain Res. 64, 191–201. Schmahmann, J. D. and Leifer, D. 1992. Parietal pseudothalamic pain syndrome. Clinical features and anatomic correlates. Arch. Neurol. 49, 1032–1037. Schott, B., Laurent, B., and Mauguiere, F. 1986. Les douleurs thalamiques. Etude critique de 43 case. Rev. Neurol. 142, 308–315. Sherman, S. M. and Guillery, R. W. 2001. Exploring the Thalamus. Academic Press. Shi, T., Stevens, R. T., Tessier, J., and Apkarian, A. V. 1993. Spinothalamocortical inputs nonpreferentially innervate the superficial and deep cortical layers of SI. Neurosci. Lett. 160, 209–213. Siegfried, J. 1987. Stimulation of Thalamic Nuclei in Human: Sensory and Therapeutical Aspects. In: Thalamus and Pain (eds. J.-M. Besson, G. Guilbaud, and M. Peschanski), pp. 271–278. Excerpta Medica. Stepniewska, I., Sakai, S. T., Qi, H. X., and Kaas, J. H. 2003. Somatosensory input to the ventrolateral thalamic region in the macaque monkey: potential substrate for parkinsonian tremor. J. Comp. Neurol. 455, 378–395.

Steriade, M., Jones, E. G., and McCormick, D. A. 1997. Thalamus. Elsevier Science. Stevens, R. T., London, S. M., and Apkarian, A. V. 1993. Spinothalamocortical projections to the secondary somatosensory cortex (SII) in squirrel monkey. Brain Res. 631, 241–246. Strigo, I. A., Duncan, G. H., Boivin, M., and Bushnell, M. C. 2003. Differentiation of visceral and cutaneous pain in the human brain. J. Neurophysiol. 89, 3294–3303. Tasker, R. R. 1984. Stereotaxic Surgery. In: Textbook of Pain (eds. P. D. Wall and R. Melzack), pp. 639–655. Churchill Livingstone. Villanueva, L. and Nathan, P. 2000. Multiple Pain Pathways. In: Proceedings of the 9th World Congress on Pain (eds. M. Devor, M. C. Rowbotham, and Z. Wiesenfeld-Hallin), pp. 371–376. IASP Press. Wall, J. T., Xu, J., and Wang, X. 2002. Human brain plasticity: an emerging view of the multiple substrates and mechanisms that cause cortical changes and related sensory dysfunctions after injuries of sensory inputs from the body. Brain Res. Brain Res. Rev. 39, 181–215. Weng, H. R., Lee, J. I., Lenz, F. A., Schwartz, A., Vierck, C., Rowland, L., and Dougherty, P. M. 2000. Functional plasticity in primate somatosensory thalamus following chronic lesion of the ventral lateral spinal cord. Neuroscience 101, 393–401. Weng, H. R., Lenz, F. A., Vierck, C., and Dougherty, P. M. 2003. Physiological changes in primate somatosensory thalamus induced by deafferentation are dependent on the spinal funiculi that are sectioned and time following injury. Neuroscience 116, 1149–1160. Willis, W. D. 1985. The Pain System. Karger. Willis, W. D., Jr. 1997. Nociceptive Functions of Thalamic Neurons. In: Thalamus, Volume II, Experimental and Clinical Aspects (eds. M. Steriade, E. G. Jones, and D. A. McCormick), pp. 373–424. Elsevier Science Ltd. Willis, W. D. and Westlund, K. N. 1997. Neuroanatomy of the pain system and of the pathways that modulate pain. J. Clin. Neurophysiol. 14, 2–31. Xiao, D. Q., Zhu, J. X., Tang, J. S., and Jia, H. 2005. 5hydroxytryptamine 1A (5-HT1A) but not 5-HT3 receptor is involved in mediating the nucleus submedius 5-HT-evoked antinociception in the rat. Brain Res. 1046, 38–44. Yang, Z. J., Tang, J. S., and Jia, H. 2002. Morphine microinjections into the rat nucleus submedius depress nociceptive behavior in the formalin test. Neurosci. Lett. 328, 141–144. Yasui, Y., Breder, C. D., Saper, C. B., and Cechetto, D. F. 1991. Autonomic responses and efferent pathways from the insular cortex in the rat. J. Comp. Neurol. 303, 355–374. Yasui, Y., Itoh, K., Kamiya, H., Ino, T., and Mizuno, N. 1988. Cingulate gyrus of the cat receives projection fibers from the thalamic region ventral to the ventral border of the ventrobasal complex. J. Comp. Neurol. 274, 91–100. Yoshida, A., Dostrovsky, J. O., and Chiang, C. Y. 1992. The afferent and efferent connections of the nucleus submedius in the rat. J. Comp. Neurol. 324, 115–133. Zhang, S., Tang, J. S., Yuan, B., and Jia, H. 1998. Inhibitory effects of glutamate-induced activation of thalamic nucleus submedius are mediated by ventrolateral orbital cortex and periaqueductal gray in rats. Eur. J. Pain 2, 153–163.

44 Psychophysics of Sensations Evoked by Stimulation of the Human Central Nervous System S Ohara, C A Bagley, H C Lawson, and F A Lenz, Johns Hopkins Hospital, Baltimore, MD, USA ª 2009 Elsevier Inc. All rights reserved.

44.1 44.2 44.3 44.4 44.4.1 44.4.2 44.5 44.5.1 44.6 References

Introduction The Spinothalamic Tract The Dorsal Column Pathway Thalamic Nuclei Lateral Thalamic Nuclei Medial and Intralaminar Thalamic Nuclei Cortex Parasylvian Cortex and Pain Memory Conclusions

656 656 657 657 657 663 663 663 665 665

Glossary dorsal columns A pathway carrying axons of fibers in the peripheral nerve through the posterior aspect of the spinal cord to the dorsal column nucleus at the posterior aspect of the medulla where they synapse and ascend through the medial lemnisus to the principal nucleus of thalamus. Classically, this pathway transmits low-threshold muscle and cutaneous afferents but recent studies demonstrate that afferents transmitting nociceptive, thermal, or visceral inputs are also transmitted. nociceptive specific (NS) neurons Neurons responding only to stimuli which are noxious or painful. wide dynamic range (WDR) neurons Neurons responding to stimuli across the intensive continuum into the painful or noxious range. projected field in the somatosensory system A part of the body at which a sensation is evoked in response to stimulation of the central nervous system. receptive field In the somatosensory system: skin region, stimulation of which can influence the discharge of the neuron under study

somatic sensory nuclear group of the thalamus Nuclei receiving input from the dorsal column nuclei, the spino- or the trigeminothalamic tract by either a direct or a transsynaptic route. Summary term for the specific somatosensory nuclei of the thalamus. Most commonly used taxonomy is for monkey thalamus: VPL (ventroposterolateral), VPM (ventroposteromedial), VPI (ventroposteroinferior) corresponding to humans: Vc (ventrocaudal, both medial and lateral). Adjacent, both posterior medial, to VPM ventral medial posterior (VMpo), a putative pain and temperature signaling nucleus may be located (Craig, A. D. et al., 1994, cf. Willis, W. D., Jr. et al., 2001, Graziano, A. and Jones, E. G., 2004; Lenz, F. A. et al., 2004). VMpo may be located medial to ventral caudal portae (Vcpor), while intralaminar nuclei mostly a thin layer of neurons located medial to Vim, Vc, and Vcpor (see Figure 1(a)). spinothalamic tract (STT) The pain and temperature signaling pathway from neurons in the spinal dorsal horn to the lateral and anterolateral funiculi of the spinal cord and the brainstem to the lateral, posterior, medial, and intralaminar nuclei of thalamus.

655

656 Psychophysics of Sensations Evoked by Stimulation of the Human Central Nervous System

spinothalamocortical pathways Cortical areas which receive input from thalamic nuclei that themselves receive STT input. These thalamocortical connections include those from Vc to primary somatosensory and secondary somatosensory cortex, from Vcpor, Vcpc, and VMpo to parietal opercular, insular, and retroinsular cortex, and finally from the medial dorsal nucleus to anterior cingulate cortex. sylvian fissure Also called lateral sulcus, the sylvian fissure separates the temporal lobe from the frontal and parietal lobes (see Figure 6, left – middle and lower levels). The insula is a cortical surface, which is located deep to the lateral fissure and parallel to the cortical surface on coronal and axial sections (Figure 6, middle and right). The frontal,

44.1 Introduction The dorsal column pathway and the spinothalamic tract (STT) are the two main somatosensory spinal tracts afferent to the thalamus. The dorsal column pathway is formed by the axons of low-threshold mechanoreceptors with cell bodies in the dorsal root ganglion. These axons terminate to the principal somatic sensory nucleus of the thalamus (human ventral caudal or Vc, monkey ventral posterior or VP) (Jones, E. G. et al., 1982; Kaas, J. H. et al., 1984; Lenz, F. A. et al., 1988; Willis, W. D. and Coggeshall, R. E., 1991). The dorsal columns do contain a postsynaptic pain pathway signaling noxious visceral stimuli, which terminates in the Vc (Uddenberg, N., 1968; Rustioni, A. et al., 1979; Willis, W. D., et al., 1991; Al Chaer, E. D. et al., 1996b). The STT is a pain pathway that originates from the spinal dorsal horn, and ascends in the anterolateral quadrant of the spinal cord before terminating in the thalamus (Willis, W. D., Jr. et al., 2001). Stimulation of these thalamic nuclei in man reveals the psychophysical dimensions of these pathways which is the subject of this chapter.

44.2 The Spinothalamic Tract Many neurons in the STT are characterized by their response to noxious or painful stimuli. Some of these respond to the somatic stimuli across the intensive

parietal, and temporal opercula are folds of cortex that extend over the insula and meet each other over the insula. The sulcus between the frontal– parietal opercula and the temporal operculum is the sylvian fissure. Talairach coordinates Initially developed for a specific stereotactic frame; based on one single brain; frequently used as common coordinate system; x: left–right, y: anterior–posterior, z: superior– inferior; the reference point (0, 0, 0) is the anterior commissure (Talairach, J. and Tournoux, P., 1988). thalamus A subcortical gray matter structure characterized by reciprocal connections with the cortical mantle and by inputs from the periphery and nuclei of the brain, such as the pallidum.

continuum into the noxious range (WDR – wide dynamic range). These cells arise from both superficial (lamina I) and deep laminae of the dorsal horn (laminae IV–V) (Kumazawa, T. and Perl, E. R., 1978; Willis, W. D., 1985; Ferrington, D. G. et al., 1987). Some neurons in the superficial dorsal horn respond only to different stimuli including noxious stimuli (nociceptive specific (NS) cells), cold (Kumazawa, T. and Perl, E. R., 1978; Willis, W. D., 1985; Ferrington, D. G. et al., 1987; Craig, A. D. et al., 1994), injection of histamine (itch – Andrew, D. and Craig, A. D., 2001; Craig, A. D., 2003b), or visceral stimuli (Craig, A. D., 2003a). The deep and superficial laminae of the dorsal horn project to the brain, respectively, through the ventral lateral (ventral STT) and the dorsal lateral spinal funiculi (dorsal STT) (Apkarian, A. V. and Hodge, C. J., 1989; Cusick, C. G. et al., 1989; Ralston, H. J. and Ralston, D. D., 1992; Craig, A. D., 1998, 2003b; Price, D. D. et al., 2003). The population of neurons in the superficial dorsal horn responding only to noxious stimuli has led to the description of the STT as a structure signaling only pain – a labeled line (Perl, E. R., 1984; Willis, W. D., 1985). A recent version of this hypothesis suggests that the STT is a series of labeled lines for cool and itch, as well as pain that jointly reflect the internal state of the body (interoception) (Craig, A. D., 2003a; 2003b). In this view, pain is the emotion produced by disequilibrium of the internal state. An alternate view is that pain is signaled by WDR neurons which transmit a

Psychophysics of Sensations Evoked by Stimulation of the Human Central Nervous System

graded signal, the strength of which might be decoded in the brain to identify the presence of a painful stimulus (Price, D. D. and Dubner, R., 1977; Willis, W. D., 1985; Price, D. D. et al., 2003). This chapter examines recent evidence from stimulation of the human central nervous system as they impact these hypotheses. One approach to identifying the pain pathway has been to stimulate the cord during cordotomy using paired-pulse stimulus parameters that selectively activate the axons arising in the superficial or deep laminae (Mayer, D. J. et al., 1975). This interpulse threshold was more consistent with that of cells in the deep than the superficial dorsal horn (Price, D. D. and Mayer, D. J., 1975). The results suggest that the sensory aspect of pain is signaled through the axons in ventral STT which originate from the WDR neurons in the deep dorsal horn (Price, D. D. and Dubner, R., 1977; Dubner, R. et al., 1989).

657

antidromic invasion from nucleus gracilis (Al Chaer, E. D. et al., 1996a), and by retrograde and anterograde tracer studies (Christensen, M. D. et al., 1996). Retrograde tracer studies depositing marker in the nucleus gracilis (Christensen, M. D. et al., 1996) label cell bodies of origin of the pathway in the medial base of the dorsal horn just above the central canal. Injection of tracer into this area resulted in fiber labeling of the dorsal column midline and in the medial aspect of the nucleus gracilis. Fibers originating in the thoracic cord terminate in the lateral part of nucleus gracilis and adjacent to the medial parts of nucleus cuneatus (Wang, C. C. et al., 1999; Willis, W. D. et al., 1999). Along with the STT, a major terminus of the postsynaptic dorsal horn pathway is the lateral thalamus.

44.4 Thalamic Nuclei 44.3 The Dorsal Column Pathway The dorsal column pathway is formed by the axons of low-threshold mechanoreceptors that project through the dorsal column nuclei and medial lemniscus to the region of the principle somatic sensory nucleus (ventral caudal, Vc) (Jones, E. G. et al., 1982; Kaas, J. H. et al., 1984; Lenz, F. A. et al., 1988; Willis, W. D. et al., 1991). As shown in Figure 1 receptive fields are quite constant within a particular parasagittal plane in Vc. From medial to lateral planes, the sequence of neuronal cutaneous receptive fields progresses from intraoral through face, thumb, fingers (radial to ulnar), and arm to leg. Proximal parts of the limbs are represented dorsal to the corresponding digits (Lenz, F. A. et al., 1988). Substantial evidence demonstrates that the dorsal columns do contain a postsynaptic pain pathway signaling noxious visceral stimuli, rather than noxious somatic stimuli, which terminates in the VP (Uddenberg, N., 1968; Rustioni, A. et al., 1979; Willis, W. D. et al., 1991; Al Chaer, E. D. et al., 1996b). This postsynaptic pathway has been demonstrated by infusion of neurotransmitter agonists/ antagonists into the dorsal horn, which alters the response of neurons in the dorsal column nuclei to visceral stimuli. Furthermore, lesions of rat nucleus gracilis diminish the response of neurons in VP to visceral as well as cutaneous stimuli (Al-Chaer, E. D. et al., 1997). The cells of origin of this pathway are located just dorsal to the central canal, as demonstrated by

44.4.1

Lateral Thalamic Nuclei

The human principal sensory nucleus (Vc) (Hassler, R., 1959) is divided into a core area (equivalent to monkey VP, see Olszewski, J., 1952; Hirai, T. and Jones, E. G., 1989), posterior, and inferior regions. These two regions are defined relative to the most posterior and inferior cell with a response to nonpainful, cutaneous stimuli (cell 57 in Figure 1(b)). In the core, the majority of cells respond to innocuous, mechanical, and cutaneous stimulation. This latter area corresponds to the posterior and inferior subnuclei of Vc, which are ventral caudal portae (Vcpor), ventral caudal parvocellular nucleus (Vcpc) (Mehler, W. R., 1966), the posterior nucleus, and the magnocellular medial geniculate (Mehler, W. R., 1962; Mehler, W. R., 1966; Lenz, F. A. et al., 1993b) (see Vc and Vcpor in sagittal section in Figure 1(a)). Studies of patients at autopsy following lesions of the STT show terminations in all this nuclei (Bowsher, D., 1957; Mehler, W. R., 1966; Mehler, W. R., 1969). This area includes the ventral medial nucleus – posterior part (VMpo), which may receive STT inputs and may signal pain and temperature (Craig, A. D. et al., 1994; Blomqvist, A. et al., 2000; cf. Willis, W. D., Jr. et al., 2001; Graziano, A. et al., 2004). The physiology recapitulates this anatomy. Cells in Vc responding to painful and thermal stimuli are of several types, including WDR and NS cells responding to painful thermal and mechanical stimuli (see figure 2 in Lee, J.-I. et al., 1999). Figure 2(a) demonstrates the response of a single neuron with WDR properties to a painful 45  C

658 Psychophysics of Sensations Evoked by Stimulation of the Human Central Nervous System

(b)

(a)

P2 P2

P1

P1

Z (+) Core

Vim Vc 35

Vop

15

Cool Vcpor

Posterio r

5 10 40 20

AC–PC line

45

1 mm

50 25

Y (+)

AC-PC line

PC

PC 55

(0, 0) 60

Inferio

r

5 mm P2

(c) PF

RF

P1 PF

30–32

RF

PF

RF

50

1

51

2

PF

RF 15–16

NR 33

NR

17

NR 34

Tremor related

5

35–36

52

53

5

NR

18

4

19

NR

NR 37

3

38–41

54

Cool 55

5

5

20

6

5

21

NR

NR 42

NR

Tremor related

5 Cool 56

Tremor related

5

43

44

7

22 10

8

57

23

NR 30

58

Tremor related

45

9

24 10

10

Cool 59

Cool 25

NR 5

46–47

5

NR 48

Cool 26

Tremor related

NR 15

10

11

60

5 Cool 27

12

61

49

13 15

5

28

5

29

NR

5 14

NR

NR 5

Psychophysics of Sensations Evoked by Stimulation of the Human Central Nervous System 45 °C (VAS 3)

(a)

50/s 1s

(b)

Wide dynamic range (WDR)

5

VAS

4 3 2 1 0

10

30

50

70

Nociceptive specific (NS) 5

*

VAS

4

*

3

p = 0.03

VAS (mean ± SEM) WDR NS

2 1 0

10

30 50 Response-baseline (Hz)

70

Figure 2 Activity of neurons in the region of Vc (ventrocaudal) responding to painful thermal stimuli. The response to nonpainful and painful heat/mechanical stimuli applied within the receptive field (RF) (Lenz, F. A. et al., 1994b; Lee, J.-I. et al., 1999) is compared with the visual analog scale of intensity (VAS) evoked by the same stimulus. (a) The response of a cell wide dynamic range (WDR) to painful heat. (b) VAS and firing rates for the response to painful stimuli are plotted for nociceptive (NS) cells which respond only to painful stimuli and WDR neurons, which respond in a graded fashion to nonpainful and painful stimuli. Average and one standard deviation scores by decade to 20 Hz and by 30 Hz steps from 20 to 80 Hz were compared by Mann–Whitney U test. Reprinted from Lenz F. A., Ohara, S., Gracely, R. H., Dougherty, P. M., and Patel, S. H. 2004. Pain encoding in the human forebrain: binary and analog exteroceptive channels. J. Neurosci. 24, 6540-6544 with permission ª2004 by the Society for Neuroscience).

659

stimulus. Responses to painful stimuli were characterized by the mean firing rate during painful stimulation, recorded through the microelectrode (Figure 2(b), x-axis), and by visual analog scale of intensity (VAS) ratings of microstimulation-evoked pain (y-axis). Some low-threshold cells respond to nonpainful mechanical and cold stimuli (Figure 2) (Lenz, F. A. et al., 1993a; Lenz, F. A. and Dougherty, P. M., 1998; Lee, J.-I. et al., 1999). Cells in the core and posterior region respond only to noxious heat stimuli (Lenz, F. A. et al., 1993a; 2004) and to noxious cold stimuli (Davis, K. D. et al., 1999). Nociceptive cells in Vc appear to signal pain based on temporary lesioning and stimulation studies. Blockade of the activity in this region by injection of local anesthetic into monkey VP, corresponding to human Vc (Hirai, T. et al., 1989), significantly interferes with the monkey’s ability to discriminate temperature in both the innocuous and noxious range (Duncan, G. H. et al., 1993). Stimulation within Vc and the regions posterior and inferior to it can evoke the sensations of pain (Hassler, R. and Reichert, T., 1959; Willis, W. D., 1985; Dostrovsky, J. O. et al., 1991; Lenz, F. A. et al., 1993b) and temperature (Lenz, F. A. et al., 1993b; Davis, et al., 1999). The largest study of stimulation-evoked pain and temperature responses examined results of threshold microstimulation of the region of Vc in 124 thalami (116 patients), as summarized in Figure 3. The location of pain and temperature responses is defined relative to the posterior and inferior borders of the principal somatic sensory nucleus (Vc). Warm sensations were evoked more frequently in the posterior region (5.7%) than in the core (2.3%). Otherwise the proportions were not significantly different for cool or pain sensations between the core or the posterior region or both (cool 2.5%, 2.2%; pain 2.8%, 4.1%).

Figure 1 Map of receptive and projected fields for trajectories in the regions of the Vc (ventrocaudal) in a single patient (number 193.97). (a) Positions of the trajectories relative to nuclear boundaries as predicted radiologically from the position of the anterior commissure–posterior commissure (AC–PC) line. The AC–PC line is indicated by the horizontal line in the panel; the trajectories are shown by the two oblique lines. The positions of nuclei are inferred from the AC–PC line and therefore are only an approximate indicator of nuclear location. Scale as indicated. Abbreviations defined in the text. (b) Location of the cells, stimulation sites, and trajectories (P1 and P2) relative to the AC–PC line (a solid line) and the ventral border of the core of Vc (a dotted line). The locations of stimulation sites are indicated by ticks to the left of the trajectory; the locations of the cells are indicated by ticks to the right of the trajectory. Cells with receptive fields (RFs) are indicated by long ticks; those without are indicated by short ticks. The cold sensation evoked is indicated by filled circles at the end of the tick to the left of the trajectory. Scale is as indicated. Each site where a cell was recorded or stimulation was carried out or both is indicated by the same number in (b) and (c). The core of Vc and the regions posterior and inferior are as labelled. (c) P1 and P2 show the site number, PF, and RF for that site. The threshold (in microamperes) is indicated below the PF diagram. Reprinted from Ohara S. and Lenz F. A. (2003) Medial lateral extent of thermal and pain sensations evoked by microstimulation in somatic sensory nuclei of human thalamus. J. Neurophysiol. 90, 2367-2377, used with permission from the American physiological society.

660 Psychophysics of Sensations Evoked by Stimulation of the Human Central Nervous System

(a)

Dorsal z

Anterior

10

y 10

–10

–10 Paresthesia

1 mm No response

(b) Cool Warm Painful

1 mm

Figure 3 Locations of sites where microstimulation evoked paresthesias (a, left), no response (NR) (a, right), and thermal and pain sensations (b). Site location is shown relative to the posterior and inferior borders of the core of Vc. Note that thermal and pain sensations were evoked both in the core and posterior regions of Vc. Paresthesic sites are most dense where NR sites are least dense over the core and the posterior regions. Scale as indicated. Reprinted from Ohara S. and Lenz F. A. 2003. Medial lateral extent of thermal and pain sensations evoked by microstimulation in somatic sensory nuclei of human thalamus. J. Neurophysiol. 90, 2367-2377, used with permission from the American Physiological Society.

Warm sensations were evoked more frequently in the lateral plane (10.8%) than in the medial planes of the posterior region (3.9%) but no other significant medial lateral differences for any sensation were found in the core or posterior region or overall. These results are in contrast to previous studies reporting a larger proportion of thermal/pain sites were evoked in the posterior and inferior regions (Lenz, F. A. et al., 1993b; Davis, K. D. et al., 1996).

These latter studies took the anterior commissure– posterior commissure line (ACPC) as the floor of Vc, contrary to atlas and physiologic maps ( Schaltenbrand, G. and Bailey, P., 1959; Lenz, F. A. et al., 1988). This recent study suggests that sites where thermal or pain sensations are evoked are located both within and posterior, inferior, and medial to Vc. If the proportion of such sites is larger in posterior and inferior regions, then those sites must be very close to the borders of the core. Patterned stimulation at sites in the region of Vc, an STT terminal region, evokes sensations consistent with one of two pathways – one binary (painþ) and the other analog (pain/þ) (Figure 3). Specifically, current was applied at five frequencies (10, 20, 38, 100, and 200 Hz) in bursts of 4, 7, 20, 50, and 100 pulses in an ascending staircase protocol, the type of protocol commonly used in studies of pain (Gracely, R. H. et al., 1988; Yarnitsky, D. and Sprecher, E., 1994), including our studies (Greenspan, J. D. et al., 2004). Stimulation at painþ sites evoked a constant high level of pain over large, often cutaneous, projected fields (PFs). These sites were characterized both by descriptors, which did not change along the staircase, or by more intense stimulation-evoked pain than that evoked at the pain/þ sites (Figure 4). These results suggest that painþ sites participate in a binary, exteroceptive, labeled line which signals the presence of a painful external stimulus. The thalamic stimulation thresholds for nonpainful and painful sensations are not significantly different (Lenz, F. A. et al., 1993b; Ohara, S. et al., 2003) suggesting that pain/þ sites did not result from activation of the system transmitting nonpainful sensations (largely medial lemniscal) before that transmitting painful sensations (largely STT) (Willis, W. D., 1985). In addition, the equivalence of current, pulse, and frequency thresholds for pain at both types of sites predicts that the neural elements, that is, possibly WDR and NS cells, should be activated together if they were found at the same site. At such sites, analog painþ responses would be predicted to occur because the combination of binary plus analog neural elements at a site will have analog properties, given the assumption of linearity. However, analog painþ sites were not observed. For all these reasons, it is plausible that our observations may be the result of selective activation of two functionally distinct pathways. Figure 2(a) demonstrates the mean firing rate minus baseline (Figure 2(b), x-axis) for the response of multiple single WDR and NS neurons to painful stimuli versus VAS score (Figure 2(b), y-axis). There

Psychophysics of Sensations Evoked by Stimulation of the Human Central Nervous System

Pain+ RF 12.9 mm

(a)

Pain–/+ RF 12.4 mm

PF 13.0 mm

PF 13.0 mm

300 Hz, 5 μA Unnatural Surface & deep Vibration Painful (7/10) Flicker Electric 200 Hz 100 Hz 38 Hz 20 Hz 10 Hz 5 μA 4 Pulses

661

300 Hz, 5 μA Natural Deep Movement from eye brow to corner of eye Painful (9/10) Hot

Same

Same

Same

Same

Same Same Same

20

50

100

7

Warm Warm 200 Hz Tingle 100 Hz Tingle Warm 38 Hz Tingle 20 Hz 10 Hz Tightness 20 μA 4 Pulses 7

Warm Warm Warm Warm Warm 20

Hot 8/10 Hot 8/10 Hot 8/10 Warm Warm 50

100

(b) VAS 5

VAS

0

0

–5

–5

20

7 38

Frequen c

100

4 200

y (Hz)

–10 10

7 20 38 100 Frequen cy (Hz)

4

se

10

100 50 20 Pu l

–10

se

100 50 20 Pu l

Nonpain

Pain

5

200

Figure 4 Painþ and pain/þ stimulation sites. Sensations evoked by threshold microstimulation were characterized by the PF and by descriptors from a validated questionnaire, and by a visual analog scale of intensity (VAS) (Lenz, F. A. et al., 1993b; 1998a; Lenz, F. A. and Byl, N. N. 1999). (a, left) Site where stimulation at 300 Hz and 5 mA produced pain in the PF shown in the figurine and of the quality as described. Pain identical to that evoked by 300 Hz was evoked at most sites with trains 20 pulses and frequencies 200 Hz (yellow rectangle, see text). (a, right) Site where tightness was evoked in the first column at 10 Hz and then tingle at 20, 38, and 100 Hz. At 200 Hz and thereafter, warm was evoked at each step in the staircase, excepting 7 pulses – 10, 20, 100 Hz, until 50 pulses – 38 Hz. At this step and further up, the staircase painful heat was evoked. (b) Average VAS ratings across all painþ and pain/þ sites. Ratings were taken in response to pulse and frequency pairs ascending the staircase. The yellow lines along the outside surfaces of the 3D displays indicate the average VAS ratings across all sites by frequency and number of pulses. Reprinted from Lenz F. A., Ohara, S., Gracely, R. H., Dougherty, P. M., and Patel, S. H. 2004. Pain encoding in the human forebrain: binary and analog exteroceptive channels. J. Neurosci. 24, 6540-6544, with permission (ª2004; by the Society for Neuroscience).

was a significantly steeper initial rise in VAS scores for the neurons that only responded to painful stimuli (NS neurons), than for WDR neurons. The steep initial rise of VAS with the firing rate of NS versus WDR neurons (Figure 2(b)) is consistent with the shorter dynamic range of thalamic NS cells (Apkarian, A. V. and Shi, T., 1994), and with the binary response to stimulation at painþ sites (Figure 2(b)). We suggest that the first pathway is characterized as a binary pain response signaling the presence/ absence of painful stimuli, consistent with an alerting/alarm function (Becker, D. E. et al., 1993;

Zaslansky, R. et al., 1995). The second pathway may be an analog route in which activity is graded with intensity of the painful stimulus, consistent with STT neurons, which encode the properties of external stimuli (Willis, W. D., 1985; Price, D. D. et al., 2003). Itch was rarely evoked and never in isolation. Emotion descriptors (e.g., nauseating, cruel, suffocating) were uncommonly endorsed at either painþ and pain/þ sites (cf. Lenz, F. A. et al., 1995). Therefore, both painful responses to stimulation were described in terms usually applied to external stimuli (exteroception) rather than to internal or emotional phenomena

662 Psychophysics of Sensations Evoked by Stimulation of the Human Central Nervous System

(interoception). Exteroreceptive sensations can be associated with a strong affective dimension. Pain with a strong unpleasant or affective component can be evoked by stimulation of the lateral thalamus in the region of Vc. These sensations have the character of memories of a previously experienced pain, unlike the pain sensations evoked by thalamic sensation which are not related to previous experience (see above) or a diffuse unpleasant sensation of the type evoked by stimulation of the medial thalamus (see below). In the first case, stimulation in Vcpc (Figure 5) evoked chest pain with an affective dimension in the case of a patient with coronary artery disease which had been effectively treated by balloon angioplasty (Lenz, F. A. et al., 1994a). Microstimulation at site 49 (Figure 5) evoked an unnatural, painful (visual analog scale – 4.6/10), mechanical sensation in the flank and an unnatural nonpainful electrical sensation involving the left arm and leg. At sites 51 and 53 (Figure 5) microstimulation evoked a sensation described by the patient as ‘‘heart pain,’’ which was ‘‘like what I took nitroglycerin for’’ except that ‘‘it starts and stops suddenly.’’ It was not accompanied by dyspnea, diaphoresis, or after effects. The PF involved the precordium and left side of the chest from the sternum in the midline to the anterior axillary line. Microstimulation at site 51 also evoked a sensation of nonpainful surface, tingling in the left leg, which coincided with the stimulation-associated angina. Characteristics of the patient’s stimulation-associated angina and usual angina were measured by using a questionnaire. The same descriptors for stimulation-associated angina were chosen intraoperatively during stimulation at both sites 51 and 53 (Figure 5) including: natural, deep, painful (visual analog scale – 10/10), squeezing, frightful, fatiguing, and identical to her angina. The questionnaire was administered three times over several months postoperatively to describe the patient’s usual angina. The following descriptors were chosen: natural (3/3 administrations), deep (3/3), painful (3/3), squeezing (3/3), frightful (2/3), suffocating (2/3), and fatiguing (2/3). Her usual angina involved the left side of the chest, arm, and neck and was associated with a surface (3/3), nonpainful (3/3), and tingling (3/3) in the left arm and hand. This coincidence of descriptors is unlikely to occur at random (p < 106, combinatorial analysis). Similar emotional responses, including crying in response to thalamic stimulation in the same region, have been reported in the case of atypical chest pain, dysparunia, and the pain of childbirth (Davis, K. D.

(a)

S2

(b)

40 Vop

45 50

Vc

Vim

PC

55

Vcpc MG

1 mm

5 mm (c)

S2

PF

RF

PF

RF

PF

RF

40

46

52

41

47

53

PC

40

42

NR

40

43

NR

25

48

54

NR 10

49

55

NR 20 44

5

NR 30

30

45

NR

51

10

56

50

20

57

40

Figure 5 (a) Thalamic map of a patient with a history of angina pectoris successfully treated with coronary artery balloon angioplasty. (b) Dark circular balloons on ticks to the right of the line indicate sites (sites 49, 51, 53) where thalamic microstimulation evoked painful sensations in PFs indicated by stippling in the figurines (c). Open square balloons in (b) indicate sites where nonpainful, tingling sensations were evoked. All abbreviations and other conventions are as in the legend to Figure 1. Reproduced from Lenz F. A., Gracely, R. H., Hope, E. J., Baker, F. H., Rowland, L. H., Dougherty, P. M., and Richardson, R. T. 1994a. The sensation of angina can be evoked by stimulation of the human thalamus. Pain 59, 119-125, with permission from Elsevier.

Psychophysics of Sensations Evoked by Stimulation of the Human Central Nervous System

et al., 1995; Lenz, F. A. et al., 1995). Clinical criteria including a battery of cardiac tests (enzymes, EKGs, stress test) ruled out angina of cardiac origin in both these patients. Explorations in 50 patients without a history of angina found that stimulation-associated angina was not evoked at any of the 19 stimulation sites with PFs on the chest wall. PFs were located on the left chest wall at three sites and the right chest wall at 16. At one of these 19 sites an unnatural, sharp, mechanical, painful, and vibration was described in response to stimulation but emotional descriptors were not endorsed. Preoperative pain was clearly of cardiac origin in the patient with angina (Lenz, F. A. et al., 1994a), but clearly not of cardiac origin in the patient with panic disorder. The association of stimulation-associated angina and the affective dimension was not unexpected (Lenz, F. A. et al., 1994a) as angina is often associated with a strong affective dimension, unlike other chest pains (Matthews, M. B., 1985; Braunwald, E., 1988; Procacci, P. and Zoppi, M., 1989; Pasternak, R. C. et al., 1992). Stimulation-evoked sharp chest pain occurred without an affective dimension in a retrospective analysis of patients without prior experience of spontaneous chest pain with a strong affective dimension. Therefore, it is possible that in the case, stimulation-associated chest pain included an affective dimension as a result of conditioning by the prior experience of spontaneous chest pain with a strong affective dimension. In retrospect, the affective dimension of stimulation-associated angina might arise by similar conditioning. 44.4.2 Medial and Intralaminar Thalamic Nuclei The medial and intralaminar nuclei also play a role in signaling pain sensations. Medial to Vc, the most dense STT terminal pattern is found in the intralaminar nucleus centralis lateralis (Mehler, W. R., 1962; 1969), while a much less dense termination is found in other interlaminar nuclei central medial, parafascicularis (Mehler, W. R., 1962), and the medial dorsal nucleus (Mehler, W. R., 1969). Nociceptive neurons have been identified in an area that apparently corresponds to the human central median nucleus (Ishijima, B. et al., 1975; Tsubokawa, T. and Moriyasu, N., 1975; Rinaldi, P. C. et al., 1991). Milliampere-current-level stimulation at sites probably located in the parafascicular, limitans, and central medial (parvocellular part) nuclei was reported to evoke a diffuse, burning pain, or

663

sometimes to exacerbate the patient’s ongoing pain (Sano, K., 1979). This pain was evoked in projected fields as large as the whole body or hemibody. Stimulation at sites, possibly the medial dorsal and periventricular nuclei evoked a generalized unpleasant sensation, not localized to a particular body part (Sano, K., 1979). Both responses may be consistent with the STT pathway or a multisynaptic pathway traversing the reticular formation (Willis, W. D., 1985).

44.5 Cortex Functional imaging studies of the response to the application of painful stimuli (Jones, A. K. et al., 1991; Talbot, J. D. et al., 1991; Casey, K. L. et al., 1994; Craig, A. D. et al., 1996; Andrew, D. et al., 2001) have identified three cortical areas with metabolic activation: primary somatosensory, parasylvian, and cingulate cortex. These cortical areas all receive input arising from nociceptors as demonstrated by cortical potentials evoked by cutaneous application of a laser (laser-evoked potentials – LEP) (Ohara, S. et al., 2004b), which selectively activates nociceptors (Bromm, B. et al., 1984). Pain-related responses to stimulation have been identified in relation to the parasylvian cortex. 44.5.1 Parasylvian Cortex and Pain Memory Parasylvian cortex receives input from the nuclei around, and subnuclei within Vc (Van Buren, J. M. and Borke, R. C., 1972) such as Vcpc, Vcpor, and putative VMpo. Parasylvian receives nociceptive input as evidenced by the presence of neurons responding to noxious stimuli (Robinson, C. J. and Burton, H., 1980; Dong, W. K. et al., 1989; 1994) and of LEP generators (Lenz, F. A. et al., 1998c; Vogel, H. et al., 2003; Ohara, S. et al., 2004b). The LEP generator is anterior to primary auditory cortex, adjacent to the S2 (secondary somatosensory cortex) generator for vibratory SEPs (somatosensory-evoked potentials) (Hamalainen, H. et al., 1990; Ohara, S. et al., 2004b). Source modeling suggests that the LEP generator is in the dorsal insula–parietal operculum (Figure 6) (Lenz, F. A. et al., 1998b; Vogel, H. et al., 2003), different from the location of the local generator for the P3 event-related potentials in the temporal base (Lenz, F. A. et al., 1998b). Differences between the locations of the late component of the LEP, the P2 wave, and the P3 suggest that the LEP P2 is not a

664 Psychophysics of Sensations Evoked by Stimulation of the Human Central Nervous System

(a)

(b) CS

14

R

23

SF

10 mm

(c)

Patient H

R

L

R

L

R

L

R

L

Patient P

LEP

Patient C

AEP

R

L

5 cm

Figure 6 Verification of subdural grid electrode position in head model for dipole source analysis. Positions of all subdural grid electrodes were determined in a postoperative CT scan. These positions were entered into a spherical head model for dipole source analysis, from which they were projected back into a preoperative magnetic resonance imaging (MRI) of this patient’s brain (patient H). (a) Intraoperative sketch shows the sylvian fissure with frontotemporal grid electrode 23 near the end of the fissure, and electrode 14 just posterior of the central sulcus. (b) Location of electrode 23 was projected from brain electromagnetic source analysis software (BESA) head coordinates into the preoperative MRI, showing excellent coincidence of the different coordinate systems used in this study. A similar correlation was found for electrode 14 and the central sulcus. (c) Projection of dipole source locations for LEP (*) and auditory – evoked potentials (AEP) (.). The projection was performed in Talairach space of a standard brain MRI. Left to right, panels show sagittal, coronal, and axial sections in patients H, P, and C, top to bottom. The LEP source was located above the sylvian fissure, and the AEP was located further posterior and below the fissure. The axial slice was aligned to pass through Heschl’s gyrus (AEP generator) to illustrate the relative location of the source of the AEP (available only in patients H and P). Reprinted from Vogel H., Port, J. D., Lenz, F. A., Solaiyappan, M., Krauss, G., and Treede, R. D. 2003. Dipole source analysis of laser-evoked subdural potentials recorded from parasylvian cortex in humans. J. Neurophysiol. 89, 3051– 3060, used with permission the American Physiological Society.

P3-like wave, signaling the alertness evoked by painful stimuli (Zaslansky, R. et al., 1995; Lenz, F. A. et al., 1998b). Rather, it is likely that the LEP P2 is primarily related to the sensation of pain (Ohara, S. et al., 2004a). The pain-related function of this area is consistent with decreased pain discrimination and tolerance with lesions of the parietal operculum and insula, respectively (Greenspan, J. D. et al., 1999). Studies in which LEPs were recorded through depth electrodes implanted in S2 and insula did not show a phase reversal in the parietal operculum, that is, S2 (Frot, M. et al., 1999). Stimulation through electrodes placed in the posterior, superior insula produced pains described as burning, stinging, electrical, and disabling sensations (Ostrowsky, K. et al., 2002). In a earlier series, stimulation of the exposed insula during awake craniotomies (n ¼ 5) produced pain uncommonly but did produce nausea, tastes, somatic sensations in the epigastric area, and rising sensations in the epigastric and umbilical areas (Penfield, W. and Jasper, H. 1954). Thus there is evidence from human stimulation studies that insula, possibly the posterior–superior portion, is involved in painrelated processes. Pain with a strong, vivid, affective dimension evoked by stimulation of the region of Vc may be related activation of its parasylvian cortical projection zone (see Section 44.4.1) (Locke, S. et al., 1961; Mehler, W. R., 1962; Van Buren, J. M. and Borke, R. C., 1972). These vivid memories are similar to those evoked by stimulation around the lateral sulcus in patients with epilepsy (Halgren, E. et al., 1978; Gloor, P. et al., 1982b; Gloor, P., 1990). These memories may be related to cortical activation rather than medial temporal structures as they are not fully formed memories like those described here (Halgren, E. et al., 1978; Gloor, P. et al., 1982a). Furthermore, fully formed memories can be evoked after removal of mesial temporal structures (Moriarity, J. L. et al., 2001). Therefore, pain with a strong affective dimension in response to thalamic stimulation results might be related to the activation of limbic and associated cortical structures (Lenz, F. A. et al., 1995). The role of the medial temporal lobe might be transiently involved in the formation of these memories, before being located in cortex, independent of medial temporal lobe structures (Mishkin, M., 1979; Friedman, D. P. et al., 1986; Zola-Morgan, S. and Squire, L. R., 1990). Painful stimuli sometimes lead to long-term changes in pain processing, as well as to signaling

Psychophysics of Sensations Evoked by Stimulation of the Human Central Nervous System

the presence of the stimulus. This appears to be the situation in the case of stimulation sites in and posterior to Vc, where stimulation can evoke complex, fully formed, pain in patients with angina or atypical chest pain. These memories seem to be due to long term changes in forebrain function, that is, conditioning, since memories of this type have not been reported in response to STT stimulation. S2 and insular cortical areas involved in pain processing also satisfy criteria for areas involved in memory through corticolimbic connections (Mishkin, M., 1979). In monkeys, a nociceptive submodality selective area has been found within S2 (Dong, W. K. et al., 1994; Willis, W. D., Jr. et al., 2001). S2 cortex projects to insular areas that project to amygdala (Friedman, D. P. et al., 1986). S2 and insular cortex have bilateral primary noxious sensory input (Chatrian, G. E. et al., 1975), and cells in these areas responding to noxious stimuli have bilateral representation (Dong, W. K. et al., 1994) and project to the medial temporal lobe (Chatrian, G. E. et al., 1975; Dong, W. K. et al., 1989). Parasylvian cortical areas receive input from nociceptive subnuclei within Vc, and from nuclei nearby (see Lateral Thalamic Nuclei) and so may be involved in memory for pain (Burton, H., 1986). This proposal is consistent with Mishkin’s hypothesis of somatic sensory memory mediated through corticolimbic connections (Mishkin, M., 1979).

44.6 Conclusions These stimulation results are consistent with those of functional imaging studies that have identified brain regions activated in a binary fashion by the application of a very specific, painful stimulus, while further increases in stimulus intensity do not produce increased activation. These brain regions may also mediate the long-term relationship of some intense pains to the strong affective dimension, which accompanies them. This relationship may also explain the affective dimension of chronic pain, which results from an intensely painful experience. These complex experiences of pain are not evoked by stimulation of the STT, again suggesting that these memories of pain involve conditioning of forebrain structures, rather than simple activation by a painful stimulus.

665

Acknowledgments This work is supported by the National Institutes of Health – National Institute of Neurological Disorders and Stroke (NS38493 and NS40059 to F. A. L.).

References Al Chaer, E. D., Lawand, N. B., Westlund, K. N., and Willis, W. D. 1996a. Pelvic visceral input into the nucleus gracilis is largely mediated by the postsynaptic dorsal column pathway. J. Neurophysiol. 76, 2675–2690. Al Chaer, E. D., Lawand, N. B., Westlund, K. N., and Willis, W. D. 1996b. Visceral nociceptive input into the ventral posterolateral nucleus of the thalamus: a new function for the dorsal column pathway. J. Neurophysiol. 76, 2661–2674. Al-Chaer, E. D., Westlund, K. N., and Willis, W. D. 1997. Nucleus gracilis: an integrator for visceral and somatic information. J. Neurophysiol. 78, 521–527. Andrew, D. and Craig, A. D. 2001. Spinothalamic lamina I neurons selectively sensitive to histamine: a central neural pathway for itch. Nat. Neurosci. 4, 72–77. Apkarian, A. V. and Hodge, C. J. 1989. Primate spinothalamic pathways. II. The cells of origin of the dorsolateral and ventral spinothalamic pathways. J. Comp. Neurol. 288, 474–492. Apkarian, A. V. and Shi, T. 1994. Squirrel monkey lateral thalamus. I. Somatic nociresponsive neurons and their relation to spinothalamic terminals. J. Neurosci. 14, 6779–6795. Becker, D. E., Yingling, C. D., and Fein, G. 1993. Identification of pain, intensity, and P300 components in the pain evoked potential. Electroencephalogr. Clin. Neurophysiol. 88, 290–301. Blomqvist, A., Zhang, E. T., and Craig, A. D. 2000. Cytoarchitectonic and immunohistochemical characterization of a specific pain and temperature relay, the posterior portion of the ventral medial nucleus, in the human thalamus. Brain 123(Pt 3), 601–619. Bowsher, D. 1957. Termination of the central pain pathway in man: the conscious appreciation of pain. Brain 80, 606–620. Braunwald, E. 1988. The History. In: Heart Disease: A Textbook of Cardiovascular Medicine (ed. E. Braunwald), pp. 1–12. W. B. Saunders. Bromm, B. and Treede, R. D. 1984. Nerve fibre discharges, cerebral potentials and sensations induced by CO2 laser stimulation. Hum. Neurobiol. 3, 33–40. Burton, H. 1986 Second Somatosensory Cortex and Related Areas. In: Cerebral Cortex, Sensory–Motor Areas and Aspects of Cortical Connectivity, (eds. E. G. Jones and A. Peters), Vol. 5. pp. 31–98. Plenum . Casey, K. L., Minoshima, S., Berger, K. L., Koeppe, R. A., Morrow, T. J., and Frey, K. A. 1994. Positron emission tomographic analysis of cerebral structures activated specifically by repetitive noxious heat stimuli. J. Neurophysiol. 71, 802–807. Chatrian, G. E., Canfield, R. C., Knauss, T. A., and Eegt, E. L. 1975. Cerebral responses to electrical tooth pulp stimulation in man. An objective correlate of acute experimental pain. Neurology 25, 745–757. Christensen, M. D., Willis, W. D., and Westlund, K. N. 1996. Anatomical evidence for cells of origin of a postsynaptic dorsal column visceral pathway: sacral spinal cord cells innervating the medial nucleus gracilis. Society For Neuroscience Abstract 22, 109.

666 Psychophysics of Sensations Evoked by Stimulation of the Human Central Nervous System Craig, A. D. 1998. A new version of the thalamic disinhibition hypothesis of central pain. Pain Focus 7, 1–14. Craig, A. D. 2003a. A new view of pain as a homeostatic emotion. Trends Neurosci. 26, 303–307. Craig, A. D. 2003b. Pain mechanisms: labeled lines versus convergence in central processing. Annu. Rev. Neurosci. 26, 1–30. Craig, A. D., Bushnell, M. C., Zhang, E. T., and Blomqvist, A. 1994. A thalamic nucleus specific for pain and temperature sensation. Nature 372, 770–773. Craig, A. D., Reiman, E. M., Evans, A., and Bushnell, M. C. 1996. Functional imaging of an illusion of pain. Nature 384, 258–260. Cusick, C. G., Wall, J. T., Felleman, D. J., and Kaas, J. H. 1989. Somatotopic organization of the lateral sulcus of owl monkeys: area 3b, S-II, and a ventral somatosensory area. J. Comp. Neurol. 282, 169–190 Davis, K. D., Kiss, Z. H. T., Tasker, R. R., and Dostrovsky, J. O. 1996. Thalamic stimulation-evoked sensations in chronic pain patients and nonpain (movement disorder) patients. J. Neurophysiol. 75, 1026–1037. Davis, K. D., Lozano, A. M., Manduch, M., Tasker, R. R., Kiss, Z. H. T., and Dostovsky, J. O. 1999. Thalamic relay site for cold perception in humans. J. Neurophysiol. 81, 1970–1973. Davis, K. D., Tasker, R. R., Kiss, Z. H. T., Hutchison, W. D., and Dostrovsky, J. O. 1995. Visceral pain evoked by thalamic microstimulation in humans. Neuroreport 6, 369–374. Dong, W. K., Chudler, E. H., Sugiyama, K., Roberts, V. J., and Hayashi, T. 1994. Somatosensory, multisensory, and taskrelated neurons in cortical area 7b (PF) of unanesthetized monkeys. J. Neurophysiol. 72, 542–564. Dong, W. K., Salonen, L. D., Kawakami, Y., Shiwaku, T., Kaukoranta, E. M., and Martin, R. F. 1989. Nociceptive responses of trigeminal neurons in SII-7b cortex of awake monkeys. Brain Res. 484, 314–324. Dostrovsky, J. O., Wells, F. E. B., and Tasker, R. R. 1991. Pain Evoked by Stimulation in Human Thalamus. In: International Symposium on Processing Nociceptive Information (ed. Y. Sjigenaga), pp. 115–120. Elsevier. Dubner, R., Kenshalo, D. R., Jr., Maixner, W., Bushnell, M. C., and Oliveras, J. L. 1989. The correlation of monkey medullary dorsal horn neuronal activity and the perceived intensity of noxious heat stimuli. J. Neurophysiol. 62, 450–457 Duncan, G. H., Bushnell, M. C., Oliveras, J. L., Bastrash, N., and Tremblay, N. 1993. Thalamic VPM nucleus in the behaving monkey. III. Effects of reversible inactivation by lidocaine on thermal and mechanical discrimination. J. Neurophysiol. 70, 2086–2096. Ferrington, D. G., Sorkin, L. S., and Willis, W. D. 1987. Responses of spinothalamic tract cells in the superficial dorsal horn of the primate lumbar spinal cord. J. Physiol. (Lond.) 388, 681–703. Friedman, D. P., Murray, E. A., O’Neill, J. B., and Mishkin, M. 1986. Cortical connections of the somatosensory fields of the lateral sulcus of macaques: evidence for a corticolimbic pathway for touch. J. Comp. Neurol. 252, 323–347. Frot, M. and Mauguiere, F. 1999. Timing and spatial distribution of somatosensory responses recorded in the upper bank of the sylvian fissure (SII area) in humans. Cereb. Cortex 9, 854–863. Gloor, P. 1990. Experiential phenomena of temporal lobe epilepsy: facts and hypotheses. Brain 113, 1673–1694. Gloor, P., Olivier, A., Quesney, L. F., Andermann, F., and Horowitz, S. 1982a. The role of the limbic system in experiential phenomena of temporal lobe epilepsy. Ann. Neurol. 12, 129–144. Gloor, P., Olivier, A., Quesney, L. F., Andermann, F., and Horowitz, S. 1982b. The role of the limbic system in

experiential phenomena of temporal lobe epilepsy. Ann. Neurol. 12, 129–144. Gracely, R. H., Lota, L., Walter, D. J., and Dubner, R. 1988. A multiple random staircase method of psychophysical pain assessment. Pain 32, 55–63. Graziano, A. and Jones, E. G. 2004. Widespread thalamic terminations of fibers arising in the superficial medullary dorsal horn of monkeys and their relation to calbindin immunoreactivity. J. Neurosci. 24, 248–256. Greenspan, J. D., Lee, R. R., and Lenz, F. A. 1999. Pain sensitivity alterations as a function of lesion location in the parasylvian cortex. Pain 81, 273–282. Greenspan, J. D., Ohara, S., Sarlani, E., and Lenz, F. A. 2004. Allodynia in patients with post-stroke central pain (CPSP) studied by statistical quantitative sensory testing within individuals. Pain 109, 357–366. Halgren, E., Walter, R. D., Cherlow, D. G., and Crandall, P. H. 1978. Mental phenomena evoked by electrical stimulation of the human hippocampal formation and amygdala. Brain 101, 83–117. Hamalainen, H., Kekoni, J., Sams, M., Reinikainen, K., and Naatanen, R. 1990. Human somatosensory evoked potentials to mechanical pulses and vibration: contributions of SI and SII somatosensory cortices to P50 and P100 components. Electroencephalogr. Clin. Neurophysiol. 75, 13–21. Hassler, R. 1959. Anatomy of the Thalamus. In: Introduction to Stereotaxis with an Atlas of the Human Brain (eds. G. Schaltenbrandand and P. Bailey), pp. 230–290. Thieme. Hassler, R. and Reichert, T. 1959 Klinische und anatomische Befunde bei stereotaktischen Schmerzoperationen im Thalamus. Arch. Psychiat. Nerverkr. 200, 93–122. Hirai, T. and Jones, E. G. 1989. A new parcellation of the human thalamus on the basis of histochemical staining. Brain Res. Rev. 14, 1–34. Ishijima, B., Yoshimasu, N., Fukushima, T., Hori, T., Sekino, H., and Sano, K. 1975. Nociceptive neurons in the human thalamus. Confin. Neurol. 37, 99–106. Jones, A. K., Brown, W. D., Friston, K. J., Qi, L. Y., and Frackowiak, R. S. 1991. Cortical and subcortical localization of response to pain in man using positron emission tomography. Proc. R. Soc. Lond. B Biol. Sci. 244, 39–44. Jones, E. G., Friedman, D. P., and Hendry, S. H. 1982. Thalamic basis of place- and modality-specific columns in monkey somatosensory cortex: a correlative anatomical and physiological study. J. Neurophysiol. 48, 545–568. Kaas, J. H., Nelson, R. J., Sur, M., Dykes, R. W., and Merzenich, M. M. 1984 The somatotopic organization of the ventroposterior thalamus of the squirrel monkey, Saimiri sciureus. J. Comp. Neurol. 226, 111–140. Kumazawa, T. and Perl, E. R. 1978. Excitation of marginal and substantia gelatinosa neurons in the primate spinal cord: indications of their place in dorsal horn functional organization. J. Comp. Neurol. 177, 417–434 Lee, J.-I., Antezanna, D., Dougherty, P. M., and Lenz, F. A. 1999. Responses of neurons in the region of the thalamic somatosensory nucleus to mechanical and thermal stimuli graded into the painful range. J. Comp. Neurol. 410, 541–555 Lenz, F. A. and Byl, N. N. 1999. Reorganization in the cutaneous core of the human thalamic principal somatic sensory nucleus (ventral caudal) in patients with dystonia. J. Neurophysiol. 82, 3204–3212. Lenz, F. A. and Dougherty, P. M. 1998. Cells in the human principal thalamic sensory nucleus (ventralis caudalis – Vc) respond to innocuous mechanical and cool stimuli. J. Neurophysiol. 79, 2227–2230.

Psychophysics of Sensations Evoked by Stimulation of the Human Central Nervous System Lenz, F. A., Dostrovsky, J. O., Tasker, R. R., Yamashiro, K., Kwan, H. C., and Murphy, J. T. 1988. Single-unit analysis of the human ventral thalamic nuclear group: somatosensory responses. J. Neurophysiol. 59, 299–316. Lenz, F. A., Gracely, R. H., Baker, F. H., Richardson, R. T., and Dougherty, P. M. 1998a. Reorganization of sensory modalities evoked by stimulation in the region of the principal sensory nucleus (ventral caudal – Vc) in patients with pain secondary to neural injury. J. Comp. Neurol. 399, 125–138. Lenz, F. A., Gracely, R. H., Hope, E. J., Baker, F. H., Rowland, L. H., Dougherty, P. M., and Richardson, R. T. 1994a. The sensation of angina can be evoked by stimulation of the human thalamus. Pain 59, 119–125. Lenz, F. A., Gracely, R. H., Romanoski, A. J., Hope, E. J., Rowland, L. H., and Dougherty, P. M. 1995. Stimulation in the human somatosensory thalamus can reproduce both the affective and sensory dimensions of previously experienced pain. Nat. Med. 1, 910–913. Lenz, F. A., Gracely, R. H., Rowland, L. H., and Dougherty, P. M. 1994b. A population of cells in the human thalamic principal sensory nucleus respond to painful mechanical stimuli. Neurosci. Lett. 180, 46–50. Lenz, F. A., Ohara, S., Gracely, R. H., Dougherty, P. M., and Patel, S. H. 2004. Pain encoding in the human forebrain: binary and analog exteroceptive channels. J. Neurosci. 24, 6540–6544. Lenz, F. A., Rios, M., Chau, D., Krauss, G. L., Zirh, T. A., and Lesser, R. P. 1998b. Painful stimuli evoke potentials recorded from the parasylvian cortex in humans. J. Neurophysiol. 80, 2077–2088. Lenz, F. A., Rios, M. R., Zirh, T. A., Krauss, G., and Lesser, R. P. 1998c. Painful stimuli evoke potentials recorded over the human anterior cingulate gyrus. J. Neurophysiol. 79, 2231–2234. Lenz, F. A., Seike, M., Lin, Y. C., Baker, F. H., Rowland, L. H., Gracely, R. H., and Richardson, R. T. 1993a. Neurons in the area of human thalamic nucleus ventralis caudalis respond to painful heat stimuli. Brain Res. 623, 235–240. Lenz, F. A., Seike, M., Richardson, R. T., Lin, Y. C., Baker, F. H., Khoja, I., Jaeger, C. J., and Gracely, R. H. 1993b. Thermal and pain sensations evoked by microstimulation in the area of human ventrocaudal nucleus. J. Neurophysiol. 70, 200–212. Locke, S., Angevine, J. B., and Marin, O. S. M. 1961. Projection of magnocellular medial geniculate nucleus in man. Anat. Rec. 139, 249–250. Matthews, M. B. 1985. Clinical Diagnosis. In: Angina Pectoris (ed. D. G. Julian), pp. 62–83. Churchill Livingstone. Mayer, D. J., Price, D. D., and Becker, D. P. 1975. Neurophysiological characterization of the anterolateral spinal cord neurons contributing to pain perception in man. Pain 1, 51–58. Mehler, W. R. 1962. The Anatomy of the So-Called ‘‘Pain Tract’’ in Man: An Analysis of the Course and Distribution of the Ascending Fibers of the Fasciculus Anterolateralis. In: Basic Research in Paraplegia (eds. J. D. French and R. W. Porter), pp. 26–55. Thomas. Mehler, W. R. 1966. The posterior thalamic region in man. Confin. Neurol. 27, 18–29. Mehler, W. R. 1969. Some neurological species differences – a posteriori. Ann. N. Y. Acad. Sci. 167, 424–468. Mishkin, M. 1979. Analogous neural models for tactual and visual learning. Neuropsychologia 17, 139–151. Moriarity, J. L., Boatman, D., Krauss, G. L., Storm, P. B., and Lenz, F. A. 2001 Human ‘‘memories’’ can be evoked by stimulation of the lateral temporal cortex after ipsilateral medial temporal lobe resection. J. Neurol. Neurosurg. Psychiatry 71, 549–551. Ohara, S. and Lenz, F. A. 2003. Medial lateral extent of thermal and pain sensations evoked by microstimulation in somatic

667

sensory nuclei of human thalamus. J. Neurophysiol. 90, 2367–2377. Ohara, S., Crone, N. E., Weiss, N., Treede, R. D., and Lenz, F. A. 2004a. Amplitudes of laser evoked potential recorded from primary somatosensory, parasylvian and medial frontal cortex are graded with stimulus intensity. Pain 110, 318–328. Ohara, S., Crone, N. E., Weiss, N., Treede, R. D., and Lenz, F. A. 2004b. Cutaneous painful laser stimuli evoke responses recorded directly from primary somatosensory cortex in awake humans. J. Neurophysiol. 91, 2734–2746. Olszewski, J. 1952. The Thalamus of Maccaca mulatta. Karger. Ostrowsky, K., Magnin, M., Ryvlin, P., Isnard, J., Guenot, M., and Mauguiere, F. 2002. Representation of pain and somatic sensation in the human insula: a study of responses to direct electrical cortical stimulation. Cereb. Cortex 12, 376–385. Pasternak, R. C., Braunwald, E., and Sobel, B. E. 1992 Acute Myocardial Infarction. In: Cardiac Disease (ed. E. Braunwald), pp. 1200–1291. W. B. Saunders. Penfield, W. and Jasper, H. 1954. Epilepsy and the Functional Anatomy of the Human Brain. Little Brown. Perl, E. R. 1984 Pain and Nociception. In: The Nervous System: Sensory Processes, Part 2 (eds. J. M. Brookhart, V. B. Mountcastle, I. Darian-Smith, and S. R. Geiger), pp. 915–975. American Physiological Society. Price, D. D. and Dubner, R. 1977. Neurons that subserve the sensory-discriminative aspects of pain. Pain 3, 307–338. Price, D. D., Greenspan, J. D., and Dubner, R. 2003. Neurons involved in the exteroceptive function of pain. Pain 106, 215–219. Price, D. D. and Mayer, D. J. 1975. Neurophysiological characterization of the anterolateral quadrant neurons subserving pain in M. mulatta. Pain 1, 59–72. Procacci, P. and Zoppi, M. 1989. Heart Pain. In: Textbook of Pain (eds. P. D. Wall and R. Melzack), pp. 410–419. Churchill Livingstone. Ralston, H. J. and Ralston, D. D. 1992. The primate dorsal spinothalamic tract: evidence for a specific termination in the posterior nuclei [Po/SG] of the thalamus. Pain 48, 107–118. Rinaldi, P. C., Young, R. F., Albe-Fessard, D. G., and Chodakiewitz, J. 1991. Spontaneous neuronal hyperactivity in the medial and intralaminar thalamic nuclei in patients with deafferentation pain. J. Neurosurg. 74, 415–421. Robinson, C. J. and Burton, H. 1980. Somatic submodality distribution within the second somatosensory (SII), 7b, retroinsular, postauditory, and granular insular cortical areas of M. fascicularis. J. Comp. Neurol. 192, 93–108. Rustioni, A., Hayes, N. L., and O’Neill, S. 1979. Dorsal column nuclei and ascending spinal afferents in macaques. Brain 102, 95–125. Sano, K. 1979. Stereotaxic Thalamolaminotomy and Posteromedial Hypothalamotomy for the Relief of Intractable Pain. In: Advances in Pain Research and Therapy (eds. J. J. Bonica and V. Ventrafridda) Vol. 2, pp. 475–485. Raven Press. Schaltenbrand, G. and Bailey, P. 1959. Introduction to Stereotaxis with an Atlas of the Human Brain. Thieme. Talairach, J. and Tournoux, P. 1988. Co-Planar Stereotaxic Atlas of the Human Brain, 3D Proportional System: An Approach to Cerebral Imaging. Georg Thieme Verlag. Talbot, J. D., Marrett, S., Evans, A. C., Meyer, E., Bushnell, M. C., and Duncan, G. H. 1991. Multiple representations of pain in human cerebral cortex. Science 251, 1355–1358. Tsubokawa, T. and Moriyasu, N. 1975. Follow-up results of centre median thalamotomy for relief of intractable pain. A method of evaluating the effectiveness during operation. Confin. Neurol. 37, 280–284. Uddenberg, N. 1968. Functional organization of long, secondorder afferents in the dorsal funiculus. Exp. Brain Res. 4, 377–382.

668 Psychophysics of Sensations Evoked by Stimulation of the Human Central Nervous System Van Buren, J. M. and Borke, R. C. 1972. Variations and Connections of the Human Thalamus. Springer. Vogel, H., Port, J. D., Lenz, F. A., Solaiyappan, M., Krauss, G., and Treede, R. D. 2003. Dipole source analysis of laserevoked subdural potentials recorded from parasylvian cortex in humans. J. Neurophysiol. 89, 3051–3060. Wang, C. C., Willis, W. D., and Westlund, K. N. 1999. Ascending projections from the area around the spinal cord central canal: a Phaseolus vulgaris leucoagglutinin study in rats. J. Comp. Neurol. 415, 341–367. Willis, W. D. 1985 The Pain System. Karger. Willis, W. D., Al Chaer, E. D., Quast, M. J., and Westlund, K. N. 1999. A visceral pain pathway in the dorsal column of the spinal cord. Proc. Natl. Acad. Sci. U. S. A. 96, 7675–7679.

Willis, W. D. and Coggeshall, R. E. 1991. Sensory Mechanisms of the Spinal Cord. Plenum. Willis, W. D., Jr., Zhang, X., Honda, C. N., and Giesler, G. J., Jr. 2001. Projections from the marginal zone and deep dorsal horn to the ventrobasal nuclei of the primate thalamus. Pain 92, 267–276. Yarnitsky, D. and Sprecher, E. 1994. Thermal testing: normative data and repeatability for various test algorithms. J. Neurol. Sci. 125, 39–45. Zaslansky, R., Sprecher, E., Tenke, C. E., Hemli, J. A., and Yarnitsky, D. 1995. The P300 in pain evoked potentials. Pain 66, 39–49. Zola-Morgan, S. and Squire, L. R. 1990. The primate hippocampal formation: evidence for a time-limited role in memory storage. Science 250, 288–290.

45 Nociceptive Processing in the Cerebral Cortex R D Treede, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany A V Apkarian, Northwestern University, Chicago, IL, USA ª 2009 Elsevier Inc. All rights reserved.

45.1 45.2 45.3 45.3.1 45.3.2 45.3.2.1 45.3.2.2 45.3.2.3 45.3.3 45.3.4 45.3.5 45.4 45.4.1 45.4.2 45.4.3 45.4.4 45.4.5 45.5 45.5.1 45.5.1.1 45.5.1.2 45.5.1.3 45.5.2 45.5.2.1 45.5.2.2 45.5.2.3 45.6 45.7 45.8 45.8.1 45.8.2 45.8.2.1 45.8.2.2 45.8.2.3 45.8.2.4 45.8.3 45.8.4 45.8.5 45.8.6 45.8.7 45.9 References

Introduction Methods to Study Nociceptive Processing in the Human Cerebral Cortex Cortical Regions that are Part of the Nociceptive System The Primary Somatosensory Cortex Parasylvian Cortex: the Operculo-Insular Region The secondary somatosensory cortex (SII) The frontal operculum The insula The Posterior Parietal Cortex The Cingulate Cortex The Prefrontal Cortex Functional Roles of Cortical Nociceptive Signal Processing Location and Quality of Phasic Pain The Time Domain Attention and Distraction Effects on Pain-Evoked Cortical Activity Anticipation and Expectation Empathy Pain Modulation Psychological Modulation of Pain Hypnosis and pain-evoked cortical activity Mood and emotional states and pain-evoked cortical activity Placebo and pain-evoked cortical activity Pharmacological Modulation of Pain Opiates Dopamine Estrogen Overview Regarding the Role of the Cortex in Acute Pain Perception Clinical Applications Chronic Pain Studying Brain Activity in Chronic Pain with Nonspecific Painful Stimuli Clinical Pain Conditions Studied by Stimulation and the Role of the Cortex Migraine Cluster headache Cardiac pain Irritable bowel syndrome Spontaneous Pain as a Confound in Assessing Brain Activity Functional Magnetic Resonance Imaging of Spontaneous Pain Neuropathic Pain Low Back Pain and Fibromyalgia Overview Regarding the Role of the Cortex in Chronic Pain Perception Conclusions and Outlook

670 671 673 673 674 675 675 676 676 677 678 678 678 680 680 681 681 681 681 681 682 682 682 682 683 683 683 684 684 684 685 686 686 686 686 687 689 689 690 690 691 691

669

670 Nociceptive Processing in the Cerebral Cortex

Glossary ACC anterior cingulate cortex (n.b.: some authors use this as a summary term for ACC and MCC) CBP Chronic back pain CRPS Complex regional pain syndrome EEG Electro-encephalography fMRI Functional magnetic resonance imaging IBS Irritable bowel syndrome IC Insular cortex MCC mid-cingulate cortex (n.b.: some authors call this region the posterior part of ACC) MEG Magneto-encephalography MRS Magnetic resonance spectroscopy

45.1 Introduction Conscious perception of external stimuli requires encoding by sensory organs, processing within the respective sensory system, and activation of the appropriate sensory cortical areas. Based on a small case series of infra- and supratentorial brain lesions, Head H. and Holmes G. (1911) postulated that the sensation of pain is an exception to this rule and that its conscious perception occurs in the essential organ of the thalamus. In spite of evidence to the contrary from clinical reports (Marshall, J., 1951; Biemond, A., 1956), evoked potentials in humans (Spreng, M. and Ichioka, M., 1964; Duclaux, R. et al., 1974; Carmon, A. et al., 1976; Chen, A. C. N. et al., 1979; Bromm, B. and Treede, R. D., 1984), single unit recordings in animals (Lamour, Y. et al., 1982; Kenshalo, D. R. and Isensee, O., 1983), neuroanatomical tracing (Gingold, S. I. et al., 1991), and some early PET studies (Buchsbaum, M. S. et al., 1984), it was maintained for a long time that the cortical representation of pain is a quantite´ negligable. This situation changed, when the modern neuroimaging techniques of positron emission tomography (PET) and later functional magnetic resonance imaging (fMRI) demonstrated systematic metabolic and perfusion changes in a large number of cortical areas following painful stimuli (Talbot, J. D. et al., 1991; Jones, A. K. P. et al., 1991a; Apkarian, A. V. et al., 1992; Davis, K. D. et al., 1995). These findings were supported by invasive and noninvasive

OIC Operculo-insular cortex, consisting of insular cortex plus the frontal, parietal and temporal operculum. PAG Periaqueductal grey PET Positron emission tomography PFC prefrontal cortex PHN Postherpetic neuralgia SI Primary somatosensory cortex SII Secondary soamtosensory cortex SCI Spinal cord injury SPECT Single photon emission computed tomography Th Thalamus

electrophysiological studies in humans, using magnetoencephalography (MEG), electroencephalography (EEG), subdural recordings directly from the surface of the brain, and depth recordings during stereotactic procedures (for a systematic review see Apkarian, A. V. et al., 2005). Meanwhile it has been recognized that painful stimuli activate a vast network of cortical areas, including the primary and secondary somatosensory cortex (SI, SII), the insula, posterior parietal cortex, anterior and mid-cingulate cortex, and parts of the prefrontal cortex (PFC; Figure 1). These areas are involved in the generation of painful percepts as well as in the descending control of pain (for review see Kenshalo, D. R. and Willis, W. D., 1991; Treede, R. D. et al., 1999; Price, D. D., 2000; Apkarian, A. V. et al., 2005). Most of these areas are also involved in other sensory, emotional, cognitive, motor or autonomic functions. Hence, the nociceptive system converges with other systems for the generation of the conscious percept of pain. In that sense, the nociceptive system is not different from the visual system, for example. But it is still an open question, to what extent any cortical regions can be considered as nociceptive specific. In this chapter we will briefly review the methods used to assess nociceptive processing in the human brain, present connectivity and functional properties of each of the principal cortical regions of the nociceptive system, and summarize the roles of the cerebral cortex in various aspects of pain perception and pain modulation.

Nociceptive Processing in the Cerebral Cortex

(a)

671

(b)

M1 S1

1 2 3

SMA PPC

2.

PCC

ACC

Insula

S2

PFC BG Amyg

AMYG

Thalamus HT

PAG

PB

1.

3. PCC

HT PAG

Figure 1 Cortical regions involved in pain perception, their interconnectivity and ascending pathways. Locations of brain regions involved in pain perception are color coded in a schematic drawing and in an example magnetic resonance image (MRI). (a) Schematic diagram shows the regions, their interconnectivity, and afferent pathways. (b) The areas corresponding to those shown in the schematic are shown in an anatomical MRI, on a coronal slice and three sagittal slices as indicated on the coronal slice: primary and secondary somatosensory cortices (S1, S2, red and orange), anterior and mid-cingulate cortex (ACC, green), insula (blue), thalamus (yellow), prefrontal cortex (PFC, purple), primary and supplementary motor cortex (M1 and SMA), posterior parietal cortex (PPC), posterior cingulate cortex (PCC), basal ganglia (BG, pink), hypothalamus (HT), amygdala (AMYG), parabrachial nuclei (PB), and periaqueductal gray (PAG). Reproduced from Apkarian, A. V., Bushnell, C., Treede, R. D., and Zubieta, J. K. 2005. Human brain mechanisms of pain perception and regulation in health and disease. Eur. J. Pain 9, 463–484.

45.2 Methods to Study Nociceptive Processing in the Human Cerebral Cortex Table 1 summarizes properties of the different brain imaging techniques that have been used to define the nociceptive network in the human brain. The most direct approach to learn about the functions of cortical neurons is direct intracellular or extracellular recording of their electrical activity during sensory stimulation and in different contexts. This technique is mostly restricted to animal studies (Kenshalo, D. R. and Isensee, O., 1983; Dong, W. K. et al., 1994) and has rarely been possible in humans (Hutchison, W. D. et al., 1999). Field potentials within the brain invert their polarity, when an electrode track passes through or close to their generator source. This technique has been used in the course of presurgical epilepsy diagnostics (Frot, M. and Mauguie`re, F., 1999), but since the electrode tracks are related to the clinical indications, only few parts of the brain have been sampled that way. Presurgical epilepsy diagnostics using subdural electrode grids samples a much larger part of the brain surface, and dipole source analysis can be used to estimate the depths of the generators below the grids (Vogel, H. et al., 2003). All of these invasive recordings in the human brain need to be interpreted with caution, because the cortical pathology that provided the

indication for the procedure (e.g., epilepsy, tumors) may have altered nociceptive signal processing. EEG and MEG are noninvasive techniques for the direct assessment of electrical activity in the brain. Mathematical algorithms are available to estimate the location of the generators within the brain from the signals recorded at the surface of the head with an accuracy of about 10 mm (Scherg, M., 1992; PascualMarqui, R. D. et al., 1994; Hari, R. and Forss, N., 1999). EEG and MEG techniques provide accurate timing information. As a result, both methods have been used mainly to identify the arrival of information to various cortical regions (stimulus-evoked potentials). Spontaneous fluctuations in EEG and MEG would provide a view of the interactions between cortical areas. However, the application of the latter to painful states has remained minimal (Chen, A. C. N., 1993; Ohara, S. et al., 2006). MEG detects brain magnetic activity, a signal that is proportional and orthogonal to the local electrical activity. Depending on the orientation of a local generator source and the gyral geometry of the brain region, evoked potentials in different brain areas may be better detected by MEG or EEG. The main weakness of EEG and MEG methods is their limited spatial resolution (on the order of 1 cm for both methods). PET, single photon emission-computed tomography (SPECT), and fMRI measure brain activity

Table 1

Brain mapping techniques, their properties, and application in pain studies

Method

Energy source

Spatial resolution (mm)

Temporal resolution (s)

Constraints

Output measured

EEG/MEG

Intrinsic electricity

10

0.001

Lack of unique localization

Electrophysiology of brain events

fMRI

Radio waves, magnetic fields Radio waves, magnetic fields

4–5

4–10

Immobilization, loud, cooperation

Relative cerebral blood flow

10

10–100

Immobilization, loud

Relative chemical concentrations

Radiation

5–10

60–1000

Radiation limits, immobilization

Physiology, neurochemistry, absolute values

Invasive, direct access to brain Immobilization, surface > depth, limited field of view Risk of seizures, immobilization, loud Immobilization, loud

Electrophysiology

Postmortem

Microarchitecture, chemoarchitecture

MRS

Nuclear (PET/ SPECT)

Brain imaging techniques available but rarely or not yet used in pain studies Single or multiunit Intrinsic 0.01–1 0.001 electrophysiology electricity Infrared light 0.05 0.05 Near infrared spectroscopy and imaging Transcranial magnetic/ Magnetic/ 10 0.01 electric electric stimulation fields Structural MRI Radio waves, 1 N/A magnetic fields Postmortem N/A 0.001 N/A

Application in pain studies Increasing in use, mainly for detecting temporal sequences Most used, mainly for localizing brain activity Recently used, for detecting long term changes in brain chemistry Decreasing in use, becoming limited to neurochemistry

Relative cerebral blood flow Electrophysiology, conduction times Structure, vasculature, white matter

EEG, electroencephalography; MEG, magnetoencephalography; fMRI, functional magnetic resonance imaging; MRS, magnetic resonance spectroscopy; PET, positron emission tomography; SPECT, single photon emission-computed tomography; N/A, not applicable.

Nociceptive Processing in the Cerebral Cortex

indirectly by imaging changes in blood flow, blood oxygenation, or local metabolic changes (Peyron, R. et al., 2000; Davis, K. D., 2003). All three methods can provide similar spatial resolution, although PET and fMRI methodologies are now far more advanced than SPECT. The statistical models and experimental designs available for PET and fMRI are robust and very rich. Therefore, these two techniques are currently most extensively used for detecting brain circuitry underlying many cognitive states, including pain. The temporal resolution of PET and SPECT is in the order of tens of seconds, while for fMRI it is shorter. PET and SPECT provide the additional opportunity for examining in vivo biochemistry and pharmacology by imaging the distributions of specific neurotransmitters or receptors. Recent MRI methods, like magnetic resonance spectroscopy (MRS), have also provided the ability to examine brain biochemistry. This approach is (a)

673

developing rapidly and has the potential to become a major method in the near future for studying brain chemistry. In addition, voxel based morphometry allows to image structural changes related to disease states (May, A. et al., 1999).

45.3 Cortical Regions that are Part of the Nociceptive System 45.3.1

The Primary Somatosensory Cortex

The primary somatosensory cortex (SI) is located in the anterior part of the parietal lobe, where it constitutes the postcentral gyrus. It consists of Brodmann areas 1, 2, 3a, and 3b (Figure 2(a)). Areas 3b and 1 receive cutaneous tactile input, areas 3a and 2 proprioceptive input. (b)

Central sulcus 1 2

3b

3a

(c)

(d) 35 50 Peak frequency (impulses s–1)

Impulses s–1

30 25 20 15 10 5

40 30 20 10 0

0

20 Brush

40

60

Pressure

80 Pinch

100

43

45 47 Stimulus intensity (°C)

50

Figure 2 Nociceptive specific neuron in the primary somatosensory cortex (SI). (a) Left: SI consists of Brodmann areas 1, 2, 3a, and 3b in the postcentral gyrus. Black dot: location of the recorded neuron. (b) The small receptive field is consistent with a role in spatial discrimination. (c) Stimulus response function to painful mechanical stimuli. (d) Stimulus response function to painful heat stimuli. Modified from Kenshalo, D. R., Iwata, K., Sholas, M., and Thomas, D. A. 2000. Response properties and organization of nociceptive neurons in area 1 of monkey primary somatosensory cortex. J. Neurophysiol. 84, 719–729.

674 Nociceptive Processing in the Cerebral Cortex

Nociceptive input to monkey SI was demonstrated anatomically. SI receives direct spinothalamocortical input from the ventrobasal nuclei, in particular the ventro-posterolateral (VPL) nucleus (Gingold, S. I. et al., 1991). Nociceptive neurons in SI are found in clusters, raising the possibility that SI may contain nociceptive specific columns (Lamour, Y. et al., 1983). Since evidence for nociceptive neurons in the most superficial cortical layers is lacking, this hypothesis has not yet been confirmed. Nociceptive neurons are rare in monkey SI and have mainly been found in area 1 (Kenshalo, D. R. et al., 2000), whereas optical imaging techniques have also suggested nociceptive input to area 3a (Tommerdahl, M. et al., 1996). Thus, nociceptive signal processing within SI may be spatially distinct from tactile signal processing that is primarily directed to area 3b. There is also some EEG and MEG evidence in humans that nociceptive areas may be situated more medially within SI than tactile areas with the same receptive fields, suggesting that nociceptive and tactile signal processing may occur in different subareas of SI (Ploner, M. et al. 2000; Schlereth, T. et al., 2003). Nociceptive input to human SI has been confirmed by subdural recordings (Kanda, M. et al., 2000; Ohara, S. et al., 2004). About 75% of the PET and fMRI studies reported activation of SI (Bushnell, M. C. et al., 1999; Apkarian, A. V. et al., 2005). Nociceptive neurons in SI have small receptive fields (Figure 2(b)) that are somatotopically arranged,

(a)

(b)

and hence are ideally suited to code for the location of nociceptive stimuli (Kenshalo, D. R. and Isensee, O., 1983). Somatotopy of nociceptive processing in the human SI has been confirmed by EEG and PET studies (Tarkka, I. M. and Treede, R. D., 1993; Andersson, J. L. R. et al., 1997). Action potential discharges of nociceptive SI neurons in monkey are modulated by the intensity of both mechanical and heat stimuli (Figures 2(c) and 2(d)) and their discharges correlate with detection speed (Kenshalo, D. R. et al., 1988). These findings suggest that nociceptive SI neurons are involved in the coding of pain intensity. This conclusion has been confirmed by a PET study of hypnotic modulation of perceived pain intensity that also modulated perfusion of SI (Hofbauer, R. K. et al., 2001) and by correlation analysis (Timmermann, L. et al., 2001).

45.3.2 Parasylvian Cortex: the OperculoInsular Region The parasylvian cortex has a complicated macroscopic structure and only some of its cytoarchitectonic areas have been charted in detail (Eickhoff, S. B. et al., 2006). In lateral views of the brain, the Sylvian fissure runs above the temporal lobe and separates it from the parietal and frontal lobes above the fissure. Hidden deep inside the Sylvian fissure lies a further lobe of the brain: the insula (Figure 3(a)). The insula is covered by the

(c)

Figure 3 Nociceptive regions in parasylvian cortex. (a) Sagittal section shows the insula as a triangular region deep inside the Sylvian fissure. (b) Transaxial section illustrates the secondary somatosensory cortex (SII) as identified by tactile stimuli (blue) and regions responsive to nociceptive stimulation (orange) that extend further rostrally and medially. (c) Coronal section shows that the temporal operculum covers the insula below the Sylvian fissure, and frontal and parietal opercula cover the insula above the fissure. Frontal and parietal opercula consist of an outer part on the convexity of the brain, a horizontal part above the Sylvian Fissure, and an inner vertical part facing the insula across its circular sulcus. Arrowheads: Sylvian fissure (lateral sulcus). Arrows: circular sulcus of the insula. Modified from Treede, R. D., Baumga¨rtner, U., and Lenz, F. A. 2007. Nociceptive Processing in the Secondary Somatosensory Cortex. In: Encyclopedia of Pain (eds. R. F. Schmidt and W. D. Willis), pp. 1376–1379. Springer.

Nociceptive Processing in the Cerebral Cortex

temporal, parietal and frontal opercula. Coronal sections reveal that the parasylvian cortex consists of the insula itself, the inner vertical surface of the opercula, the horizontal banks of the Sylvian fissure, and most laterally the outer surface of the convexity of the brain (Figure 3(c)). The majority of human imaging studies showed consistent activation of the parasylvian cortex during painful stimulation, and this activation overlapped only partly with that by tactile stimuli (Treede, R. D. et al., 2007). Lesions in parasylvian cortex cause deficits in pain perception (Greenspan, J. D. et al., 1999), and intracortical electrical stimulation of this region is painful (Ostrowsky, K. et al., 2002). Thus, this region is a good candidate to contain some nociceptive specific cortical areas, if they exist. About 75% of the PET and fMRI studies reported activation of the SII region, and 94% found activation of the insula (Treede, R. D. et al., 2000; Apkarian, A. V. et al., 2005). But due to the curvature and ¨ zcan, M. oblique course of the Sylvian fissure (O et al., 2005), activated areas are often misallocated, even across major sulci. Whereas the operculo-insular cortex in the parasylvian region has been recognized as one of the most important nociceptive cortical areas, its precise anatomical and functional organization has yet to be determined. In particular it is not yet known, whether insula and operculum subserve distinct functions or form one uniform area. 45.3.2.1 The secondary somatosensory cortex (SII)

The secondary somatosensory cortex is located in the superior bank of the Sylvian fissure, where it makes up a major part of the parietal operculum (Figures 1(b), 3(b), and 3(c)). Nociceptive input to monkey SII was demonstrated anatomically. SII receives direct spino-thalamo-cortical input from the ventrobasal nuclei, in particular the ventro-postero-inferior nucleus VPI (Stevens, R. T. et al., 1993). Nociceptive input to human SII has been confirmed by subdural recordings (Lenz, F. A. et al., 1998a). Single neuron recordings in SII have largely focused on the tactile representation (Robinson, C. J. and Burton, H. 1980; Fitzgerald, P. J. et al., 2006). The SII region contains multiple somatotopic representations of the body, suggesting the existence of several subregions (Disbrow, E. et al., 2000, Fitzgerald, P. J. et al., 2004). Although most neurons in SII have contralateral receptive fields, this is the first part of the somatosensory system with a sizable proportion of bilateral receptive fields. Hence, most imaging and

675

electrophysiological studies in humans have shown a bilateral response to unilateral stimulation, with a contralateral preponderance. Functionally, SII is considered to play a role in tactile object recognition and memory (Seitz, R. J. et al., 1991). Evoked potential recordings in humans following brief laser heat stimuli showed that SII was activated simultaneously with or even earlier than SI (Ploner, M. et al., 1999; Schlereth, T. et al., 2003). Combined anterograde and retrograde tracer studies in monkey (Apkarian, A. V. and Shi, T., 1994) support the concept that nociceptive input reaches SII more directly than tactile input. Hence, SII has been supposed to be important for the recognition of painful stimuli as such. In contrast to the abundance of evidence for nociceptive activation of the SII region from human studies, there are few single neuron recordings in this area showing specific nociceptive responses (Treede, R. D. et al., 2000). In monkey, some convergence with visual input encoding the approach of a sharp object to the face has raised the possibility of a representation of threat. These neurons, however, were not in SII proper but in area 7b which is adjacent to SII in monkey but not in humans (Dong, W. K. et al., 1994). These neurons are now considered to be part of the posterior parietal cortex (see below). Since neurons in all studies on SII were searched using mechanical skin stimulation, it is possible that these studies missed nociceptive specific neurons, because many primary nociceptive afferents are mechanically insensitive (Treede, R. D. et al., 1998). Thus, an intriguing possibility is that tactile and nociceptive inputs are represented in different areas within the SII region. 45.3.2.2

The frontal operculum Dipole source analysis of laser-evoked potentials (LEPs) in healthy volunteers, and subdural and depth recordings in patients undergoing epilepsy surgery have identified an area in the inner vertical surface of the frontal operculum (Figure 4(a)) that was activated by painful heat stimuli with a shorter latency (about 150 ms) than any other cortical area (Tarkka, I. M. and Treede, R. D., 1993; Valeriani, M. et al., 1996; Ploner, M. et al., 1999; Frot, M. and Mauguie`re, F., 2003; Schlereth, T. et al., 2003; Vogel, H. et al., 2003). This area anterior of the tactile SII area has a different somatotopic orientation (face: anterior, foot: posterior) than SII itself (face: lateral, foot: medial; Vogel, H. et al., 2003). The thalamic source of nociceptive input to this region is not yet

676 Nociceptive Processing in the Cerebral Cortex

SF

SF

Source activity (nAm)

60

Left hemisphere (c) 70 Right hemisphere 60

50

*

40

*

30 20 10

Pain rating (%)

(b) 70

(a)

Right hand Left hand

50 40 30 20 10

0

0 Dis Easy Diff

Dis Easy Diff

Figure 4 Nociceptive input to the frontal operculum. (a) Projection of dipole source locations for the first component of laser-evoked potentials (LEPs) onto a coronal magnetic resonance image slice at Talairach y ¼ 6 mm. The distribution around the roof of the circular insular sulcus, ranging from the inner vertical face of the frontal operculum to the adjacent dorsal insula matches the projection area of the nociceptive thalamic nucleus VMpo. (b) Task effects and interhemispheric differences. (c) The hemispheric asymmetry of opercular activation (left hemisphere > right hemisphere) was not reflected or caused by different visual analog score pain ratings between both hands. Dis, distraction task; Easy, easy spatial and intensity discrimination tasks; diff, difficult discrimination tasks. ANOVA: P < 0.05. Modified from Schlereth, T., Baumga¨rtner, U., Magerl, W., Stoeter, P., and Treede, R. D. 2003. Left-hemisphere dominance in early nociceptive processing in the human parasylvian cortex. Neuroimage 20, 441–454.

clear: it may be VPI like for the posteriorly adjacent SII, or it may be VMpo like for the medially adjacent dorsal insula. Somatotopy in the frontal operculum would be consistent with that of a VMpo projection target (Craig, A. D., 1995). Nociceptive input to the frontal operculum in humans has been confirmed by subdural and depth recordings (Lenz, F. A. et al., 1998a; Frot, M. et al., 1999). Responses in this area are modulated during spatial and intensity discrimination tasks and show a left-hemisphere dominance (Figures 4(b) and 4(c)).

The insula The insula is located deep inside the Sylvian fissure, where it can be visualized as a triangular shape in sagittal sections (Figure 3(a)). It often contains two long sulci in its posterior part and three short sulci rostrally. Several functional subdivisions of the insula have been suggested (Dieterich, M. et al., 2003; Schweinhardt, P. et al., 2006), but there is no consensus yet. Parts of the insula subserve varied functions in the somatosensory, vestibular, gustatory and autonomic nervous system, which led to the suggestion that this region serves for a central representation of the internal state of the body (Craig, A. D., 2002). This concept is consistent with the interoceptive aspects of nociception. Another source of nociceptive input into the parasylvian cortex is the posterior inferior part of the

ventrobasal nucleus (Lenz, F. A. et al., 1993), a region designated as VMpo by some authors (Craig, A. D. et al., 1994). VMpo projects to the dorsal insula and the adjacent frontal operculum. Nociceptive input to the insula in humans has been confirmed by depth recordings (Frot, M. et al., 2003). The somatotopic representation of pain in the dorsal insula in monkey (face: anterior, foot: posterior) is orthogonal to that in SII (face: lateral, foot: medial; Baumga¨rtner, U. et al., 2006b). Direct electrical stimulation of the insula is painful with a strong affective component (Ostrowsky, K. et al., 2002).

45.3.2.3

45.3.3

The Posterior Parietal Cortex

The posterior parietal cortex is located adjacent and posterior to SI. It comprises Brodmann areas 5 and 7 (Figure 5(c)). Nociceptive input to this region is suggested by studies in monkey that reported shortlatency responses to nociceptive stimuli in area 7b; the same neurons also responded to visual stimuli of sharp objects directed at their receptive field (Dong, W. K. et al., 1994). In the tactile system, this region is part of a dorsally directed stream involved in stimulus location, convergence with visual information and the generation of spatial information for motor control. Nociceptive input to this region in humans has not yet been explored with subdural recordings, but there is some evidence from EEG

Nociceptive Processing in the Cerebral Cortex

Visual stimulation

Syringe

target

(b)

e

trod

Elec

Impulses / 200 ms bin

(a)

B

A t.

Ipslla

lat.

a Contr

15 10 5 0

Withdraw A Hold Approach

B

C

D

E

10 s

E

D

677

C

(c) cs 1 3b

2

(d)

3a

LS T3

7b

6

S2 Ri

Pa

Spikes s–1

7b

38 °c

45 – 51 °c

15

IPS 5

Thermal stimulus - response function 20

4

10 5 0 –5 44

45

46

47 48 49 50 Temperature (°c)

51

52

Figure 5 Nociceptive neuron in posterior parietal cortex (Area 7b threat neuron). (a) Bilateral receptive field in the orofacial region; seeing a syringe approach the receptive field was also an adequate stimulus. (b) Responses to the stimuli shown in (a). (c) Location of the recorded neuron on a coronal section that passes through both the central sulcus (CS) and the Sylvian fissure (LS: lateral sulcus). (d) Stimulus response function to painful heat stimuli. IPS, Intraparietal sulcus. Modified from Dong, W. K., Chudler, E. H., Sugiyama, K., Roberts, V. J., and Hayashi, T. 1994. Somatosensory, multisensory, and task-related neurons in cortical area 7b (PF) of unanesthetized monkeys. J. Neurophysiol. 72, 542–564.

and MEG studies in humans that nociceptive stimuli activate parietal lobe posterior of SI (Schlereth, T. et al., 2003; Forss, N. et al., 2005). Few fMRI studies have assessed this region (Kulkarni, B. et al., 2005; Schmahl, C. et al., 2006).

45.3.4

The Cingulate Cortex

The cingulate cortex is located above the corpus callosum and around its anterior knee (Figure 6). The anterior cingulate cortex (ACC) comprises Brodmann areas 24 and 32, whereas the posterior cingulate cortex (PCC) contains areas 23 and 31 (Vogt, B. A. et al., 1995). ACC receives nociceptive thalamocortical input from the mediodorsal (MD) and parafascicular (Pf) nuclei (Vogt, B. A. et al., 1979). ACC has been further subdivided into midcingulate cortex, which is associated with response selection and motor efferent functions, and ACC proper that is related to emotion and autonomic efferent functions (Vogt, B. A., 2005). Nociceptive

input to human cingulate cortex has been confirmed by subdural recordings and by intracortical recordings (Lenz, F. A. et al., 1998b; Hutchison, W. D. et al., 1999). About 87% of the PET and fMRI studies reported activation of the cingulate cortex (Apkarian, A. V. et al., 2005), but no region of the cingulate cortex is considered to be nociceptive specific (Vogt, B. A., 2005). Nociceptive neurons in ACC have large or even whole-body receptive fields (Figure 7, Sikes, R. W. and Vogt, B. A., 1992; Yamamura, H. et al., 1996). For this reason it is unlikely that they contribute to the sensory dimension of pain. Monkey ACC neurons activate during pain avoidance behavior, reflecting anticipation, and response selection (Koyama, T. et al., 1998; 2001). The cingulate cortex is supposed to participate in the affective-motivational dimension of pain. This conclusion has been confirmed by a PET study of hypnotic modulation of perceived pain affect that also modulated perfusion of ACC (Hofbauer, R. K. et al., 2001) and by correlation analysis (To¨lle, T. R. et al., 1999).

678 Nociceptive Processing in the Cerebral Cortex

Figure 6 Distribution of cingulate cortex regions and subregions. Region borders are marked with arrows. Cross-hair shows vertical plane at the anterior commissure (VCA) and the anterior–posterior commissural line. A functional overview, derived from the analysis of a large volume of literature illustrates general regional function. aMCC, anterior mid-cingulate cortex; cas, callosal sulcus; cgs, cingulate sulcus; dPCC, dorsal posterior cingulate cortex; irs, inferior rostral sulcus; mr, marginal ramus of cgs; pACC, pregenual anterior cingulate cortex; pcgs, paracingulate sulcus; pMCC, posterior mid-cingulate cortex; RSC, retrosplenial cortex; sACC, subgenual anterior cingulate cortex; spls, splenial sulci; vPCC, ventral posterior cingulate cortex. Reproduced from Vogt, B. A. 2005. Pain and emotion interactions in subregions of the cingulate gyrus. Nat. Rev. Neurosci. 6, 533–544.

45.3.5

The Prefrontal Cortex

The PFC (including Brodmann areas 9, 10, 46) comprises the major part of the frontal lobe and is located anterior of the motor cortical areas. There is no evidence that it would receive a direct nociceptive thalamo-cortical input, but the PFC receives cortico-cortical input from the cingulate gyrus that may convey nociceptive information. About 55% of the PET and fMRI studies reported activation of the PRC in healthy subjects, and 81% of the studies in chronic pain patients (Apkarian, A. V. et al., 2005). The PRC is assumed to participate in the cognitive-evaluative dimension of pain and in endogenous pain control (Lorenz, J. et al., 2003; Schmahl, C. et al., 2006).

45.4 Functional Roles of Cortical Nociceptive Signal Processing Pain perception has been conceived to consist of sensory-discriminative, affective-motivational and cognitive-evaluative dimensions (Melzack, R. and Casey, K. L. 1968). The sensory-discriminative

dimension includes intensity discrimination, pain qualities, stimulus localization and timing discrimination; this dimension is traditionally thought to involve lateral thalamic nuclei and the somatosensory cortices SI and SII. The affective-motivational dimension includes perception of the negative hedonic quality of pain, autonomic nervous system manifestations of emotions, and motivated behavioral responses; this dimension is traditionally thought to involve medial thalamic nuclei and the limbic cortices ACC and MCC. The insula has an intermediate position in that concept, receiving input from lateral thalamus but projecting into the limbic system. The cognitive-evaluative dimension includes interaction with previous experience, cognitive influence on perceived pain intensity and an overall evaluation of its salience; this dimension is traditionally thought to involve the PRC. Numerous neuroimaging studies have assessed various experimental paradigms derived from several psychological concepts that do not easily fit into the traditional three dimensions of pain. Therefore, we here report imaging evidence for involvement of cortical areas in specific functions instead of the dimensions of pain. 45.4.1 Pain

Location and Quality of Phasic

Neuroimaging studies have examined brain regions activated by many types of painful stimulation, including noxious heat and cold, muscle stimulation using electric shock or hypertonic saline, topical and intradermal capsaicin, colonic distention, rectal distension, gastric distension, esophageal distension, ischemia, cutaneous electric shock, ascorbic acid, laser heat, as well as an illusion of pain evoked by combinations of innocuous temperatures (Apkarian, A. V. et al., 2005; Bushnell, M. C. and Apkarian, A. V., 2005). Despite the differences in sensation, emotion and behavioral responses provoked by these different types of pain, individuals can easily identify each as being painful. Thus, there appears to be a common construct of pain with an underlying network of brain activity in the areas described above. Nevertheless, despite the similarities in pain experiences and similarities in neural activation patterns, each pain experience is unique. Subjects can usually differentiate noxious heat from noxious cold from noxious pressure. This ability to differentiate pains is particularly puzzling, since there is ubiquitous convergence of information from cutaneous, visceral and muscle tissue throughout the

(b) (a) (c)

I II–III V

squeezing

VI

1 squeezing

8

squeezing D

2

7

1 mm

3

squeezing

4

6 squeezing

L

squeezing

5

squeezing

25 mV squeezing

100 μm

1 sec

#6T1.2443 type: N6

Figure 7 Nociceptive neuron in the anterior cingulate gyrus. (a) Responses to painful mechanical stimuli show a whole-body receptive field for this neuron. (b) Intracellular dye injection reveals a lamina V pyramidal neuron. (c) Location of the recorded neuron in the rat cingulate cortex. Reproduced from Yamamura, H., Iwata, K., Tsuboi, Y., Toda, K., Kitajima, K., Shimizu, N., Nomura, H., Hibiya, J., Fujita, S. and Sumino, R. 1996. Morphological and electrophysiological properties of ACCx nociceptive neurons in rats. Brain Res. 735, 83–92.

680 Nociceptive Processing in the Cerebral Cortex

afferent nociceptive system (Willis, W. D. and Coggeshall, R. E., 2004). The convergence and the similarities in brain regions activated by different types of pain are consistent with phenomena such as referred pain, but cannot explain either the ability to identify the origin of pain or with contrasting behavioral reactions to cutaneous and visceral pain (withdrawal versus quiescence). There is evidence from single neuron recordings, MEG, PET, and fMRI that neural activity in SI cortex could underlie the identification of the locus of cutaneous pain. Kenshalo and colleagues (Kenshalo, D. R. et al., 1988; Kenshalo, D. R. and Isensee, O., 1983) showed that SI nociceptive neurons have discrete receptive fields, so that different neurons respond to painful stimulation in different skin areas. Correspondingly, EEG, PET, and fMRI studies have shown a topographic organization of nociceptive responses in SI cortex similar to the organization of tactile responses, i.e., a medio-lateral organization of foot, hand, face, and intra-abdominal areas (Tarkka, I. M. and Treede, R. D., 1993; Andersson, J. L. R. et al., 1997; DaSilva, A. F. M. et al., 2002; Strigo, I. A. et al., 2003; Vogel, H. et al., 2003). Most imaging studies find little somatotopic organization of pain in other cortical areas (Tarkka, I. M. and Treede, R. D., 1993; Xu, X. P. et al., 1997), thus suggesting that responses in SI cortex may be most important for pain localization. More recently, a somatotopic organization has also been documented for operculo-insular cortex (Vogel, H. et al., 2003; Baumga¨rtner, U. et al., 2006a). A left hemisphere dominance has been reported for the sensory dimension of pain (Schlereth, T. et al., 2003), whereas right hemisphere dominance was observed for the affective dimension (Pauli, P. et al., 1999; Brooks, J. C. W. et al., 2002). Strigo I. A. and colleagues (2003) directly compared brain activations produced by esophageal distension and cutaneous heat on the chest that were matched for pain intensity. They found that the two qualitatively different pains produced different primary loci of activation with insula, SI, motor and prefrontal cortices. Such local differences in responses within the nociceptive network might subserve our ability to distinguish visceral and cutaneous pain as well as the differential emotional, autonomic, and motor responses associated with these different sensations. 45.4.2

The Time Domain

Most information about the temporal sequence of pain-evoked brain activation comes from EEG or

MEG studies. The dual pain sensation elicited by a single brief painful stimulus that is due to the different conduction times in nociceptive A- and C-fibers (about 1 s difference) is reflected in two sequential brain activations in EEG and MEG recordings from SI, SII, and MCC (Bromm, B. et al., 1983; Bragard, D. et al., 1996; Magerl, W. et al., 1999; Opsommer, E. et al., 2001; Iannetti, G. D. et al., 2003). EEG mapping studies (Kunde, V. and Treede, R. D., 1993; Miyazaki, M. et al., 1994), source analysis (Tarkka, I. M. and Treede, R. D., 1993; Valeriani, M. et al., 1996; Ploner, M. et al., 1999), and intracranial recordings (Lenz, F. A. et al., 1998a; Frot, M. et al., 1999) show that the earliest pain-induced brain activity originates in the vicinity of SII. In contrast, tactile stimuli activate this region only after processing in the primary somatosensory cortex (Ploner, M. et al., 2000). The adjacent dorsal insula is activated slightly but significantly later than the operculum (Frot, M. and Mauguie`re, F., 2003). These observations support the suggestion derived from anatomical studies that the SII region and adjacent insula are primary receiving areas for nociceptive input to the brain (Apkarian, A. V. and Shi, T., 1994; Craig, A. D., 2002). 45.4.3 Attention and Distraction Effects on Pain-Evoked Cortical Activity Early human brain imaging studies examining the effects of attention and distraction show modulation of pain-evoked activity in a number of cortical regions, including sensory and limbic structures, as well as prefrontal areas (Bushnell, M. C. et al., 1999; Longe, S. E. et al., 2001; Bantick, S. J. et al., 2002; Schlereth, T. et al., 2003). These results generally show reduced activations in sensory regions of the cortex and some increased activity in more frontal regions, suggesting that attentional modulation is mediated through the latter structures resulting in reduced sensory processing, where the attentional distraction is usually reported resulting in reduced perceived magnitude of pain. A more recent study extends these notions by showing that during distraction there is a functional interaction between pregenual ACC and frontal cortex exerting a topdown modulation on periaqueductal gray (PAG) and thalamus to in turn reduce activity in cortical sensory regions and correspondingly decrease perception of pain (Petrovic, P. et al., 2000; Tracey, I. et al., 2002; Valet, M. et al., 2004). Given that ACC is implicated in attentional modulation as well as pain perception, a distraction study indicates that some portions of the

Nociceptive Processing in the Cerebral Cortex

pregenual ACC region are decreased with distraction while others are increased, consistent with these two different functions (Frankenstein, U. N. et al., 2001). 45.4.4

Anticipation and Expectation

Anticipation or expectation of pain can activate many of the cortical areas related to perception of pain in the absence of a physical pain stimulus (Ploghaus, A. et al., 1999; Hsieh, J. C. et al., 1999b; Sawamoto, N. et al., 2000; Porro, C. A. et al., 2002). Two studies have attempted to identify the circuitry for modulation of pain by expectation. In one study MCC, caudate nucleus, cerebellum, and nucleus cuneiformis were modulated by systematic manipulation of pain intensity expectation by two different cues (Keltner, J. R. et al., 2006), whereas pain intensity itself modulated somatosensory cortex, insula, and rostral ACC. In the second study expectancy was modulated by a placebo procedure, resulting mainly in modulation including MCC, PRC, cerebellum, pons, and parahippocampal gyrus (Kong, J. et al., 2006). The latter study is complicated by the fact that the procedure is a combination of manipulation of expectancy and placebo acupuncture treatment. Generally, there remains a strong need for systematic studies to identify brain elements that modulate pain responses due to expectation. 45.4.5

Empathy

A provocative study opened the field regarding the interaction between pain and empathy, where the authors defined empathy as the ability to have an experience of another’s pain. Using this definition and comparing brain activity for experiencing pain or knowing that their loved one, present in the same room, was experiencing the same pain, the authors showed many cortical regions similarly activated for both conditions, especially bilateral operculo-insular cortex and MCC (Singer, T. et al., 2004). These results were interpreted as evidence for the affective component of pain being active in both empathy and pain, and thus concluded that empathy for pain involves the affective component, but not the sensory component, of pain. The study induced a flurry of activity in attempting to understand the relationship between empathy and pain. Multiple groups have replicated the main finding and proposed different underlying mechanisms (Morrison, I. et al., 2004; Botvinick, M. et al., 2005; Jackson, P. L. et al., 2005), with multiple studies showing that at least MCC

681

activity reflects the pain experienced by others and that multiple cortical areas involved in sensory processing of pain are also activated. The overall notion that empathy involves assessment of the pain experienced by others – pain mirroring – was tested directly in subjects with alexithymia, a cognitive and emotional deficit leading to difficulty in identifying one’s own emotional state and also other people’s emotional state. The study showed in fact reduced activity in PRC and MCC during a pain empathy condition in this patient population (Moriguchi, Y. et al., 2006). Even though these results are internally consistent, their interpretation remains problematic. Simple introspection casts doubt on the notion that empathy means actually experiencing another person’s pain. Instead, what is called empathy may be the assessment of the magnitude of negative emotion that the other person may be experiencing, i.e., a cognitive function of interpersonal communication. According to that concept, empathy may be defined as a complex form of psychological inference that enables us to understand the personal experience of another person through cognitive/evaluative and affective processes. A study in patients with congenital insensitivity to pain (Danziger, N. et al., 2006) reported a deficit in rating pain-inducing events, but normal inference of pain from facial expressions (empathy), indicating that empathy for pain does not require an intact pain percept.

45.5 Pain Modulation 45.5.1

Psychological Modulation of Pain

The psychological modulation of pain has been observed very early on and studied in the clinical and laboratory settings (Beydoun, A. et al., 1993; Villemure, C. and Bushnell, M. C., 2002). Modern brain imaging techniques now provide powerful tools with which mechanisms of these modulations can be documented and dissected. Given that these are cognitive/attentional modulations their effects should be observed at the cortical level. 45.5.1.1 Hypnosis and pain-evoked cortical activity

Hypnosis can alter pain perception. It has been used to differentially modulate sensory and affective dimensions of pain and thus distinguish the cortical regions involved in these dimensions. Such studies indicate that SI activity is preferentially modulated

682 Nociceptive Processing in the Cerebral Cortex

when the hypnotic instructions are directed to the intensity of pain, while MCC activity is preferentially modulated when hypnosis is directed to the unpleasantness of pain (Rainville, P. et al., 1997, Hofbauer, R. K. et al., 2001). Brain activity for hypnotically induced pain perception seem to be different from activity for imagined pain in sensory, limbic, and prefrontal activation patterns (Derbyshire, S. W. et al., 2004). The sensory and limbic cortical activations for hypnotically induced and stimulationinduced pain seem relatively similar, the only region that may be differentiating them seems to be the medial PRC (Raij, T. T. et al., 2005). 45.5.1.2 Mood and emotional states and pain-evoked cortical activity

Studies show that experimental procedures that improve mood generally reduce pain, while those that have a negative effect on mood increase pain (Zelman, D. C. et al., 1991; Marchand, S. and Arsenault, P., 2002). One study showed that looking at fearful faces increased their level of anxiety and discomfort, which also resulted in enhanced esophageal stimulation-evoked activity in limbic regions like ACC and insula (Phillips, M. L. et al., 2003). 45.5.1.3 activity

Placebo and pain-evoked cortical

Placebo is a potent modulator of pain; it afflicts all clinical studies of pain pharmacology. Placebo effects have also been seen in depression and in Parkinson’s disease and recent brain imaging studies show a robust brain and subcortical reward circuitry’s involvement in these (Lidstone, S. C. and Stoessl, A. J., 2007). The first neurochemical evidence for opiate involvement of placebo was demonstrated about 30 years ago by showing that placebo analgesia can be blocked by naloxone (Levine, J. D. et al., 1978). Consistent with this notion, changes in endogenous opiate release are shown to be involved in placeboinduced analgesia, where PRC (medial and lateral) as well as insula and ventral striatum seem to be involved, where high placebo responders increased opiate release in ventral striatum was positively correlated with pain ratings (Zubieta, J. K. et al., 2005). Results generally consistent with this brain response pattern have been demonstrated by a number of other groups (Wager, T. D. et al., 2004; Benedetti, F. et al., 2005; Kong, J. et al., 2006); the medial prefrontal/rostral ACC responses for placebo seem to recruit PAG and amygdala (Bingel, U. et al., 2006); and involvement of PAG in placebo-induced analgesia

is observed in the above studies as well, which links opiate descending modulation with prefrontal cortical control of placebo analgesia. The correspondence between placebo analgesia and reward was directly studied and the results show a strong correspondence between brain regions involved in each (Petrovic, P. et al., 2005). 45.5.2 Pharmacological Modulation of Pain A league table of analgesic efficacy has been generated based on pain-related evoked potentials (Scharein, E. and Bromm, B., 1998). Since these studies used electrical stimuli that circumvent peripheral nociceptive transduction mechanisms, this table reflects central rather than peripheral analgesic actions, as evidenced, e.g., by the higher efficacy of the antidepressant imipramine than the nonsteroidal anti-inflammatory drug (NSAID) acetylsalicylic acid. Since dipole source analysis has not been applied in these EEG studies, possible cortical sites of actions were not differentiated. Combining fMRI and pharmacology promises to provide that type of information (Tracey, I., 2001; Borsook, D. et al., 2006). In addition, PET techniques can be used for direct tracing of cortical distribution of a given drug, when it has been labeled with the positron emitting 11C isotope. 45.5.2.1

Opiates There is a vast literature regarding opiate-mediated descending modulation through the PAG and a similarly large literature on its effects on inhibitory interneurons in the spinal cord. At the cortical level, it has been noted that opiate receptors are present in many parts of the nociceptive system, with high specific binding in ACC, insula, and frontal operculum, and with moderate specific binding in MCC, SII, and SI (Jones, A. K. P. et al., 1991b; Baumga¨rtner, U. et al., 2006a). Recent studies of opiate-mediated responses in the brain have used two approaches, examination of metabolic function in response to pharmacological agents and direct measurement of opiate receptor binding potential. Exogenous administration of -opioid receptor agonist drugs show dose-dependent increased metabolic activity in regions rich with -opioid receptors, which in the cortex are mainly localized to PRC and ACC (Firestone, L. L. et al., 1996; Schlaepfer, T. E. et al., 1998; Wagner, K. J. et al., 2001). Also, -opioid agonist fentanyl on brain responses to painful stimuli

Nociceptive Processing in the Cerebral Cortex

have been explored, showing that most cortical responses to pain are reduced or eliminated, confirming analgesic effects of the opiate (Casey, K. L. et al., 2000; Petrovic, P. et al., 2002). Changes in endogenous opioid system is studied using a selective -opioid radiotracer, showing activation of opiate neurotransmission in rostral ACC, PRC, and insula during a tonic muscle pain (Zubieta, J. K. et al., 2001). 45.5.2.2

Dopamine Dopamine is best known for its role in motor, motivation, and pleasure control. There is accumulating evidence to suggest that dopamine acting at the level of the basal ganglia may also be involved in pain modulation. Human brain imaging studies document increased pain sensitivity to be associated with lower levels of endogenous dopamine (Pertovaara, A. et al., 2004; Martikainen, I. K. et al., 2005; Scott, D. J. et al., 2006); and sustained experimental pain results in release of dopamine in the basal ganglia (Scott, D. J. et al., 2006), and indicate an interaction between opiate activity and dopamine where alfentanil administration results in decreased mechanical pain and decreased release of dopamine in the basal ganglia (Hagelberg, N. et al., 2002). Moreover, abnormal levels of dopamine in the basal ganglia have been associated with chronic pain in burning mouth syndrome and atypical facial pain (Jaaskelainen, S. K. et al., 2001; Hagelberg, N. et al., 2003a; 2003b), and perhaps in fibromyalgia (Wood, P. B. et al., 2007). Patients with restless legs syndrome display a pronounced mechanical hyperalgesia to pinprick stimuli that is slowly reversed by dopaminergic agonists (Stiasny-Kolster, K. et al., 2004), but this action is probably mediated by extrastriatal dopamine receptors. 45.5.2.3

Estrogen Gender is one of the most important determinants of human health. Women far outnumber men in susceptibility to many autoimmune disorders, fibromyalgia, and chronic pain, differences in physiological responses to stress may potentially be an important risk factor for these disorders as physiologic responses to stress seem to differ according to gender, with phase of menstrual cycle, menopausal status and with pregnancy (Kajantie, E. and Phillips, D. I., 2006). Consistent with this idea recent fMRI study shows that brain activity in premenopausal women as studied for negative valence/high arousal in contrast to neutral visual stimuli show differences when the task is performed during early

683

follicular menstrual cycle phase compared to late follicular/mid-cycle; with greater activity found during early follicular phase in amygdala, hypothalamus, hippocampus, orbital frontal cortex, and ACC, suggesting that estrogen may attenuate arousal in women through cortical-subcortical control of hypothalamic–pituitary–adrenal circuitry (Goldstein, J. M. et al., 2005). There is also growing evidence of gender differences in the anatomy of the brain, its connectivity, and in cognitive abilities (Hampson, E., 2002; Becker, J. B. et al., 2005). Multiple studies have documented that threshold and tolerance for pain is lower for women (Wiesenfeld-Hallin, Z., 2005; Rolke, R. et al., 2006; Wilson, J. F., 2006). Gender differences in cortical activity for acute pain has been observed in early studies (Paulson, P. E. et al., 1998). The association of sex hormones with pain perception and pain memory was studied by Zubieta J. K. and colleagues (Zubieta, J. K. et al., 2002; Smith, Y. R. et al., 2006). They scanned healthy women during their early follicular phase when estrogen levels are low and then repeated the scan during that same phase in another month after they had worn for a week an estrogen-releasing skin patch which increased their estrogen to levels normally seen in the menstrual cycle. These studies showed that more -opioid receptors were available in the presence of high estrogen levels, and women reported less pain in response to acute painful stimuli than when their estrogen levels were low. Moreover, estrogen-associated variations in the activity of -opioid neurotransmission correlated with individual ratings of the sensory and affective perceptions of pain and the subsequent recall of that experience. These data demonstrate a significant role of estrogen in modulating endogenous opioid neurotransmission and associated psychophysical responses to an acute pain stressor in humans. Approximately similar results have been reported by another group (De Leeuw, R. et al., 2006).

45.6 Overview Regarding the Role of the Cortex in Acute Pain Perception The above sections describe the contribution of modern imaging studies to our understanding of the involvement of the cortex in pain perception. Cortical activity is demonstrated to possess properties necessary for involvement in pain perception, like somatotopic representation of painful stimuli,

684 Nociceptive Processing in the Cerebral Cortex

correlation with stimulus intensity, modulation with attention, modulation with expectation and other psychological variables, and distinct brain regions showing differential activity for sensory and affective dimensions of pain, as well as attenuation of responses with analgesic drugs (Apkarian, A. V. et al., 2005). Thus, human brain imaging studies have asserted the role of the cortex in acute pain. However, because imaging studies identify brain responses in a correlative manner, they may all reflect secondary processes. Perception of pain automatically directs attention to the source of pain, results in autonomic responses, motor reflexes to escape from the pain, and other emotional and cognitive responses that undoubtedly are at least partially mediated through cortical processes. Therefore, the role of the cortex in pain perception in contrast to its activity as a consequence of these secondary responses remains unclear and needs to be properly addressed in future studies (Apkarian, A. V., 2004). In fact, unpublished data from Apkarian’s laboratory suggest that a large proportion of the brain network activated with acute pain may be responses that are commonly involved in general magnitude estimation for any sensory modality, and as a result are not specific for nociception (abstract Society for Neuroscience 2006), suggesting that the majority of cortical activity for acute pain are instead sensory, cognitive, emotional, and attentional responses to nociceptive inputs. Careful clinical and neuropsychological examination of patients with small brain lesions, combined with high-resolution structural and neuropharmacological neuroimaging in the same patients, will be needed to address the question what brain structures are necessary for acute pain perception. Anatomical tracing studies and single unit recordings should address the question, to what extent nociceptive specific neurons exist in these brain structures. For most parts of the nociceptive cortical network, as illustrated above, it is likely that they participate only partly in pain perception, by providing certain feature extraction functions, but they also participate in other functions in different contexts.

(Treede, R. D., 2001), there is currently no measure of brain activity that would objectively show whether or not a person is in pain. Therefore, neither EEG/ MEG nor imaging with fMRI or PET can be used to verify the presence of ongoing spontaneous pain. EEG and MEG recordings of evoked potentials, however, are sensitive enough to verify whether the ascending nociceptive pathways are intact in a given individual patient (Bromm, B. and Lorenz, J., 1998; Treede, R. D. et al., 2003; Cruccu, G. et al., 2004). A prerequisite for this use of EEG and MEG technology is a phasic adequate stimulus for nociceptor activation. Radiant heat pulses of a few milliseconds duration, as generated by infrared lasers, have been validated for this purpose (Plaghki, L. and Mouraux, A., 2003), and LEPs can thus be used to verify the presence of negative sensory signs of nociception (hypoalgesia). Neither fMRI nor PET are sensitive enough to allow clinical assessment of nociceptive pathways in individual cases, since so far no activation paradigm has been developed that would reliably induce a particular cortical activation pattern in each and every healthy subject. Thus, negative findings with these techniques are inconclusive. For the study of pathological nociceptive processing at the group level, however, fMRI and PET techniques are extremely powerful. These techniques have broadened our understanding of the pathophysiology of conditions with decreased pain perception such as afferent pathway lesions or borderline personality disorder, and conditions with increased pain perception such as neuropathic pain or fibromyalgia (Gracely, R. H. et al., 2004; Maiho¨fner, C. et al., 2005; Garcia-Larrea, L. et al., 2006; Schmahl, C. et al., 2006; Schweinhardt, P. et al., 2006). In addition, PET allows direct estimation of pharmacological and biochemical processes in the brain, such as alterations in dopamine or opioid receptor availability (Hagelberg, N. et al., 2003a; Willoch, F. et al., 2004).

45.7 Clinical Applications

Chronic pain might result from cortical processing of chronic nociceptive spinothalamic input according to the same mechanisms as in acute pain, or there might be specific changes in cortical processing of nociceptive input in patients with chronic pain. Such changes

It should be emphasized that although the subjective phenomenon of being in pain can be considered an emergent phenomenon of cortical activity

45.8 Chronic Pain 45.8.1 Studying Brain Activity in Chronic Pain with Nonspecific Painful Stimuli

Nociceptive Processing in the Cerebral Cortex

could then either be a causal factor for or a consequence of the chronicity of the pain condition. A recent meta-analysis in fact shows that across some 100 studies one can establish statistically significant differences in incidence of different brain areas activated by experimental painful stimuli between acute and chronic pain conditions: PRC shows a stronger activation in chronic pain patients, whereas other nociceptive cortical areas and the thalamus show a weaker response (Table 2). A simple interpretation of these findings would be that nociceptive signal processing for experimental painful stimuli in chronic pain patients involves a reduced sensory discriminative component and an increased affectivemotivational or cognitive-evaluational component. That interpretation would also be consistent with the stronger affective component of clinical pain as compared to experimental pain (Chen, A. C. N. and Treede, R. D., 1985). But there are further implications: Is the result a consequence of some trivial confounds or does it signify changes in the physiology of pain? One could construct a long list of confounds that may underlie the observation, from attentional shifts, to coping mechanisms, to effects of drug use, and heightened anxiety and depression. The standard approach for studying brain activity for acute pain is to induce pain by a mechanical or thermal stimulus and determine brain regions modulated with the stimulus period and even with the various intensities used. Therefore, it is natural to carry the same technology to the clinical arena and apply it to chronic pain patients. As an example, we discuss one study which attempted to identify brain activity in complex regional pain syndrome (CRPS) patients using fMRI (Apkarian, A. V. et al., 2001a; 2001b). Table 2 conditions

685

The design of the study was to examine brain activity for thermal stimuli applied to the body part where CRPS pain was present, and compare brain responses to this stimulus between CRPS and healthy subjects. Moreover, as the pain in CRPS patients with sympathetically maintained pain (SMP) may be modulated by a sympathetic block, it was reasoned that one could decrease the patients’ ongoing pain and then re-examine brain activity responses to the same stimulus. The study was done in a small group of patients and this by itself is an important weakness. The main observation was that thermal stimuli in CRPS evoked more prefrontal cortical activity than usually seen in healthy subjects, and this was reversed (became more similar in pattern to normal subjects’ brain activity to thermal stimuli) following sympathetic blocks. The introduction of sympathetic blocks necessitated the use of the same procedure in healthy subjects as well, where its effects were minimal. The study also observed that when a placebo block resulted in decreased pain perception then the cortical response pattern changed similarly to that of effective blocks. These results show that brain activity may be distinct between CRPS and healthy subjects for thermal stimuli.

45.8.2 Clinical Pain Conditions Studied by Stimulation and the Role of the Cortex A direct approach to studying clinical pain states is to provoke it and examine brain activity. This is doable by drugs in headaches and in cardiac pain. As a result there is growing literature in both fields. There is also now good evidence that migraine with aura is accompanied with decreased blood flow and decreased activity in the occipital cortex, and migraine with or

Frequency of brain areas active during pain in normal subjects as compared to patients with clinical pain

Pain in normal subjects in 68 studies Clinical pain conditions in 30 studies Comparison between pain in normal subjects and in clinical conditions

ACC

SI

SII

IC

Th

PFC

47/54 (87%)

39/52 (75%)

38/51 (75%)

45/48 (94%)

28/35 (80%)

23/42 (55%)

13/29 (45%)

7/25 (28%)

5/25 (20%)

15/26 (58%)

16/27 (59%)

21/26 (81%)

P < 0.001

P < 0.001

P < 0.001

P < 0.001

P ¼ 0.095

P ¼ 0.038

Incidence values are based on positron emission tomography, single photon emission-computed tomography, and functional magnetic resonance imaging studies. For details see Apkarian et al., 2005. P values are based on Fisher’s exact statistics contrasting incidence for each area. ACC, anterior cingulate cortex; IC, insular cortex; PFC, prefrontal cortex; SI, primary somatosensory cortex; SII, secondary somatosensory cortex; Th, thalamus.

686 Nociceptive Processing in the Cerebral Cortex

without aura is associated with increased cortical thickness in visual cortical regions involved in motion detection (Granziera, C. et al., 2006). 45.8.2.1

Migraine Migraine attacks are characterized by unilateral severe headache often accompanied by nausea, phonophobia and photophobia. Activation of the trigeminovascular system is thought to be responsible for the pain itself, and cortical spreading depression (CSD) seems to underlie the aura symptoms. This view has been greatly advanced and substantiated by brain imaging studies. fMRI studies show CSD-typical cerebrovascular changes in the cortex of migraineurs while experiencing a visual aura (Hadjikhani, N. et al., 2001). The subsequent decrease in fMRI signal is temporally correlated with the scotoma that follows the scintillations. These fMRI signal changes develop first in the extrastriate cortex, contralateral to the visual changes. It then slowly migrated towards more anterior regions of the visual cortex, representing peripheral visual fields, in agreement with the progressive movement of the scintillations and scotoma from the centre of vision towards the periphery. A recent study that analyzed visually triggered attacks showed hyperemia in the occipital cortex, independently of whether the headache was preceded by visual symptoms (Cao, Y. et al., 1999). An alternative view considers migraine aura and headache as parallel rather than sequential processes, and proposes that the primary cause of migraine headache is an episodic dysfunction in brainstem nuclei that are involved in the central control of nociception (Goadsby, P. J. et al., 2002). 45.8.2.2

Cluster headache The pathophysiology of cluster headache is thought to involve multiple brain regions. Brain imaging studies imply that the associated excruciatingly severe unilateral pain is likely mediated by activation of the first (ophthalmic) division of the trigeminal nerve, while the autonomic symptoms are due to activation of the cranial parasympathetic out-flow from the VIIth cranial nerve. The circadian rhythmicity of cluster headache has led to the concept of a central origin for its initiation (Strittmatter, M. et al., 1996). Using PET in cluster headache patients, significant activations ascribable to the acute cluster headache were observed in the ipsilateral hypothalamic gray matter and in multiple cortical areas including cingulate and PRC. When compared to

the headache-free state only hypothalamic activity was distinct (May, A. et al., 2000). This highly significant activation was not seen in cluster headache patients out of the bout when compared to the patients experiencing an acute cluster headache attack. In contrast to migraine, no brainstem activation was found during the acute attack compared to the resting state. Newer MRS results further substantiate this idea by showing reduced metabolites within the hypothalamus of cluster headache patients in contrast to healthy or migraine headache controls (Wang, S. J. et al., 2006). These data suggest that while primary headaches such as migraine and cluster headache may share a common pain pathway, the trigeminovascular innervation, and activate similar cortical regions, the underlying pathogenesis may be quite different. 45.8.2.3

Cardiac pain Cardiac pain and its variants have been studied by brain imaging using various drugs that bring about these symptoms (Rosen, S. D. et al., 1996; 2002). In patients with myocardial ischemia the perception of angina is associated with activity in the hypothalamus, PAG, thalami, rostral ACC, and bilateral PRC. In patients with silent myocardial ischemia it seems that the silence is not due to impaired afferent signaling, but rather it is associated with a failure of transmission of signals from the thalamus to the frontal cortex. In contrast, in patients with syndrome X, a condition of chest pain with ischemiclike stress electrocardiography but entirely normal coronary angiogram, activity in the right anterior insula distinguished these patients from patients with known coronary disease. These patients appear to have a deficit in central pain habituation (Valeriani, M. et al., 2005). Overall, these studies imply that difference between different cardiac pain conditions are due to central processing, e.g., syndrome X is interpreted as a cortical pain syndrome, a top-down process, in contrast with the bottom-up generation of a pain percept caused by myocardial ischemia in coronary artery disease. 45.8.2.4

Irritable bowel syndrome Irritable bowel syndrome (IBS) is a disorder of abdominal pain or discomfort associated with bowel dysfunction. Hypersensitivity to visceral, but not somatic, stimuli has been demonstrated in IBS. A number of groups have examined brain activity in this condition mainly by monitoring responses to

Nociceptive Processing in the Cerebral Cortex

painful and nonpainful rectal distensions, as well as responses to the anticipation of painful distensions. Two studies are interesting since both show in normal subjects a significant positive correlation between cingulate cortex activity and subjective rating of rectal distension pain, and in both studies this relationship completely disappears in IBS patients (Silverman, D. H. et al., 1997; Mertz, H. et al., 2000). IBS is more prevalent in women than in men. Brain imaging studies have now shown gender differences in brain activity in IBS (Berman, S. M. et al., 2000; Naliboff et al., 2001; Berman, S. M. et al., 2002b; Nakai, A. et al., 2003). There are large differences between the studies, making their synthesis difficult (see Ringel, Y., 2006). More recent studies show a hint for sensitization in IBS patients because subliminal and supraliminal distensions of rectal distension seem to indicate small differences between IBS and healthy controls in the total cortical volume activated or in regional activity as a function of distention volume (Andresen, V. et al., 2005; Lawal, A. et al., 2006). A study of IBS in contrast to healthy subjects examined thermal and visceral hyperalgesia and related brain activity (Verne, G. N. et al., 2003). This seems the only study where besides pain intensity and unpleasantness measures, the authors also document fear and anxiety and show that all are rated higher by IBS for both heat and rectal distention, and not surprisingly these increased sensations and emotions give rise to larger cortical activations in IBS. The latter is most likely a reflection of a perceptual magnitude mismatch between the groups and says little as to the IBS cortical activity abnormalities. Such mismatches at least for fear and anxiety most likely are common in the majority of studies of IBS. One assumes that the simple introduction of a rectal balloon in IBS would result in increased anxiety, which undoubtedly effects cortical activity to visceral and somatic pain, yet its specific contribution has remained unexplored. In a more elegant study the authors use perception-related ratings during rectal distention to evoke either urge to defecate or pain, and compared brain activity related to the ratings between IBS patients and healthy subjects. (Kwan, C. L. et al., 2005). The approach is similar to the technique used in mapping brain activity for spontaneous pain in chronic back pain (CBP) and in postherpetic neuralgia (PHN; Baliki, M. N. et al., 2006; Geha, P. Y. et al., 2007). The results show large differences between the two groups contrasted, with far more extensive brain activations in the healthy subjects. The results are

687

complicated by the fact that the authors do not take into consideration the influence of spontaneous pain. Still, this is perhaps one of the best-controlled IBS studies, and indicates distinct cortical areas involved in the urge and pain perceptions in each group. There is now evidence that serotonin (5-HT) may be involved in IBS. One study (Nakai, A. et al., 2003) examined serotonin synthesis in the brain and indicated greater brain regional serotonin synthesis in female IBS. There is also evidence that alosetron, a 5-HT3 receptor antagonist, is clinically effective in treating some subtypes of IBS. Berman S. M. et al. (2002a) examined brain activity in a large population of IBS, before and after a randomized, placebo-controlled, 3-week use of alosetron. Treatment improved IBS symptoms and regional cerebral blood flow in brain regions rich with 5-HT3 receptor and involved in emotional and aversive functions: amygdala, ventral striatum, and dorsal pons, implying that the therapeutic effects are due to central actions and not peripheral. Thus, generally the IBS studies show that brain responses are different to rectal stimuli in patients, and that these central events may be critical to IBS. 45.8.3 Spontaneous Pain as a Confound in Assessing Brain Activity A person who has lived for years in the presence of pain, must have developed some coping mechanisms that aid in pursuing other everyday life interests in spite of the presence of the pain. How does this impact the brain? Can one consider the patient in chronic pain as composed of a brain-signaling pain together with a brain undertaking other tasks as in healthy subjects? Or, does the presence of ongoing pain interact and impact other processes as well? Certainly our cognitive and anatomic studies suggest that the latter is more likely. We have now direct evidence of the modulation that ongoing pain imposes on brain activity in general. A recent study reported brain activity for spontaneous pain in PHN patients before and after topical lidocaine treatment (Geha, P. Y. et al., 2007). The PHN patients were imaged before, after 6-hours and 2-weeks treatment with lidocaine. Behaviorally and based on questionnaires most participants showed a modest but significant decrease in their ongoing pain. The patients were scanned while they were either rating their ongoing pain or rating a visual bar that varied in time in a pattern that mimicked their ratings of pain (Figure 8). Thus, the

688 Nociceptive Processing in the Cerebral Cortex

2

Z-score

Pain

0

–2

–4 0

20

40 60 Pain intensity

80

100

0

20

40 60 Pain intensity

80

100

R PP MPFC

2

Z-score

Visual

0

–2

–4

–6.0

–2.3

2.3

6.0

Figure 8 Intensity of ongoing pain changes brain activity and thus cognitive processing. Eleven postherpetic neuralgia patients were studied by functional magnetic resonance imaging (fMRI) once before and twice after lidocaine application on the painful skin. In all sessions, patients performed two different tasks: in the Pain task they continuously rated the fluctuations of their spontaneous pain, and brain activity related to this was identified using methods. In the Visual task they rated fluctuations of a bar varying in time, brain activity was determined with the same approach as for the pain task. The relationship between brain activity and intensity of ongoing pain was determined by using a covariate analysis, where for each fMRI scan its related pain intensity was used to determine the effect of this parameter on brain responses. Across-subject and across all scans average variation of brain activity is displayed for both tasks in the left. Red are brain regions that are positively correlated and blue regions that are negatively correlated with intensity of ongoing pain (normalized to z-values). The right scatter-grams show this effect for two brain regions (right posterior parietal cortex, R PP, x ¼ 33 y ¼ 45 z ¼ 50; and medial prefrontal cortex, MPFC, x ¼ 9 y ¼ 50 z ¼ 40, as respectively circled). Each dot represents a single patient’s activity at a single time. Top scatter-gram is for Pain task; bottom for Visual task, red symbols and regression line are for MPFC; blue for R PP. MPFC exhibited significant positive correlations with pain intensity for pain ( r ¼ 0.49, P < 0.05) and visual (r ¼ 58, P < 0.01) task, while R PP showed negative correlation for pain (r ¼ 0.48, P < 0.05) and visual (r ¼ 0.64, P < 0.01) task. Brain areas that show increased correlation with ongoing pain are interpreted as a functional compensation for the decreased attentional resources. Reproduced from Geha, P. Y., Baliki, M. N., Chialvo, D. R., Harden, R. N., Paice, J. A., and Apkarian, A. V. 2007. Brain activity for spontaneous pain of postherpetic neuralgia and its modulation by lidocaine patch therapy. Pain 128, 88–100.

latter is a control task that captures motor and cognitive parts of the task but, of course, it does not reflect the pain. Brain activity for both tasks was increasing from first to third session. This observation is similar to earlier reports that decrease in clinical pain in many cases results in increased brain activity. In this case, however, the internal control was also changing in a manner parallel to

the pain condition, hinting that the effects of decreased pain was modulating more than just painrelated circuitry. To identify the role of spontaneous pain on brain activity in general, a correlation analysis was done for both tasks with mean spontaneous pain. Figure 8 shows the influence of pain intensity on across-sessions averaged brain activity for both tasks.

Nociceptive Processing in the Cerebral Cortex

The resultant map is generally similar for both tasks: activity in medial and lateral prefrontal regions was positively correlated, while posterior parietal attentional areas were negatively correlated with mean pain intensity. This result shows that brain activity for both tasks is influenced by the level of spontaneous pain, implying that pain intensity influences task performance in general. This is in line with previous studies showing that ongoing pain may interfere with cognitive functions (Lorenz, J. et al., 1997). This result reinforces the need for correcting brain activity by a control condition performed at the same pain level that is the necessity of subtracting the visual task from spontaneous pain rating task, at each treatment session. For both tasks, the fact that posterior parietal cortical activity was negatively correlated with mean ongoing pain suggests that the attentional abilities of patients are directly related to the intensity of their pain, which would in turn impact their abilities in performing anything that would demand concentration. Moreover, multiple prefrontal regions were positively correlated to the mean pain, suggesting that the patients’ brain regions underlying higher cognitive functions become more active as the pain intensity increases. The exact cognitive implications for these brain activity patterns remain unclear. In contrast, the finding indicates that the intensity of spontaneous pain impacts brain activity for any task that the subject attempts to perform, enhancing some aspects and inhibiting others. Therefore, the decreased brain activity reported for pain tasks in many clinical pain conditions (Peyron, R. et al., 2000; Derbyshire, S. W., 2003; Apkarian, A. V. et al., 2005; Kupers, R. and Kehlet, H., 2006) is most likely a reflection of the presence of the spontaneous pain, and is not specific to the task being investigated. The fact that pain intensity seems to modulate brain activity in general has another powerful consequence. It suggests that simply studying brain activity, in tasks unrelated to pain, one should be able to identify the presence of pain and study its effects on sensory/cognitive/motor/attentional processing, an exciting prospect that remains to be pursued. 45.8.4 Functional Magnetic Resonance Imaging of Spontaneous Pain Spontaneous pain is highly prevalent in clinical pain conditions, and is usually the primary drive for patients seeking medical care. Thus, understanding its related brain circuitry is both scientifically and

689

therapeutically imperative. Cortical responses to standard mechanical or thermal stimulation are of limited value for understanding these clinical pain conditions. Spontaneous pain fluctuates unpredictably in the time scale of seconds to minutes, and these fluctuations have characteristic properties that differentiate between different chronic pain conditions such as PHN and CBP (Foss, J. M. et al., 2006). This variability (specific fractal dimension) can also be observed in fMRI signals when such patients rate their spontaneous pain. Therefore, this technique was applied to study brain activity in CBP (Baliki, M. N. et al., 2006) and PHN patients (Geha, P. Y. et al., 2007) in relation to their subjective report of fluctuations of spontaneous pain. The combination of relating brain activity to spontaneous pain and correcting for confounds by subtracting brain activity for visual bar lengths, provides a robust approach with which clinical pain may be studied directly. Note that in this case the brain activity is related to exactly the event that the patient complains about. With this approach, in CBP patients (Baliki, M. N. et al., 2006) it was shown that the brain regions activated when the pain was increasing correspond to brain regions seen for acute pain in normal subjects. In contrast, for time periods when the pain was high and sustained, the brain activity was mainly limited to medial PRC, a region usually not activated for acute pain. The resultant brain activity was strongly correlated to the patients’ reported pain intensity at the time of the scan, specifically with medial prefrontal activity. Also, the duration or chronicity of the pain was captured in the insular activity, a region activated only during increases in spontaneous pain. Thus, two fundamental properties of CBP its intensity and duration were directly reflected in the brain activity identified in these patients. By applying a thermal painful stimulus in the same patients (as well as in healthy subjects) the same study showed that brain regions reflecting the stimulus intensity were not related to that reflecting the intensity of spontaneous pain. In turn, the brain region that reflected spontaneous pain intensity was only activated for the latter and did not reflect thermal painful stimulus intensity. Therefore, at least in the patient group studied spontaneous pain involved a different brain activity pattern than acute pain. 45.8.5

Neuropathic Pain

Patients with neuropathic pain show decreased responses in the thalamus to experimental painful

690 Nociceptive Processing in the Cerebral Cortex

stimuli (Peyron, R. et al., 2000). A MRS study showed a decrease in the level of N-acetyl-aspartate, a neuronal marker, in the thalami of patients with chronic neuropathic pain after spinal cord injury (SCI), when compared to patients with SCI but without pain (Pattany, P. M. et al., 2002). Thus, neurochemical brain imaging provides evidence for the occurrence of long-term changes in the brain chemistry and morphology of chronic neuropathic pain patients. Thalamic activity in neuropathic patients was also reported to increase after pain relief (Hsieh, J. C. et al., 1995), and to be significantly negatively correlated with the duration of the condition in CRPS patients (Fukumoto, M. et al., 1999). Thus, the reduced activation of the thalamus may also be an altered functional state rather than an irreversible degeneration. Neuropathic pain patients in addition show a reduced availability of opioid receptor binding sites (Maarrawi, J. et al., 2007). This reduction was symmetric in peripheral neuropathic pain, suggesting a possible release of endogenous opioids, but lateralized to the hemisphere contralateral to the pain in central pain patients, consistent with a loss of receptors (Jones, A. K. P. et al., 2004, Willoch, F. et al., 2004). Brain activity differences between healthy subjects and patients in activation paradigms are difficult to interpret since they do not distinguish between brain activity specifically related to the clinical condition and abnormalities in sensory processing secondarily associated with the clinical state. Particularly in neuropathic pain, the accompanying sensory deficit may be reflected in the imaging results and not the pain. Reduced relevance of the acute stimulus to subjects who are already in pain may also account for much of the decreased regional brain activity in neuropathic pain. To overcome such nonspecific brain activity differences one needs to compare brain activity for stimuli where perceptual evaluation has been equated between patients and normal healthy subjects. Three studies (Hsieh, J. C. et al., 1995; 1999a; Apkarian, A. V. et al., 2001b) have looked at the regions of the brain modulated by relief of chronic neuropathic pain: CRPS, peripheral neuropathy, and trigeminal neuropathy. Two of these studies show that the PRC activity is decreased, and all three studies report decreased rostral ACC activity, after successful pain relief. It is to be noted that in addition to those regions some areas were also less activated with pain relief such as the insula (Hsieh, J. C. et al., 1995) and the anterior limbic thalamus (Hsieh, J. C. et al., 1999a), whereas others were more activated

after pain relief like the medial PRC (Hsieh, J. C. et al., 1999a). This heterogeneity is not surprising because pattern of brain activity may be specific to each neuropathic pain condition. 45.8.6

Low Back Pain and Fibromyalgia

As mentioned above, brain activity of healthy subjects and patients with increased pain sensitivity should be compared in such a way that perceived intensity has been matched across the two groups. A recent study used such a design and showed generally heightened brain activity for painful stimuli of equivalent perceptual intensity both in fibromyalgia and CBP patients as compared to healthy subjects (Gracely, R. H. et al., 2002; Giesecke, T. et al., 2004). Morphometric and neurochemical brain imaging studies provide evidence for the occurrence of long-term changes in the brain chemistry and morphology of chronic pain patients. The level of N-acetyl-aspartate, a neuronal marker, was decreased in the medial and lateral PRC of CBP patients compared to an age- and gender-matched control group (Grachev, I. D. et al., 2000). A morphometric study in chronic pain showed also a decrease in gray matter density in the dorsolateral PRC and the thalamus of CBP patients when compared to matched controls (Apkarian, A. V. et al., 2004). Furthermore, these longterm chemical and morphological changes are significantly correlated with different characteristics of pain such as pain duration (Apkarian, A. V. et al., 2004), pain intensity (Pattany, P. M. et al., 2002; Grachev, I. D. et al., 2002; Apkarian, A. V. et al., 2004), and sensory-affective components (Grachev, I. D. et al., 2002). The morphometric and neurochemical studies imply an active role of the central nervous system in chronic pain, suggesting that supraspinal reorganization may be critical for chronic pain. 45.8.7 Overview Regarding the Role of the Cortex in Chronic Pain Perception In spite of a plethora of data there remains a host of uncertainties about their significance. Overall, the clinical brain imaging studies indicate reduced information transmission through the thalamus to the cortex, and increased activity in PFC, mostly in medial PFC coupled with atrophy in dorsolateral PFC. The number of studies remain very small and hence our confidence as to the reproducibility of these changes remain minimal. Still, the observations

Nociceptive Processing in the Cerebral Cortex

regarding cortical and thalamic activity changes in chronic pain are in general consistent with the notion that chronic pain conditions preferentially engage brain areas involved in cognition/emotion and decreases activity in regions involved in sensory evaluation of nociceptive inputs. Evidence has been presented that brain activity, chemistry, and morphology may be reorganized in chronic pain conditions. Does this evidence imply that there is supraspinal reorganization, above and beyond what is established in the periphery and spinal cord? That is, even if we establish a brain pattern of activity for some chronic pain condition, does this reflect some unique contribution of the brain to this state or is it simply a reflection of lower level reorganization? The answer is not straightforward. However, only by answering such questions will brain imaging be able to provide new information to the myriad mechanisms described for peripheral and spinal cord reorganization in chronic pain.

45.9 Conclusions and Outlook The study of nociceptive processing in the cerebral cortex has come a long way. In contrast to earlier assumptions, the classical somatosensory cortex areas are not the only ones activated by painful stimuli. In addition, limbic areas such as the anterior and midcingulate cortex and the insula have also been recognized as part of the nociceptive network, and more recently also cognitive areas in the PRC. Limbic areas are usually considered to mediate emotional processes, but they are also involved in autonomic and motor functions. In this way, progress in understanding the cortical nociceptive network mirrors that in understanding the subcortical networks, which also include many connections to autonomic and motor nuclei as well as hypothalamus, cerebellum, and basal ganglia. Images of brain activation by painful stimuli leave the impression that at least half of the brain participates in processing nociceptive information. At other times, many of the same areas participate in visual, motor, emotional, cognitive, or other signal processing. In that sense, our current understanding of the nociceptive network in the brain is consistent with our current understanding of how the brain uses distributed processing for its many functions. It is not clear, however, to what extent any part of the cerebral cortex is specific for nociception. The best candidate region for such a

691

function lies in the parasylvian cortex, in the vicinity of SII and the dorsal insula. In chronic pain, nociceptive processing in the cerebral cortex is partly preserved and partly altered, in particular with respect to PRC functions. This reorganization may be a neuroplastic response to the chronicity of pain, it may reflect activation of antinociceptive processes, or it may even represent a predisposing factor for the development of chronic pain. The methods available for the study of nociceptive processing in the brain allow to address many of these open questions in the near future, and this part of pain research is bound to remain a very productive one.

References Andersson, J. L. R., Lilja, A., Hartvig, P., La˚ngstro¨m, B., Gordh, T., Handwerker, H., and Torebjo¨rk, E. 1997. Somatotopic organization along the central sulcus, for pain localization in humans, as revealed by positron emission tomography. Exp. Brain Res. 117, 192–199. Andresen, V., Bach, D. R., Poellinger, A., Tsrouya, C., Stroh, A., Foerschler, A., Georgiewa, P., Zimmer, C., and Monnikes, H. 2005. Brain activation responses to subliminal or supraliminal rectal stimuli and to auditory stimuli in irritable bowel syndrome. Neurogastroenterol. Motil. 17, 827–837. Apkarian, A. V. 2004. Cortical pathophysiology of chronic pain. Novartis Found. Symp. 261, 239–245. Apkarian, A. V. and Shi, T. 1994. Squirrel monkey lateral thalamus. I. Somatic nociresponsive neurons and their relation to spinothalamic terminals. J. Neurosci. 14, 6779–6795. Apkarian, A. V., Bushnell, C., Treede, R. D., and Zubieta, J. K. 2005. Human brain mechanisms of pain perception and regulation in health and disease. Eur. J. Pain 9, 463–484. Apkarian, A. V., Grachev, I. D., and Krauss, B. R. 2001a. Imaging brain pathophysiology of chronic CRPS pain. In: Complex Regional Pain Syndrome (eds. R. Harden, W. Janig, and J. C. Baron), pp. 209–227. IASP Press. Apkarian, A. V., Sosa, Y., Sonty, S., Levy, R. E., Harden, R., Parrish, T., and Gitelman, D. 2004. Chronic back pain is associated with decreased prefrontal and thalamic gray matter density. J. Neurosci. 24, 10410–10415. Apkarian, A. V., Stea, R. A., Manglos, S. H., Szeverenyi, N. M., King, R. B., and Thomas, F. D. 1992. Persistent pain inhibits contralateral somatosensory cortical activity in humans. Neurosci. Lett. 140, 141–147. Apkarian, A. V., Thomas, P. S., Krauss, B. R., and Szeverenyi, N. M. 2001b. Prefrontal cortical hyperactivity in patients with sympathetically mediated chronic pain. Neurosci. Lett. 311, 193–197. Baliki, M. N., Chialvo, D. R., Geha, P. Y., Levy, R. M., Harden, R. N., Parrish, T. B., and Apkarian, A. V. 2006. Chronic pain and the emotional brain: specific brain activity associated with spontaneous fluctuations of intensity of chronic back pain. J. Neurosci. 26, 12165–12173. Bantick, S. J., Wise, R. G., Ploghaus, A., Clare, S., Smith, S. M., and Tracey, I. 2002. Imaging how attention modulates pain in humans using functional MRI. Brain 125, 310–319.

692 Nociceptive Processing in the Cerebral Cortex Baumga¨rtner, U., Buchholz, H. G., Bellosevich, A., Magerl, W., Siessmeier, T., Rolke, R., Ho¨hnemann, S., Piel, M., Ro¨sch, F., Wester, H. J., Henriksen, G., Stoeter, P., Bartenstein, P., Treede, R. D., and Schreckenberger, M. 2006a. High opiate receptor binding potential in the human lateral pain system. Neuroimage 30, 692–699. Baumga¨rtner, U., Tiede, W., Treede, R. D., and Craig, A. D. 2006b. Laser-evoked potentials are graded and somatotopically organized anteroposteriorly in the operculoinsular cortex of anesthetized monkeys. J. Neurophysiol. 96, 2802–2808. Becker, J. B., Arnold, A. P., Berkley, K. J., Blaustein, J. D., Eckel, L. A., Hampson, E., Herman, J. P., Marts, S., Sadee, W., Steiner, M., Taylor, J., and Young, E. 2005. Strategies and methods for research on sex differences in brain and behavior. Endocrinology 146, 1650–1673. Benedetti, F., Mayberg, H. S., Wager, T. D., Stohler, C. S., and Zubieta, J. K. 2005. Neurobiological mechanisms of the placebo effect. J. Neurosci. 25, 10390–10402. Berman, S. M., Chang, L., Suyenobu, B., Derbyshire, S. W., Stains, J., Fitzgerald, L., Mandelkern, M., Hamm, L., Vogt, B., Naliboff, B. D., and Mayer, E. A. 2002a. Conditionspecific deactivation of brain regions by 5-HT3 receptor antagonist Alosetron. Gastroenterology 123, 969–977. Berman, S., Munakata, J., Naliboff, B. D., Chang, L., Mandelkern, M., Silverman, D., Kovalik, E., and Mayer, E. A. 2000. Gender differences in regional brain response to visceral pressure in IBS patients. Eur. J. Pain 4, 157–172. Berman, S. M., Naliboff, B. D., Chang, L., Fitzgerald, L., Antolin, T., Camplone, A., and Mayer, E. A. 2002b. Enhanced preattentive central nervous system reactivity in irritable bowel syndrome. Am. J. Gastroenterol. 97, 2791–2797. Beydoun, A., Morrow, T. J., Shen, J. F., and Casey, K. L. 1993. Variability of laser-evoked potentials: attention, arousal and lateralized differences. Electroencephalogr. Clin. Neurophysiol. 88, 173–181. Bingel, U., Lorenz, J., Schoell, E., Weiller, C., and Bu¨chel, C. 2006. Mechanisms of placebo analgesia: rACC recruitment of a subcortical antinociceptive network. Pain 120, 8–15. Borsook, D., Becerra, L., and Hargreaves, R. 2006. A role for fMRI in optimizing CNS drug development. Nat. Rev. Drug Discov. 5, 411–424. Biemond, A. 1956. The conduction of pain above the level of the thalamus opticus. Arch. Neurol. Psychiat. 75, 231–244. Botvinick, M., Jha, A. P., Bylsma, L. M., Fabian, S. A., Solomon, P. E., and Prkachin, K. M. 2005. Viewing facial expressions of pain engages cortical areas involved in the direct experience of pain. Neuroimage 25, 312–319. Bragard, D., Chen, A. C. N., and Plaghki, L. 1996. Direct isolation of ultra-late (C-fibre) evoked brain potentials by CO2 laser stimulation of tiny cutaneous surface areas in man. Neurosci. Lett. 209, 81–84. Bromm, B. and Lorenz, J. 1998. Neurophysiological evaluation of pain. Electroenceph. Clin. Neurophysiol. 107, 227–253. Bromm, B. and Treede, R. D. 1984. Nerve fibre discharges, cerebral potentials and sensations induced by CO2 laser stimulation. Human Neurobiol. 3, 33–40. Bromm, B., Neitzel, H., Tecklenburg, A., and Treede, R. D. 1983. Evoked cerebral potential correlates of C-fibre activity in man. Neurosci. Lett. 43, 109–114. Brooks, J. C. W., Nurmikko, T. J., Bimson, W. E., Singh, K. D., and Roberts, N. 2002. fMRI of thermal pain: effects of stimulus laterality and attention. Neuroimage 15, 293–301. Buchsbaum, M. S., Kessler, R., King, A., Johnson, J., and Cappelletti, J. 1984. Simultaneous cerebral glucography with positron emission tomography and topographic electroencephalography. Prog. Brain Res. 62, 263–269. Bushnell, M. C. and Apkarian, A. V. 2005. Representation of Pain in the Brains. In: Wall and Melzack’s Textbook of Pain,

Chapter 6, 5th Edition (eds. S. B. McMahon and M. Koltzenburg), pp. 107–124. Elsevier. Bushnell, M. C., Duncan, G. H., Hofbauer, R. K., Ha, B., Chen, J. I., and Carrier, B. 1999. Pain perception: is there a role for primary somatosensory cortex? Proc. Natl. Acad. Sci. U. S. A. 96, 7705–7709. Cao, Y., Welch, K. M. A., Aurora, S., and Vikingstad, E. M. 1999. Functional MRI-BOLD of visually triggered headache in patients with migraine. Arch. Neurol. 56, 548–554. Carmon, A., Mor, J., and Goldberg, J. 1976. Evoked cerebral responses to noxious thermal stimuli in humans. Exp. Brain Res. 25, 103–107. Casey, K. L., Svensson, P., Morrow, T. J., Raz, J., Jone, C., and Minoshima, S. 2000. Selective opiate modulation of nociceptive processing in the human brain. J. Neurophysiol. 84, 525–533. Chen, A. C. N. 1993. Human brain measures of clinical pain: a review. I. Topographic mappings. Pain 54, 115–132. Chen, A. C. N. and Treede, R. D. 1985. The McGill pain questionnaire in the assessment of phasic and tonic experimental pain: behavioral evaluation of the ‘pain inhibiting pain’ effect. Pain 22, 67–69. Chen, A. C. N., Chapman, C. R., and Harkins, S. W. 1979. Brain evoked potentials are functional correlates of induced pain in man. Pain 6, 365–374. Craig, A. D. 1995. Supraspinal Projections of Lamina I Neurons. In: Forebrain Areas Involved in Pain Processing (eds. J. M. Besson, G. Guilbaud, and H. Ollat), pp. 13–25. John Libbey Eurotext. Craig, A. D. 2002. How do you feel? Interoception: the sense of the physiological condition of the body. Nat. Rev. 3, 655–666. Craig, A. D., Bushnell, M. C., Zhang, E. T., and Blomqvist, A. 1994. A thalamic nucleus specific for pain and temperature sensation. Nature 372, 770–773. Cruccu, G., Anand, P., Attal, N., Garcia-Larrea, L., Haanpa¨a¨, M., Jørum, E., Serra, J., and Jensen, T. S. 2004. EFNS guidelines on neuropathic pain assessment. Eur. J. Neurol. 11, 153–162. DaSilva, A. F. M., Becerra, L., Makris, N., Strassman, A. M., Gonzalez, R. G., Geatrakis, N., and Borsook, D. 2002. Somatotopic activation in the human trigeminal pain pathway. J. Neurosci. 22, 8183–8192. Danziger, N., Prkachin, K. M., and Willer, J. C. 2006. Is pain the price of empathy? The perception of others’ pain in patients with congenital insensitivity to pain. Brain 129, 2494–2507. Davis, K. D. 2003. Neurophysiological and anatomical considerations in functional imaging of pain. Pain 105, 1–3. Davis, K. D., Wood, M. L., Crawley, A. P., and Mikulis, D. J. 1995. fMRI of human somatosensory and cingulated cortex during painful electrical nerve stimulation. Neuroreport 7, 321–325. De Leeuw, R., Albuquerque, R. J., Andersen, A. H., and Carlson, C. R. 2006. Influence of estrogen on brain activation during stimulation with painful heat. J. Oral Maxillofac. Surg. 64, 158–166. Derbyshire, S. W. 2003. A systematic review of neuroimaging data during visceral stimulation. Am. J. Gastroenterol. 98, 12–20. Derbyshire, S. W., Whalley, M. G., Stenger, V. A., and Oakley, D. A. 2004. Cerebral activation during hypnotically induced and imagined pain. Neuroimage 23, 392–401. Dieterich, M., Bense, S., Lutz, S., Drzezga, A., Stephan, T., Bartenstein, P., and Brandt, T. 2003. Dominance for vestibular cortical function in the non-dominant hemisphere. Cereb. Cortex 13, 994–1007. Disbrow, E., Roberts, T., and Krubitzer, L. 2000. Somatotopic organization of cortical fields in the lateral sulcus of homo sapiens: evidence for SII and PV. J. Comp. Neurol. 418, 1–21.

Nociceptive Processing in the Cerebral Cortex Dong, W. K., Chudler, E. H., Sugiyama, K., Roberts, V. J., and Hayashi, T. 1994. Somatosensory, multisensory, and taskrelated neurons in cortical area 7b (PF) of unanesthetized monkeys. J. Neurophysiol. 72, 542–564. Duclaux, R., Franzen, O., Chatt, A. B., Kenshalo, D. R., and Stowell, H. 1974. Responses recorded from human scalp evoked by cutaneous thermal stimulation. Brain Res. 78, 279–290. Eickhoff, S. B., Schleicher, A., Zilles, K., and Amunts, K. 2006. The human parietal operculum. I. Cytoarchitectonic mapping of subdivisions. Cereb. Cortex 16, 254–267. Firestone, L. L., Gyulai, F., Mintun, M., Adler, L. J., Urso, K., and Winter, P. M. 1996. Human brain activity response to fentanyl imaged by positron emission tomography. Anesth. Analg. 82, 1247–1251. Fitzgerald, P. J., Lane, J. W., Thakur, P. H., and Hsiao, S. S. 2004. Receptive field properties of the macaque second somatosensory cortex: evidence for multiple functional representations. J. Neurosci. 24, 11193–11204. Fitzgerald, P. J., Lane, J. W., Thakur, P. H., and Hsiao, S. S. 2006. Receptive field (RF) properties of the macaque second somatosensory cortex: RF size, shape, and somatotopic organization. J. Neurosci. 26, 6485–6495. Foss, J. M., Apkarian, A. V., and Chialvo, D. R. 2006. Dynamics of pain: fractal dimension of temporal variability of spontaneous pain differentiates between pain States. J. Neurophysiol. 95, 730–736. Forss, N., Raij, T. T., Seppa, M., and Hari, R. 2005. Common cortical network for first and second pain. Neuroimage 24, 132–142. Frankenstein, U. N., Richter, W., McIntyre, M. C., and Remy, F. 2001. Distraction modulates anterior cingulate gyrus activations during the cold pressor test. Neuroimage 14, 827–836. Frot, M. and Mauguie`re, F. 1999. Operculo-insular responses to nociceptive skin stimulation in humans (A review). Neurophysiol. Clin. 29, 401–410. Frot, M. and Mauguie`re, F. 2003. Dual representation of pain in the operculo-insular cortex in humans. Brain 126, 438–450. Frot, M., Rambaud, L., Gue´not, M., and Mauguie`re, F. 1999. Intracortical recordings of early pain-related CO2-laser evoked potentials in the human second somatosensory (SII) area. Clin. Neurophysiol. 110, 133–145. Fukumoto, M., Ushida, T., Zinchuk, V. S., Yamamoto, H., and Yoshida, S. 1999. Contralateral thalamic perfusion in patients with reflex sympathetic dystrophy syndrome. Lancet 354, 1790–1791. Garcia-Larrea, L., Maarrawi, J., Peyron, R., Costes, N., Mertens, P., Magnin, M., and Laurent, B. 2006. On the relation between sensory deafferentation, pain and thalamic activity in Wallenberg’s syndrome: a PET-scan study before and after motor cortex stimulation. Eur. J. Pain 10, 677–688. Geha, P. Y., Baliki, M. N., Chialvo, D. R., Harden, R. N., Paice, J. A., and Apkarian, A. V. 2007. Brain activity for spontaneous pain of postherpetic neuralgia and its modulation by lidocaine patch therapy. Pain 128, 88–100. Giesecke, T., Gracely, R. H., Grant, M. A., Nachemson, A., Petzke, F., Williams, D. A., and Clauw, D. J. 2004. Evidence of augmented central pain processing in idiopathic chronic low back pain. Arthritis Rheum. 50, 613–623. Gingold, S. I., Greenspan, J. D., and Apkarian, A. V. 1991. Anatomic evidence of nociceptive inputs to primary somatosensory cortex: relationship between spinothalamic terminals and thalamocortical cells in squirrel monkeys. J. Comp. Neurol. 308, 467–490. Goadsby, P. J., Lipton, R. B., and Ferrari, M. D. 2002. Migraine – current understanding and treatment. N. Engl. J. Med. 346, 257–270.

693

Goldstein, J. M., Jerram, M., Poldrack, R., Ahern, T., Kennedy, D. N., Seidman, L. J., and Makris, N. 2005. Hormonal cycle modulates arousal circuitry in women using functional magnetic resonance imaging. J. Neurosci. 25, 9309–9316. Gracely, R. H., Geisser, M. E., Giesecke, T., Grant, M. A., Petzke, F., Williams, D. A., and Clauw, D. J. 2004. Pain catastrophizing and neural responses to pain among persons with fibromyalgia. Brain 127, 835–843. Gracely, R. H., Petzke, F., Wolf, J. M., and Clauw, D. J. 2002. Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Arthritis Rheum. 46, 1333–1343. Grachev, I. D., Fredrickson, B. E., and Apkarian, A. V. 2000. Abnormal brain chemistry in chronic back pain: an in vivo proton magnetic resonance spectroscopy study. Pain 89, 7–18. Grachev, I. D., Fredrickson, B. E., and Apkarian, A. V. 2002. Brain chemistry reflects dual states of pain and anxiety in chronic low back pain. J. Neural Transm. 109, 1309–1334. Granziera, C., DaSilva, A. F., Snyder, J., Tuch, D. S., and Hadjikhani, N. 2006. Anatomical alterations of the visual motion processing network in migraine with and without aura. PLoS Med. 3, e402. Greenspan, J. D., Lee, R. R., and Lenz, F. A. 1999. Pain sensitivity alterations as a function of lesion location in the parasylvian cortex. Pain 81, 273–282. Hadjikhani, N., Sanchez, d. R., Wu, O., Schwartz, D., Bakker, D., Fischl, B., Kwong, K. K., Cutrer, F. M., Rosen, B. R., Tootell, R. B., Sorensen, A. G., and Moskowitz, M. A. 2001. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc. Natl. Acad. Sci. U. S. A. 98, 4687–4692. Hagelberg, N., Forssell, H., Aalto, S., Rinne, J. O., Scheinin, H., Taiminen, T., Nagren, K., Eskola, O., and Jaaskelainen, S. K. 2003a. Altered dopamine D2 receptor binding in atypical facial pain. Pain 106, 43–48. Hagelberg, N., Forssell, H., Rinne, J. O., Scheinin, H., Taiminen, T., Aalto, S., Luutonen, S., Nagren, K., and Jaaskelainen, S. 2003b. Striatal dopamine D1 and D2 receptors in burning mouth syndrome. Pain 101, 149–154. Hagelberg, N., Kajander, J. K., Nagren, K., Hinkka, S., Hietala, J., and Scheinin, H. 2002. Mu-receptor agonism with alfentanil increases striatal dopamine D2 receptor binding in man. Synapse 45, 25–30. Hampson, E. 2002. Sex Differences in Human Brain and Cognition: the Influence of Sex Steroids in Early and Adult Life. In: Behavioral endocrinology, 2nd edn. (eds. J. B. Becker, S. M. Breedlove, D. Crews, and M. M. McCarthy) pp. 579–628. MIT Press. Hari, R. and Forss, N. 1999. Magnetoencephalography in the study of human somatosensory cortical processing. Phil. Trans. R. Soc. Lond. B 354, 1145–1154. Head, H. and Holmes, G. 1911. Sensory disturbances from cerebral lesions. Brain 34, 102–254. Hofbauer, R. K., Rainville, P., Duncan, G. H., and Bushnell, M. C. 2001. Cortical representation of the sensory dimension of pain. J. Neurophysiol. 86, 402–411. Hsieh, J. C., Belfrage, M., Stoneelander, S., Hansson, P., and Ingvar, M. 1995. Central representation of chronic ongoing neuropathic pain studied by positron emission tomography. Pain 63, 225–236. Hsieh, J. C., Meyerson, B. A., and Ingvar, M. 1999a. PET study on central processing of pain in trigeminal neuropathy. Eur. J. Pain 3, 51–65. Hsieh, J. C., Stone-Elander, S., and Ingvar, M. 1999b. Anticipatory coping of pain expressed in the human anterior

694 Nociceptive Processing in the Cerebral Cortex cingulate cortex: a positron emission tomography study. Neurosci. Lett. 262, 61–64. Hutchison, W. D., Davis, K. D., Lozano, A. M., Tasker, R. R., and Dostrovsky, J. O. 1999. Pain-related neurons in the human cingulate cortex. Nature Neurosci. 2, 403–405. Iannetti, G. D., Truini, A., Romaniello, A., Galeotti, F., Rizzo, C., Manfredi, M., and Cruccu, G. 2003. Evidence of a specific spinal pathway for the sense of warmth in humans. J. Neurophysiol. 89, 562–570. Jaaskelainen, S. K., Rinne, J. O., Forssell, H., Tenovuo, O., Kaasinen, V., Sonninen, P., and Bergman, J. 2001. Role of the dopaminergic system in chronic pain – a fluorodopa-PET study. Pain 90, 257–260. Jackson, P. L., Meltzoff, A. N., and Decety, J. 2005. How do we perceive the pain of others? A window into the neural processes involved in empathy. Neuroimage 24, 771–779. Jones, A. K. P., Brown, W. D., Friston, K. J., Qi, L. Y., and Frackowiak, R. S. J. 1991a. Cortical and subcortical localization of response to pain in man using positron emission tomography. Proc. R. Soc. Lond. B 244, 39–44. Jones, A. K. P., Qi, L. Y., Fujirawa, T., Luthra, S. K., Ashburner, J., Bloomfield, P., Cunningham, V. J., Itoh, M., Fukuda, H., and Jones, T. 1991b. In vivo distribution of opioid receptors in man in relation to the cortical projections of the medial and lateral pain systems measured with positron emission tomography. Neurosci. Lett. 126, 25–28. Jones, A. K. P., Watabe, H., Cunningham, V. J., and Jones, T. 2004. Cerebral decreases in opioid receptor binding in patients with central neuropathic pain measured by [11C]diprenorphine binding and PET. Eur. J. Pain 8, 479–485. Kajantie, E. and Phillips, D. I. 2006. The effects of sex and hormonal status on the physiological response to acute psychosocial stress. Psychoneuroendocrinology 31, 151–178. Kanda, M., Nagamine, T., Ikeda, A., Ohara, S., Kunieda, T., Fujiwara, N., Yazawa, S., Sawamoto, N., Matsumoto, R., Taki, W., and Shibasaki, H. 2000. Primary somatosensory cortex is actively involved in pain processing in human. Brain Res. 853, 282–289. Keltner, J. R., Furst, A., Fan, C., Redfern, R., Inglis, B., and Fields, H. L. 2006. Isolating the modulatory effect of expectation on pain transmission: a functional magnetic resonance imaging study. J. Neurosci. 26, 4437–4443. Kenshalo, D. R. and Isensee, O. 1983. Responses of primate SI cortical neurons to noxious stimuli. J. Neurophysiol. 50, 1479–1496. Kenshalo, D. R. and Willis, W. D. 1991. The Role of the Cerebral Cortex in Pain Sensation. In: Cerebral Cortex, Vol. 9 (ed. A. Peters), pp. 153–212. Plenum Press. Kenshalo, D. R., Chudler, E. H., Anton, F., and Dubner, R. 1988. SI nociceptive neurons participate in the encoding process by which monkeys perceive the intensity of noxious thermal stimulation. Brain Res. 454, 378–382. Kenshalo, D. R., Iwata, K., Sholas, M., and Thomas, D. A. 2000. Response properties and organization of nociceptive neurons in area 1 of monkey primary somatosensory cortex. J. Neurophysiol. 84, 719–729. Kong, J., Gollub, R. L., Rosman, I. S., Webb, J. M., Vangel, M. G., Kirsch, I., and Kaptchuk, T. J. 2006. Brain activity associated with expectancy-enhanced placebo analgesia as measured by functional magnetic resonance imaging. J. Neurosci. 26, 381–388. Koyama, T., Kato, K., Tanaka, Y. Z., and Mikami, A. 2001. Anterior cingulate activity during pain-avoidance and reward tasks in monkeys. Neurosci. Res. 39, 421–430.

Koyama, T., Tanaka, Y. Z., and Mikami, A. 1998. Nociceptive neurons in the macaque anterior cingulate activate during anticipation of pain. Neuroreport 9, 2663–2667. Kunde, V. and Treede, R. D. 1993. Topography of middlelatency somatosensory evoked potentials following painful laser stimuli and non-painful electrical stimuli. Electroenceph. Clin. Neurophysiol. 88, 280–289. Kulkarni, B., Bentley, D. E., Elliott, R., Youell, P., Watson, A., Derbyshire, S. W., Frackowiak, R. S., Friston, K. J., and Jones, A. K. 2005. Attention to pain localization and unpleasantness discriminates the functions of the medial and lateral pain systems. Eur. J. Neurosci. 21, 3133–3142. Kupers, R. and Kehlet, H. 2006. Brain imaging of clinical pain states: a critical review and strategies for future studies. Lancet Neurol. 5, 1033–1044. Kwan, C. L., Diamant, N. E., Pope, G., Mikula, K., Mikulis, D. J., and Davis, K. D. 2005. Abnormal forebrain activity in functional bowel disorder patients with chronic pain. Neurology 65, 1268–1277. Lamour, Y., Guilbaud, G., and Willer, J. C. 1983. Rat somatosensory (SmI) cortex: II. Laminar and columnar organization of noxious and non-noxious inputs. Exp. Brain Res. 49, 46–54. Lamour, Y., Willer, J. C., and Guilbaud, G. 1982. Neuronal responses to noxious stimulation in rat somatosensory cortex. Neurosci. Lett. 29, 35–40. Lawal, A., Kern, M., Sidhu, H., Hofmann, C., and Shaker, R. 2006. Novel evidence for hypersensitivity of visceral sensory neural circuitry in irritable bowel syndrome patients. Gastroenterology 130, 26–33. Lenz, F. A., Rios, M., Chau, D., Krauss, G. L., Zirh, T. A., and Lesser, R. P. 1998a. Painful stimuli evoke potentials recorded from the parasylvian cortex in humans. J. Neurophysiol. 80, 2077–2088. Lenz, F. A., Seike, M., Richardson, R. T., Lin, Y. C., Baker, F. H., Khoja, I., Jaeger, C. J., and Gracely, R. H. 1993. Thermal and pain sensations evoked by microstimulation in the area of human ventrocaudal nucleus. J. Neurophysiol. 70, 200–212. Lenz, F. A., Rios, M., Zirh, A., Chau, D., Krauss, G., and Lesser, R. P. 1998b. Painful stimuli evoke potentials recorded over the human anterior cingulate gyrus. J. Neurophysiol. 79, 2231–2234. Levine, J. D., Gordon, N. C., and Fields, H. L. 1978. The mechanism of placebo analgesia. Lancet 2, 654–657. Lidstone, S. C. and Stoessl, A. J. 2007. Understanding the placebo effect: contributions from neuroimaging. Mol. Imaging Biol. 9, 176–185. Longe, S. E., Wise, R., Bantick, S., Lloyd, D., JohansenBerg, H., McGlone, F., and Tracey, I. 2001. Counterstimulatory effects on pain perception and processing are significantly altered by attention: an fMRI study. Neuroreport 12, 2021–2025. Lorenz, J., Beck, H., and Bromm, B. 1997. Cognitive performance, mood and experimental pain before and during morphine-induced analgesia in patients with chronic non-malignant pain. Pain 73, 369–375. Lorenz, J., Minoshima, S., and Casey, K. L. 2003. Keeping pain out of mind: the role of the dorsolateral prefrontal cortex in pain modulation. Brain 126, 1079–1091. Maarrawi, J., Peyron, R., Mertens, P., Costes, N., Magnin, M., Sindou, M., Laurent, B., and Garcia-Larrea, L. 2007. Differential brain opioid receptor availability in central and peripheral neuropathic pain. Pain 127, 183–194. Magerl, W., Ali, Z., Ellrich, J., Meyer, R. A., and Treede, R. D. 1999. C- and Ad-fiber components of heat-evoked cerebral potentials in healthy human subjects. Pain 82, 127–137. Maiho¨fner, C., Forster, C., Birklein, F., Neundo¨rfer, B., and Handwerker, H. O. 2005. Brain processing during

Nociceptive Processing in the Cerebral Cortex mechanical hyperalgesia in complex regional pain syndrome: a functional MRI study. Pain 114, 93–103. Marchand, S. and Arsenault, P. 2002. Odors modulate pain perception: a gender-specific effect. Physiol. Behav. 76, 251–256. Martikainen, I. K., Hagelberg, N., Mansikka, H., Hietala, J., Nagren, K., Scheinin, H., and Pertovaara, A. 2005. Association of striatal dopamine D2/D3 receptor binding potential with pain but not tactile sensitivity or placebo analgesia. Neurosci. Lett. 376, 149–153. Marshall, J. 1951. Sensory disturbances in cortical wounds with special reference to pain. J. Neurol. Neurosurg. Psychiatry 14, 187–204. May, A., Ashburner, J., Bu¨chel, C., McGonigle, D. J., Friston, K. J., Frackowiak, R. S., and Goadsby, P. J. 1999. Correlation between structural and functional changes in brain in an idiopathic headache syndrome. Nat. Med. 5, 836–838. May, A., Bahra, A., Buchel, C., Frackowiak, R. S., and Goadsby, P. J. 2000. PET and MRA findings in cluster headache and MRA in experimental pain. Neurology 55, 1328–1335. Melzack, R. and Casey, K. L. 1968. Sensory, Motivational, and Central Control Determinants of Pain. A New Conceptual Model. In: The Skin Senses. (eds. D. R Kenshalo and C. Charles), pp. 423–443. Thomas. Mertz, H., Morgan, V., Tanner, G., Pickens, D., Price, R., Shyr, Y., and Kessler, R. 2000. Regional cerebral activation in irritable bowel syndrome and control subjects with painful and nonpainful rectal distention. Gastroenterology 118, 842–848. Miyazaki, M., Shibasaki, H., Kanda, M., Xu, X., Shindo, K., Honda, M., Ikeda, A., Nagamine, T., Kaji, R., and Kimura, J. 1994. Generator mechanism of pain-related evoked potentials following CO2 laser stimulation of the hand: scalp topography and effect of predictive warning signal. J. Clin. Neurophysiol. 11, 242–254. Moriguchi, Y., Decety, J., Ohnishi, T., Maeda, M., Mori, T., Nemoto, K., Matsuda, H., and Komaki, G. 2006. Empathy and judging other’s pain: an fMRI study of alexithymia. Cereb. Cortex doi: 10.1093/cercor/bh1130. Morrison, I., Lloyd, D., di Pellegrino, G., and Roberts, N. 2004. Vicarious responses to pain in anterior cingulate cortex: is empathy a multisensory issue? Cogn. Affect. Behav. Neurosci. 4, 270–278. Nakai, A., Kumakura, Y., Boivin, M., Rosa, P., Diksic, M., D’Souza, D., and Kersey, K. 2003. Sex differences of brain serotonin synthesis in patients with irritable bowel syndrome using a [11C]methyl-l-tryptophan, positron emission tomography and statistical parametric mapping. Can. J. Gastroenterol. 17, 191–196. ¨ zcan, M., Baumga¨rtner, U., Vucurevic, G., Stoeter, P., and O Treede, R. D. 2005. Spatial resolution of fMRI in the human parasylvian cortex: comparison of somatosensory and auditory activation. Neuroimage 25, 877–887. Ohara, S., Crone, N. E., Weiss, N., and Lenz, F. A. 2006. Analysis of synchrony demonstrates ‘pain networks’ defined by rapidly switching, task-specific, functional connectivity between pain-related cortical structures. Pain 123, 244–253. Ohara, S., Crone, N. E., Weiss, N., Treede, R. D., and Lenz, F. A. 2004. Cutaneous painful laser stimuli evoke responses recorded directly from primary somatosensory cortex in awake humans. J. Neurophysiol. 91, 2734–2746. Opsommer, E., Weiss, T., Plaghki, L., and Miltner, W. H. R. 2001. Dipole analysis of ultralate (C-fibres) evoked potentials after laser stimulation of tiny cutaneous surface areas in humans. Neurosci. Lett. 298, 41–44. Ostrowsky, K., Magnin, M., Ryvlin, P., Isnard, J., Guenot, M., and Mauguie`re, F. 2002. Representation of

695

pain and somatic sensation in the human insula: a study of responses to direct electrical cortical stimulation. Cereb. Cortex 12, 376–385. Pascual-Marqui, R. D., Michel, C. M., and Lehmann, D. 1994. Low resolution electromagnetic tomography: a new method for localizing electrical activity in the brain. Int. J. Psychophysiol. 18, 49–65. Pattany, P. M., Yezierski, R. P., Widerstrom-Noga, E. G., Bowen, B. C., Martinez-Arizala, A., Garcia, B. R., and Quencer, R. M. 2002. Proton magnetic resonance spectroscopy of the thalamus in patients with chronic neuropathic pain after spinal cord injury. AJNR Am. J. Neuroradiol. 23, 901–905. Pauli, P., Wiedemann, G., and Nickola, M. 1999. Pain sensitivity, cerebral laterality, and negative affect. Pain 80, 359–364. Paulson, P. E., Minoshima, S., Morrow, T. J., and Casey, K. L. 1998. Gender differences in pain perception and patterns of cerebral activation during noxious heat stimulation in humans. Pain 76, 223–229. Pertovaara, A., Martikainen, I. K., Hagelberg, N., Mansikka, H., Nagren, K., Hietala, J., and Scheinin, H. 2004. Striatal dopamine D2/D3 receptor availability correlates with individual response characteristics to pain. Eur. J. Neurosci. 20, 1587–1592. Petrovic, P., Dietrich, T., Fransson, P., Andersson, J., Carlsson, K., and Ingvar, M. 2005. Placebo in emotional processing-induced expectations of anxiety relief activate a generalized modulatory network. Neuron 46, 957–969. Petrovic, P., Kalso, E., Petersson, K. M., and Ingvar, M. 2002. Placebo and opioid analgesia- imaging a shared neuronal network. Science 295, 1737–1740. Petrovic, P., Petersson, K. M., Ghatan, P. H., Stone-Elander, S., and Ingvar, M. 2000. Pain-related cerebral activation is altered by a distracting cognitive task. Pain 85, 19–30. Peyron, R., Laurent, B., and Garcı´a-Larrea, L. 2000. Functional imaging of brain responses to pain. A review and metaanalysis 2000. Neurophysiol. Clin. 30, 263–288. Phillips, M. L., Gregory, L. J., Cullen, S., Cohen, S., Ng, V., Andrew, C., Giampietro, V., Bullmore, E., Zelaya, F., Amaro, E., Thompson, D. G., Hobson, A. R., Williams, S. C., Brammer, M., and Aziz, Q. 2003. The effect of negative emotional context on neural and behavioural responses to oesophageal stimulation. Brain 126, 669–684. Plaghki, L. and Mouraux, A. 2003. How do we selectively activate skin nociceptors with a high power infrared laser? Physiology and biophysics of laser stimulation. Neurophysiol. Clin. 33, 269–277. Ploghaus, A., Tracey, I., Gati, J. S., Clare, S., Menon, R. S., Matthews, P. M., and Rawlins, J. N. 1999. Dissociating pain from its anticipation in the human brain. Science 284, 1979–1981. Ploner, M., Schmitz, F., Freund, H. J., and Schnitzler, A. 1999. Parallel activation of primary and secondary somatosensory cortices in human pain processing. J. Neurophysiol. 81, 3100–3104. Ploner, M., Schmitz, F., Freund, H. J., and Schnitzler, A. 2000. Differential organization of touch and pain in human primary somatosensory cortex. J. Neurophysiol. 83, 1770–1776. Porro, C. A., Baraldi, P., Pagnoni, G., Serafini, M., Facchin, P., Maieron, M., and Nichelli, P. 2002. Does anticipation of pain affect cortical nociceptive systems? J. Neurosci. 22, 3206–3214. Price, D. D. 2000. Psychological and neural mechanisms of the affective dimension of pain. Science 288, 1769–1772. Raij, T. T., Numminen, J., Narvanen, S., Hiltunen, J., and Hari, R. 2005. Brain correlates of subjective reality of physically and

696 Nociceptive Processing in the Cerebral Cortex psychologically induced pain. Proc. Natl. Acad. Sci. U. S. A. 102, 2147–2151. Rainville, P., Duncan, G. H., Price, D. D., Carrier, B., and Bushnell, M. C. 1997. Pain affect encoded in human anterior cingulate but not somatosensory cortex. Science 277, 968–971. Ringel, Y. 2006. New directions in brain imaging research in functional gastrointestinal disorders. Dig. Dis. 24, 278–285. Robinson, C. J. and Burton, H. 1980. Somatic submodality distribution within the second somatosensory (SII), 7b, retroinsular, postauditory, and granular insular cortical areas of M. fascicularis. J. Comp. Neurol. 192, 93–108. Rolke, R., Baron, R., Maier, C., To¨lle, T. R., Treede, R. D., Beyer, A., Binder, A., Birbaumer, N., Birklein, F., Botefur, I. C., Braune, S., Flor, H., Huge, V., Klug, R., Landwehrmeyer, G. B., Magerl, W., Maihofner, C., Rolko, C., Schaub, C., Scherens, A., Sprenger, T., Valet, M., and Wasserka, B. 2006. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values. Pain 123, 231–243. Rosen, S. D., Paulesu, E., Nihoyannopoulos, P., Tousoulis, D., Frackowiak, R. S., Frith, C. D., Jones, T., and Camici, P. G. 1996. Silent ischemia as a central problem: regional brain activation compared in silent and painful myocardial ischemia. Ann. Intern. Med. 124, 939–949. Rosen, S. D., Paulesu, E., Wise, R. J., and Camici, P. G. 2002. Central neural contribution to the perception of chest pain in cardiac syndrome X. Heart 87, 513–519. Sawamoto, N., Honda, M., Okada, T., Hanakawa, T., Kanda, M., Fukuyama, H., Konishi, J., and Shibasaki, H. 2000. Expectation of pain enhances responses to nonpainful somatosensory stimulation in the anterior cingulate cortex and parietal operculum/posterior insula: an event-related functional magnetic resonance imaging study. J. Neurosci. 20, 7438–7445. Scharein, E. and Bromm, B. 1998. The intracutaneous pain model in the assessment of analgesic efficacy. Pain Rev. 5, 216–246. Scherg, M. 1992. Functional imaging and localization of electromagnetic brain activity. Brain Topogr. 5, 103–111. Schlaepfer, T. E., Strain, E. C., Greenberg, B. D., Preston, K. L., Lancaster, E., Bigelow, G. E., Barta, P. E., and Pearlson, G. D. 1998. Site of opioid action in the human brain: mu and kappa agonists’ subjective and cerebral blood flow effects. Am. J. Psychiatry 155, 470–473. Schlereth, T., Baumga¨rtner, U., Magerl, W., Stoeter, P., and Treede, R. D. 2003. Left-hemisphere dominance in early nociceptive processing in the human parasylvian cortex. Neuroimage 20, 441–454. Schmahl, C., Bohus, M., Esposito, F., Treede, R. D., Di Salle, F., Greffrath, W., Ludaescher, P., Jochims, A., Lieb, K., Scheffler, K., Hennig, J., and Seifritz, E. 2006. Neural correlates of antinociception in borderline personality disorder. Arch. Gen. Psychiatry 63, 659–667. Schweinhardt, P., Glynn, C., Brooks, J., McQuay, H., Jack, T., Chessell, I., Bountra, C., and Tracey, I. 2006. An fMRI study of cerebral processing of brush-evoked allodynia in neuropathic pain patients. Neuroimage 32, 256–265. Scott, D. J., Heitzeg, M. M., Koeppe, R. A., Stohler, C. S., and Zubieta, J. K. 2006. Variations in the human pain stress experience mediated by ventral and dorsal basal ganglia dopamine activity. J. Neurosci. 26, 10789–10795. Seitz, R. J., Roland, P. E., Bohm, C., Greitz, T., and StoneElander, S. 1991. Somatosensory discrimination of shape: tactile exploration and cerebral activation. Eur. J. Neurosci. 3, 481–492.

Sikes, R. W. and Vogt, B. A. 1992. Nociceptive neurons in area 24 of rabbit cingulate cortex. J. Neurophysiol. 68, 1720–1732. Silverman, D. H., Munakata, J. A., Ennes, H., Mandelkern, M. A., Hoh, C. K., and Mayer, E. A. 1997. Regional cerebral activity in normal and pathological perception of visceral pain. Gastroenterology 112, 64–72. Singer, T., Seymour, B., O’Doherty, J., Kaube, H., Dolan, R. J., and Frith, C. D. 2004. Empathy for pain involves the affective but not sensory components of pain. Science 303, 1157–1162. Smith, Y. R., Stohler, C. S., Nichols, T. E., Bueller, J. A., Koeppe, R. A., and Zubieta, J. K. 2006. Pronociceptive and antinociceptive effects of estradiol through endogenous opioid neurotransmission in women. J. Neurosci. 26, 5777–5785. Spreng, M. and Ichioka, M. 1964. Langsame Rindenpotentiale bei Schmerzreizung am Menschen. Pflu¨gers Arch. 279, 121–132. Stevens, R. T., London, S. M., and Apkarian, A. V. 1993. Spinothalamocortical projections to the secondary somatosensory cortex (SII) in squirrel monkey. Brain Res. 631, 241–246. Stiasny-Kolster, K., Magerl, W., Oertel, W. H., Mo¨ller, J. C., and Treede, R. D. 2004. Static mechanical hyperalgesia without dynamic tactile allodynia in patients with restless legs syndrome. Brain 127, 773–782. Strigo, I. A., Duncan, G. H., Boivin, M., and Bushnell, M. C. 2003. Differentiation of visceral and cutaneous pain in the human brain. J. Neurophysiol. 89, 3294–3303. Strittmatter, M., Hamann, G. F., Grauer, M., Fischer, C., Blaes, F., Hoffmann, K. H., and Schimrigk, K. 1996. Altered activity of the sympathetic nervous system and changes in the balance of hypophyseal, pituitary and adrenal hormones in patients with cluster headache. Neuroreport 7, 1229–1234. Talbot, J. D., Marrett, S., Evans, A. C., Meyer, E., Bushnell, M. C., and Duncan, G. H. 1991. Multiple representations of pain in human cerebral cortex. Science 251, 1355–1358. Tarkka, I. M. and Treede, R. D. 1993. Equivalent electrical source analysis of pain-related somatosensory evoked potentials elicited by a CO2 laser. J. Clin. Neurophysiol. 10, 513–519. Timmermann, L., Ploner, M., Haucke, K., Schmitz, F., Baltissen, R., and Schnitzler, A. 2001. Differential coding of pain intensity in the human primary and secondary somatosensory cortex. J. Neurophysiol. 86, 1499–1503. To¨lle, T. R., Kaufmann, T., Siessmeier, T., Lautenbacher, S., Berthele, A., Munz, F., Zieglga¨nsberger, W., Willoch, F., Schwaiger, M., Conrad, B., and Bartenstein, P. 1999. Region-specific encoding of sensory and affective components of pain in the human brain: a positron emission tomography correlation analysis. Ann. Neurol. 45, 40–47. Tommerdahl, M., Delemos, K. A., Vierck, C. J., Favorov, O. V., and Whitsel, B. L. 1996. Anterior parietal cortical response to tactile and skin-heating stimuli applied to the same skin site. J. Neurophysiol. 75, 2662–2670. Tracey, I. 2001. Prospects for human pharmacological functional magnetic resonance imaging (phMRI). J. Clin. Pharmacol. Suppl. 21S–28S. Tracey, I., Ploghaus, A., Gati, J. S., Clare, S., Smith, S., Menon, R. S., and Matthews, P. M. 2002. Imaging attentional modulation of pain in the periaqueductal gray in humans. J. Neurosci. 22, 2748–2752. Treede, R. D. 2001. Neural Basis of Pain. In: International Encyclopedia of the Social & Behavioral Sciences (eds. N. J. Smelser and P. B. Baltes), pp. 11000–11005. Elsevier.

Nociceptive Processing in the Cerebral Cortex Treede, R. D., Apkarian, A. V., Bromm, B., Greenspan, J. D., and Lenz, F. A. 2000. Cortical representation of pain: functional characterization of nociceptive areas near the lateral sulcus. Pain 87, 113–119. Treede, R. D., Baumga¨rtner, U., and Lenz, F. A. 2007. Nociceptive Processing in the Secondary Somatosensory Cortex. In: Encyclopedia of Pain (eds. R. F. Schmidt and W. D. Willis), pp. 1376–1379. Springer. Treede, R. D., Kenshalo, D. R., Gracely, R. H., and Jones, A. K. P. 1999. The cortical representation of pain. Pain 79, 105–111. Treede, R. D., Meyer, R. A., and Campbell, J. N. 1998. Myelinated mechanically insensitive afferents from monkey hairy skin: heat response properties. J. Neurophysiol. 80, 1082–1093. Treede, R. D., Lorenz, J., and Baumga¨rtner, U. 2003. Clinical usefulness of laser-evoked potentials. Neurophysiol. Clin. 33, 303–314. Valeriani, M., Rambaud, L., and Mauguie`re, F. 1996. Scalp topography and dipolar source modelling of potentials evoked by CO2 laser stimulation of the hand. Electroenceph. Clin. Neurophysiol. 100, 343–353. Valeriani, M., Sestito, A., Le Pera, D., De Armas, L., Infusino, F., Maiese, T., Sgueglia, G. A., Tonali, P. A., Crea, F., Restuccia, D., and Lanza, G. A. 2005. Abnormal cortical pain processing in patients with cardiac syndrome X. Eur. Heart J. 26, 975–982. Valet, M., Sprenger, T., Boecker, H., Willoch, F., Rummeny, E., Conrad, B., Erhard, P., and To¨lle, T. R. 2004. Distraction modulates connectivity of the cingulo-frontal cortex and the midbrain during pain – an fMRI analysis. Pain 109, 399–408. Verne, G. N., Himes, N. C., Robinson, M. E., Gopinath, K. S., Briggs, R. W., Crosson, B., and Price, D. D. 2003. Central representation of visceral and cutaneous hypersensitivity in the irritable bowel syndrome. Pain 103, 99–110. Villemure, C. and Bushnell, M. C. 2002. Cognitive modulation of pain: how do attention and emotion influence pain processing? Pain 95, 195–199. Vogel, H., Port, J. D., Lenz, F. A., Solaiyappan, M., Krauss, G., and Treede, R. D. 2003. Dipole source analysis of laser-evoked subdural potentials recorded from parasylvian cortex in humans. J. Neurophysiol. 89, 3051–3060. Vogt, B. A. 2005. Pain and emotion interactions in subregions of the cingulate gyrus. Nat. Rev. Neurosci. 6, 533–544. Vogt, B. A., Nimchinsky, E. A., Vogt, L. J., and Hof, P. R. 1995. Human cingulate cortex: surface features, flat maps, and cytoarchitecture. J. Comp. Neurol. 359, 490–506. Vogt, B. A., Rosene, D. L., and Pandya, D. N. 1979. Thalamic and cortical afferents differentiate anterior from posterior cingulate cortex in the monkey. Science 204, 205–207. Wager, T. D., Rilling, J. K., Smith, E. E., Sokolik, A., Casey, K. L., Davidson, R. J., Kosslyn, S. M., Rose, R. M., and Cohen, J. D. 2004. Placebo-induced changes in fMRI in the

697

anticipation and experience of pain. Science 303, 1162–1167. Wagner, K. J., Willoch, F., Kochs, E. F., Siessmeier, T., To¨lle, T. R., Schwaiger, M., and Bartenstein, P. 2001. Dosedependent regional cerebral blood flow changes during remifentanil infusion in humans: a positron emission tomography study. Anesthesiology 94, 732–739. Wang, S. J., Lirng, J. F., Fuh, J. L., and Chen, J. J. 2006. Reduction in hypothalamic 1H-MRS metabolite ratios in patients with cluster headache. J. Neurol. Neurosurg. Psychiatry 77, 622–625. Wiesenfeld-Hallin, Z. 2005. Sex differences in pain perception. Gend. Med. 2, 137–145. Willis, W. D. and Coggeshall, R. E. 2004. Sensory Mechanisms of the Spinal Cord: Primary Afferent Neurons and the Spinal Dorsal Horn, Vol. 1. Kluwer Academic/ Plenum Publishers. Willoch, F., Schindler, F., Wester, H. E., Empl, M., Straube, A., Schwaiger, M., Conrad, B., and To¨lle, T. R. 2004. Central poststroke pain and reduced opioid receptor binding within pain processing circuitries: a [C-11]diprenorphine PET study. Pain 108, 213–220. Wilson, J. F. 2006. The pain divide between men and women. Ann. Intern. Med 144, 461–464. Wood, P. B., Patterson, J. C., Sunderland, J. J., Tainter, K. H., Glabus, M. F., and Lilien, D. L. 2007. Reduced presynaptic dopamine activity in fibromyalgia syndrome demonstrated with positron emission tomography: a pilot study. J. Pain 8, 51–58. Yamamura, H., Iwata, K., Tsuboi, Y., Toda, K., Kitajima, K., Shimizu, N., Nomura, H., Hibiya, J., Fujita, S., and Sumino, R. 1996. Morphological and electrophysiological properties of ACCx nociceptive neurons in rats. Brain Res. 735, 83–92. Xu, X. P., Fukuyama, H., Yazawa, S., Mima, T., Hanakawa, T., Magata, Y., Kanda, M., Fujiwara, N., Shindo, K., Nagamine, T., and Shibasaki, H. 1997. Functional localization of pain perception in the human brain studied by PET. Neuroreport 8, 555–559. Zelman, D. C., Howland, E. W., Nichols, S. N., and Cleeland, C. S. 1991. The effects of induced mood on laboratory pain. Pain 46, 105–111. Zubieta, J. K., Smith, Y. R., Bueller, J. A., Xu, Y., Kilbourn, M. R., Jewett, D. M., Meyer, C. R., Koeppe, R. A., and Stohler, C. S. 2001. Regional mu opioid receptor regulation of sensory and affective dimensions of pain. Science 293, 311–315. Zubieta, J. K., Bueller, J. A., Jackson, L. R., Scott, D. J., Xu, Y., Koeppe, R. A., Nichols, T. E., and Stohler, C. S. 2005. Placebo effects mediated by endogenous opioid activity on -opioid receptors. J. Neurosci. 25, 7754–7762. Zubieta, J. K., Smith, Y. R., Bueller, J. A., Xu, Y., Kilbourn, M. R., Jewett, D. M., Meyer, C. R., Koeppe, R. A., and Stohler, C. S. 2002. -Opioid receptor-mediated antinociceptive responses differ in men and women. J. Neurosci. 22, 5100–5107.

This page intentionally left blank

46 Phantom Limb Pain H Flor, Central Institute of Mental Health, Mannheim, Germany ª 2009 Elsevier Inc. All rights reserved.

46.1 46.2 46.3 46.3.1 46.3.2 46.4 46.5 References

Definition Peripheral Mechanisms of Phantom Limb Pain Central Factors The Spinal Cord Supraspinal Changes Implications for the Treatment and Prevention of Phantom Limb Pain Future Developments

699 700 701 701 702 703 704 704

Glossary cortical reorganization Changes in the maps of the primary sensory or motor areas of the cortex related to injury or stimulation. Cortical representations can increase or decrease in size or they can shift to other locations on the sensory or motor map. central sensitization Short- or long-term changes in the excitability of central neurons and their synaptic strength that lead to an enhanced or altered processing of peripheral sensory input resulting in hypersensibility. neuroma When a limb is severed, a terminal swelling or endbulb is formed with axonal sprouting occurring. In the case of an amputation this sprouting and endbulb formation lead to neuroma, a tangled mass that is formed when the axons cannot reconnect or can only partially reconnect as is the case in partial lesions. These neuroma generate abnormal activity that is called ectopic because it does not originate from the nerve endings. nonpainful phantom limbs and nonpainful phantom sensations These phenomena refer to the continued presence of the limb (corporeal awareness of the limb) and nonpainful sensations such as tingling or pressure sensations. nonpainful residual limb sensations The residual limb can also have nonpainful sensations such as

46.1 Definition The amputation of a body part is often followed by the sensation that the deafferented body part is still present. These sensations may include not only the feeling

tingling or cramping sensations that can be distinguished from phantom sensation as well as from painful sensation. phantom limb pain or phantom pain Pain in a body part that is no longer present. It may be related to a certain position or movement of the phantom and may be elicited or exacerbated by a range of physical (e.g., changes in weather or pressure on the residual limb) and psychological factors (e.g., emotional stress). It seems to be more intense in the distal portions of the phantom and may have a number of different qualities such as stabbing, throbbing, burning, or cramping. Phantom limb pain is often confused with pain in the area adjacent to the amputated body part. postamputation pain Pain at the site of the wound that must be distinguished from pain in the residual limb and phantom limb pain that may all co-occur in the early phase after amputation. preamputation pain Pain that occurred in the amputated body part before the amputation. It may be related to the incidence, type, and severity of phantom limb pain in the phase following the amputation. residual limb pain or stump pain Pain in the body part adjacent to the amputation. It is usually positively correlated with phantom limb pain.

of the continued presence of the limb but also nonpainful and painful phantom sensations such as the feeling of a specific position, shape, or movement of the missing limb, feelings of warmth or cold, itching, tingling or electric sensations, and other paresthesias. 699

700 Phantom Limb Pain

Phantom limb pain (or phantom pain) is pain in the body part that is no longer present. This occurs to some degree in 50–80% of all amputees (Nikolajsen, L. and Jensen, T. S., 2006). Phantom limb pain may be related to a certain position or movement of the phantom and may be elicited or exacerbated by a range of physical (e.g., changes in weather or pressure on the residual limb) and psychological factors (e.g., emotional stress). It seems to be more intense in the distal portions of the phantom and may have a number of different qualities such as stabbing, throbbing, burning, or cramping (Hill, A., 1999). Phantom limb pain belongs to the neuropathic pain syndromes and is assumed to be related to damage to the axons of peripheral neurons with secondary changes induced in central neurons. Phantom body pain may also occur following spinal cord injury. Phantom limb pain is infrequent if the amputation occurred at a very young age. However, older children exhibit as high an incidence of phantom limb pain as adults. Although phantom sensations seem to occur occasionally in congenital amputees (i.e., those born without a limb), phantom limb pain seems to be very rare under these circumstances (Flor, H., 2002). The long-term course of phantom limb pain is unclear. While some authors report a slight decline in pain prevalence over the course of several years, others have described high prevalence rates also in longterm amputees. Both peripheral and central factors have been discussed as determinants of phantom limb pain. Psychological factors do not seem to be a primary cause, but they may well affect the course and the severity of the pain (Sherman, R. A., 1997). The general view today is that multiple changes along the neuraxis contribute to the experience of phantom limb pain.

46.2 Peripheral Mechanisms of Phantom Limb Pain Peripheral changes that give rise to nociceptive input from the residual limb have been viewed as an important determinant of phantom limb pain. This is supported by the moderately high correlation between pain in the residual limb (stump) and phantom limb pain. Ectopic discharge from stump neuromas has been postulated as a potential source of such nociceptive input (Devor, M., 2006). When peripheral nerves are cut or injured, terminal swelling and regenerative sprouting of the injured axon end occur. In this process, neuromas form in the residual limb. The disorganized endings of C fibers and demyelinated A fibers in neuromas have

increased excitability and often show spontaneous impulse activity (ectopic discharge). Mechanical, chemical, and thermal stimulation may further exacerbate this ectopic discharge. The increased excitability of injured nerves that results in ectopic discharge seems to result from upregulation or novel expression, and altered trafficking, of molecules that are responsible for neuronal excitability, such as voltage-sensitive sodium channels (Devor, M., 2006). In addition, abnormal connections between injured axons, such as ephapses, may contribute to the spontaneous ectopic activity. Phantom limb pain is often present very soon after amputation before a palpable, swollen neuroma could have formed. However, ectopic discharge also appears rapidly, apparently originating at first in swollen endbulbs at the cut axon end rather than in outgrowing sprouts. Local anesthesia of the stump does not eliminate phantom limb pain in all amputees (Birbaumer, N. et al., 1997). This fact motivated a search for other potential sources of ectopic input from the periphery. An additional site of ectopic discharge is the dorsal root ganglion (DRG). Ectopia originating in the DRG can summate with ectopia originating from neuromas in the stump. Indeed, processes such as cross-excitation can lead to the depolarization and activation of neighboring neurons, significantly amplifying the overall ectopic barrage (Devor, M., 2006). In experimental preparations and in humans it was found that anesthetic block of neuromas eliminates spontaneous and stimulation-induced nerve activity related to the stump, but not ectopic activity potentially originating in the DRG (Nystrom, B. and Hagbarth, K. E., 1981). Interestingly, there is evidence for genetic factors in the predisposition to develop ectopic neuroma, DRG discharge, and neuropathic pain. For example, Devor M. et al. (2005) presented evidence for the presence of several genes that predisposes to the pain behavior that follows peripheral neurectomy in rodents. This neuroma model of neuropathic pain has been considered to be a valid animal surrogate of phantom limb pain in humans. Elevated sympathetic discharge, as well as increased levels of circulating epinephrine, can trigger and exacerbate ectopic neuronal activity from neuromas (Devor, M., 2006). In addition to such sympathetic–sensory coupling at the level of the neuroma, sympathetic–sensory coupling also occurs at the level of the DRG. This may account for the frequent exacerbation of phantom pain at times of emotional distress. Additional factors such as temperature, oxygenation level, and local inflammation

Phantom Limb Pain

in neuromas and associated DRGs may also play a role. The sympathetic maintenance of phantom limb pain in some patients is supported by evidence that systemic adrenergic blocking agents, and targeted chemical or surgical blockade of sympathetic nerves and ganglia, sometimes reduce phantom limb pain. Likewise, injections of epinephrine into stump neuromas have been shown to increase phantom limb pain and paresthesias in some amputees. Although sympathetically maintained pain does not necessarily covary with regional sympathetic abnormalities, in some patients, sympathetic dysregulation in the residual limb is apparent. Reduced near-surface blood flow to a limb has been implicated as a predictive physiological correlate of burning phantom limb pain. Correspondingly, onset and intensity of cramping and squeezing descriptions of phantom pain have been related to muscle tension in the residual limb. This relationship seems not to hold for any other descriptors of phantom pain. In addition, lower skin temperature in the residual limb in amputees with phantom limb pain and phantom sensation and a close relationship between phantom limb sensation and skin conductance responses in the residual limb can be viewed as evidence of a sympathetic-efferent somatic-afferent mechanism (for review see Sherman, R. A., 1997).

46.3 Central Factors 46.3.1

The Spinal Cord

Anecdotal evidence in human amputees first suggested that spinal mechanisms may play a role in phantom limb pain. For example, during spinal anesthesia, phantom pains have been reported to reoccur in patients who were pain-free at the time of the procedure. Experimental data in human amputees are lacking, but increasing amounts of evidence based on animal models of nerve injury are becoming available. Increased activity in peripheral nociceptors leads to an enduring change in the synaptic responsiveness of neurons in the dorsal horn of the spinal cord, a process called central sensitization (Woolf, C. J. and Salter, M., 2006). Central sensitization is also triggered by nerve injury such as occurs during amputation. For example, spinal changes associated with nerve injury include increased firing of the dorsal horn neurons, structural changes at the central endings of the primary sensory neurons, and reduced inhibitory processes. Inhibitory GABAergic and

701

glycinergic interneurons in the spinal cord may actually be destroyed by rapid ectopic discharge or other effects of axotomy, contributing to a hyperexcitable spinal cord (Scholz, J. and Woolf, C., 2006). Changes have also been noted in ascending projection neurons. The cascade of biological events that take place in the spinal cord after peripheral nerve damage may trigger abnormal firing of spinal origin. Part of this sensitization is due to facilitation of the response of N-methyl-D-aspartic acid (NMDA) receptors to the primary afferent neurotransmitter glutamate (Sandku¨hler, J., 2000). A remarkable effect of the spinal changes evoked by nerve injury is that lowthreshold afferents may become functionally connected to ascending spinal projection neurons that carry nociceptive information. When this happens, normally innocuous A-fiber input from the periphery, ectopic input as well as input from residual intact low-threshold afferents, may contribute to phantom pain sensation. A number of additional central nervous system (CNS) processes are thought to contribute to the hyperexcitability of spinal cord circuitry following major nerve damage. For example, there may be downregulation of opioid receptors, both on primary afferent endings and on intrinsic spinal neurons. This is expected to add to disinhibition due to the reduction of GABA and glycine activity. In addition, cholycystokinin, an endogenous inhibitor of the opiate receptor, is upregulated in injured tissue (for review see Woolf, C. J. and Salter, M., 2006). Another interesting example of changed gene expression after axotomy is the appearance of the neuropeptide substance P in low-threshold A neurons. Substance P is normally expressed only by A and C afferents, most of which are nociceptors. The injury-triggered expression of substance P by A fibers may render them more like nociceptors. For example, it may permit ectopic or normal activity in A fibers to trigger and maintain central sensitization. Changes such as these in gene expression in injured afferents (and in some postsynaptic spinal neurons), which result in a change in their functioning (i.e., their phenotype), are referred to as phenotypic switch. Recent work based on gene chip technology indicates that hundreds of genes are upor downregulated in DRG and spinal neurons following peripheral nerve injury. Following peripheral nerve injury, degeneration of central projection axon occurs. Massive deafferentation is observed when dorsal roots are injured, or avulsed from the spinal cord. Deafferentation may act

702 Phantom Limb Pain

hand-in-hand with the central effects of peripheral denervation to bring about the changes that contribute to spinal hyperexcitability. A mechanism that may be of special relevance to phantom phenomena is the invasion of regions of the spinal cord functionally vacated from injured afferents. For example, in the neuroma model in rats and cats, there is an expansion of receptive fields on skin adjacent to the denervated part of the limb, and a shift of activity from these adjacent areas into regions of the spinal cord that previously served the part of the limb that was functionally deafferented by the nerve lesion (Devor, M. and Wall, P. D., 1978). Such reorganization of the spinal map of the limb, which is probably due to unmasking of previously silent connections, is reflected in brainstem and cortical remapping also.

46.3.2

Supraspinal Changes

Supraspinal changes related to phantom limb pain involve the brain stem, the thalamus, and the cerebral cortex (for review see Flor, H. et al., 2006). New insights into phantom limb pain have come from studies demonstrating changes in the functional and structural architecture of primary somatosensory cortex subsequent to amputation and deafferentation in adult monkeys. In these studies, the amputation of digits in an adult owl monkey led to an invasion of adjacent areas into the representation zone of the deafferented fingers. Several imaging studies (for review see Flor, H., 2002) have reported that upper extremity amputees actually show a shift of the mouth into the hand representation in primary somatosensory and motor cortex (Figure 1). Flor H. et al. (1995) provided evidence that these cortical changes are less related to referred sensations but rather have a close association with phantom limb pain. The larger the shift of the mouth representation into the zone that formerly represented the amputated hand and arm the larger the phantom limb pain. These cortical changes could be reversed by the elimination of peripheral input from the amputation stump using brachial plexus anesthesia. Peripheral anesthesia completely eliminated cortical reorganization and phantom limb pain in half of the amputees that were studied. In the remaining half, both cortical reorganization and phantom limb pain remained unchanged (Birbaumer, N. et al., 1997). This result suggests that in some amputees, cortical reorganization and phantom limb pain may be maintained by

Figure 1 The representation of lip movements in amputees with phantom limb pain (left) and without phantom limb pain (right) in primary somatosensory cortex based on functional magnetic resonance imaging. Note that the amputees with phantom limb pain activate both the cortical hand and the mouth representation whereas the amputees without phantom limb pain activate only the cortical mouth representation.

peripheral input whereas in others central, potentially intracortical changes might be more important. It is so far not known to what extent spinal changes contribute to these supraspinal alterations. It was shown that axonal sprouting in the cortex underlies the reorganizational changes observed in amputated monkeys (Florence, S. L. et al., 1998). Thalamic stimulation and recordings in human amputees have revealed that reorganizational changes may also occur at the thalamic level and are closely related to the perception of phantom limbs and phantom limb pain (Davis, K. D. et al., 1998). Studies in animals have shown that these changes may be relayed from the spinal and brain stem level; however, changes on the subcortical levels may also originate in the cortex, which has strong efferent connections to the thalamus and lower structures. Sometimes pain in the phantom is similar to the pain that existed in the limb prior to amputation. The likelihood of this ranges from 10% to 79% in different reports and depends on the type and time of assessment (see Katz, J. and Melzack, R., 1990). The type and time of assessment and potential errors in retrospective reports are important determinants of the incidence of these pain memories. It has been proposed that pain memories established prior to the amputation are powerful elicitors of phantom limb pain (Katz, J. and Melzack, R., 1990; Flor, H., 2002). Pain memories may be implicit and not readily accessible to conscious recollection. The term implicit pain memory refers to central changes related to nociceptive input that lead to subsequent altered processing of the somatosensory system and do not require changes

Phantom Limb Pain

in conscious processing of the pain experience (Flor, H., 2002). In patients with chronic back pain it was shown that increasing chronicity is correlated with an increase in the representation zone of the back in primary somatosensory cortex, and it was also reported that the experience of acute pain alters the map in primary somatosensory cortex. These data suggest that long-lasting noxious input may lead to long-term changes at the central and especially at the cortical level. It has long been known that the primary somatosensory cortex is involved in the processing of pain and that it may be important for the sensory-discriminative aspects of the pain experience. There have also been reports that phantom limb pain was abolished after the surgical removal of portions of the primary somatosensory cortex and that stimulation of somatosensory cortex evoked phantom limb pain. If a somatosensory pain memory has been established with an important neural correlate in spinal and supraspinal structures, such as in primary somatosensory cortex, subsequent deafferentation and an invasion of the amputation zone by neighboring input may preferentially activate cortical neurons coding for pain. Since the cortical area coding input from the periphery seems to stay assigned to the original zone of input, the activation in the cortical zone representing the amputated limb is referred to this limb and the activation is interpreted as phantom sensation and phantom limb pain. It is likely that not only the areas involved in sensorydiscriminative aspects of pain reorganize but also that those areas that mediate affective–motivational aspects of pain such as the insula and the anterior cingulate cortex undergo plastic changes that contribute to the experience of phantom pain. A prospective study (Larbig et al., unpublished data) showed that the best predictor of phantom limb pain 12 months after an amputation is chronic pain before the amputation thus supporting the pain memory hypothesis. However, these authors tested a sample that did not include traumatic amputees but mainly amputees with long-standing prior pain problems. Further research is needed to better clarify these relationships.

46.4 Implications for the Treatment and Prevention of Phantom Limb Pain Several studies, including large surveys of amputees, have shown that most treatments for phantom limb pain are ineffective and fail to consider the

703

mechanisms underlying the production of the pain (Sindrup, S. H. and Jensen, T. S., 1999). Most studies are uncontrolled short-term assessments of small samples of phantom limb pain patients. The maximum benefit reported from a host of treatments such as local anesthesia, sympathectomy, dorsal root entry zone lesions, cordotomy and rhizotomy, neurostimulation methods, or pharmacological interventions such as anticonvulsants, barbiturates, antidepressants, neuroleptics, and muscle relaxants seems to be around 30%. This does not exceed the placebo effect reported in other studies. Controlled studies have been performed for opioids, calcitonin, ketamine, dextromethorphan, and gabapentin (see Nikolajsen, L. and Jensen, T. S., 2006), all of which were found to effectively reduce phantom limb pain. Mechanismbased treatments are rare but have been shown to be effective in a few small but mostly uncontrolled studies. Lidocaine was found to reduce phantom limb pain of patients with neuromas in two smallsample controlled studies. Biofeedback treatments resulting in vasodilatation of the residual limb or decreased muscle tension in the residual limb help to reduce phantom limb pain and seem promising in patients where peripheral factors contribute to the pain (Flor, H., 2002). Based on the findings from neuroelectric and neuromagnetic source imaging, changes in cortical reorganization might influence phantom limb pain. Animal work on stimulation-induced plasticity would suggest that extensive behaviorally relevant stimulation of a body part leads to the expansion of its representation zone. It was shown that intensive use of a myoelectric prosthesis was positively correlated with both reduced phantom limb pain and reduced cortical reorganization. When cortical reorganization was partialled out, the relationship between prosthesis use and reduced phantom limb pain was no longer significant suggesting that cortical reorganization mediates this relationship. An alternative approach in patients where prosthesis use is not viable is the application of behaviorally relevant stimulation. A 2-week training that consisted of a discrimination training of electric stimuli to the stump for 2 h per day led to significant improvements in phantom limb pain and a significant reversal of cortical reorganization (Flor, H. et al., 2001). A control group of patients who received standard medical treatment and general psychological counseling in this time period did not show similar changes in cortical reorganization and phantom limb pain. The basic idea of the

704 Phantom Limb Pain

treatment was to provide input into the amputation zone and thus undo the reorganizational changes that occurred subsequent to the amputation. Mirror treatment (where a mirror is used to trick the brain into perceiving movement of the phantom when the intact limb is moved) might be effective but has so far only been tested in an anecdotal manner. Preemptive analgesia refers to the attempt to prevent chronic pain by early intervention before acute pain occurs, for example, before and during surgery. Based on the data on sensitization of spinal neurons by afferent barrage it has been suggested that general anesthesia should be complemented by peripheral anesthesia thus preventing peripheral nociceptive input from reaching the spinal cord and higher centers. However, preemptive analgesia that included both general and spinal anesthesia has not consistently been efficacious in preventing the onset of phantom limb pain (for review see Nikolajsen, L. and Jensen, T. S., 2006). A preexisting pain memory that has already led to central and especially cortical changes would not necessarily be affected by a shortterm elimination of afferent barrage. Thus, it is possible that peripheral analgesia would eliminate new but not preexisting central changes in the perioperative phase. In addition, a short-term blockade is not sufficient to prevent discharges from severed peripheral nerves to reach the CNS. The perioperative use of NMDA receptor antagonists or GABA agonists might therefore be useful.

46.5 Future Developments Both peripheral and central factors and their interaction need to be examined more closely in animal models of amputation-related pain and in human amputees. The role of spinal mechanisms has so far not been sufficiently elucidated. The detection of genes relevant for the development of phantom pain-like behaviors in animal is an important step and may aid in the identification of predisposing factors for phantom limb pain as well as in the development of new interventions. The development of more powerful treatments for phantom limb pain needs controlled treatment outcome, prospective and double-blind placebo-controlled outcome research. Only then effective evidence-based interventions will be available.

Acknowledgment The preparation of this article was supported by a grant from the Deutsche Forschungsgemeinschaft (FL 156/29).

References Birbaumer, N., Lutzenberger, W., Montoya, P., Larbig, W., Unertl, K., To¨pfner, S., and Flor, H. 1997. Effects of regional anesthesia on phantom limb pain are mirrored in changes in cortical reorganization. J. Neurosci. 17, 5503–5508. Davis, K. D., Kiss, Z. H. T., Luo, L., Tasker, R. R., Lozano, A. M., and Dostrovsky, J. O. 1998. Phantom sensations generated by thalamic microstimulation. Nature 391, 385–387. Devor, M. 2006. Response of Nerves to Injury in Relation to Neuropathic Pain. In: Melzack and Wall’s Textbook of Pain, 5th edn. (eds. S. McMahon and M. Koltzenburg), pp. 905–927. Churchill-Livingstone. Devor, M. and Wall, P. D. 1978. Reorganization of the spinal cord sensory map after peripheral nerve injury. Nature 276, 76. Devor, M., del Canho, S., and Raber, P. 2005. Heritability of symptoms in the neuroma model of neuropathic pain: replication and complementation analysis. Pain 116, 294–301. Flor, H. 2002. Phantom limb pain: characteristics, aetiology and treatment. Lancet Neurology 3, 182–189. Flor, H., Denke, C., Schaefer, M., and Gru¨sser, S. 2001. Sensory discrimination training alters both cortical reorganization and phantom limb pain. Lancet 357, 1763–1764. Flor, H., Elbert, T., Knecht, S., Wienbruch, C., Pantev, C., Birbaumer, N., and Taub, E. 1995. Phantom limb pain as a perceptual correlate of cortical reorganization following arm amputation. Nature 357, 482–484. Flor, H, Nikolajsen, L, and Jensen, T. 2006. Neuroplastic changes in phantom limbs and phantom limb pain. Nat. Neurosci. Rev. 1, 813–881. Florence, S. L., Taub, H. B., and Kaas, J. H. 1998. Large-scale sprouting of cortical connections after peripheral injury in adult macaque monkeys. Science 282, 1117–1120. Hill, A. 1999. Phantom limb pain: a review of the literature on attributes and potential mechanisms. J. Pain Sympt. Manage 17, 125–142. Jensen, T. S. and Nikolajsen, L. 2000. Pre-emptive analgesia in postamputation pain: an update. Prog. Brain Res. 129, 493–503. Katz, J. and Melzack, R. 1990. Pain ‘memories’ in phantom limbs: review and clinical observations. Pain 43, 319–336. Nikolajsen, L. and Jensen, T. S. 2006. Phantom Limb and Other Postamputation Phenomena. In: Wall and Melzacks Textbook of Pain, 5th edn. (eds. M. Koltzenburg and S. McMahon), pp. 961–971. Churchill-Livingstone. Nystrom, B. and Hagbarth, K. E. 1981. Microelectrode recordings from transsected nerves in amputees with phantom limb pain. Neurosci. Lett. 27, 211–216. Sandku¨hler, J. 2000. Learning and memory in pain pathways. Pain 88, 113–118. Sherman R. A. (ed.) 1997. Phantom Limb Pain. Plenum. Sindrup, S. H. and Jensen, T. S. 1999. Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain 83, 389–400. Scholz, J. and Woolf, C. 2006. Neuropathic Pain: A Neurodegenerative Disease. In: Proceedings of the 11th

Phantom Limb Pain World Congress on Pain (eds. H. Flor, E. Kalso. and J. Dostrovsky), pp. 373–384. IASP Press. Woolf, C. J. and Salter, M. 2006. Plasticity and Pain: Role of the Dorsal Horn. In: Melzack and Wall’s Textbook of Pain, 5th edn. (eds. S. McMahon and M. Koltzenburg), pp. 91–105. Churchill-Livingstone.

Further Reading Abraham, R. B., Marouani, N., and Weinbroum, A. A. 2003. Dextromethorphan mitigates phantom pain in cancer amputees. Ann. Surg. Oncol. 10, 268–274. Appenzeller, O. and Bicknell, J. M. 1969. Effects of nervous system lesion on phantom experience in amputees. Neurology 19, 141–146. Bone, M., Critchley, P., and Buggy, D. J. 2002. Gabapentin in postamputation phantom limb pain: a randomized, doubleblind, placebo-controlled, cross-over study. Reg. Anesth. Pain Med. 27, 481–486. Chabal, C., Jacobson, L., Russell, L. C., and Burchiel, K. J. 1989. Pain responses to perineuromal injection of normal saline, gallamine, and lidocaine in humans. Pain 36, 321–325. Chabal, C., Jacobson, L., Russell, L. C., and Burchiel, K. J. 1992. Pain response to perineuromal injection of normal saline, epinephrine, and lidocaine in humans. Pain 49, 9–12. Cronholm, B. 1951. Phantom limbs in amputees. A study of changes in the integration of centripetal impulses with special reference to referred sensations. Acta. Psychiatr. Neurol. Scand. Suppl. 72, 1–310. Devor, M. and Govrin-Lippman, R. 1993. Angelides K. Naþ channels immunolocalization in peripheral mammalian axons and changes following nerve injury and neuroma formation. J. Neurosci. 13, 1976–1992. Devor, M. and Raber, P. 1990. Heritability of symptoms in an experimental model of neuropathic pain. Pain 42, 51–67. Devor, M., Ja¨nig, W., and Michaelis, M. 1994. Modulation of activity in dorsal root ganglion neurones by sympathetic activation in nerve-injured rats. J. Neurophysiol. 71, 38–47. Ehde, D. M., Czerniecki, J. M., Smith, D. G., Campbell, K. M., Edwards, W. T., et al. 2000. Chronic phantom sensations, phantom pain, residual limb pain, and other regional pain after lower limb amputation. Arch. Phys. Med. Rehab. 8, 1039–1044. Ephraim, P. L., Wegener, S. T., Mackenzie, E. J., Dillingham, T. R., and Pezzin, L. E. 2005. Phantom pain, residual limb pain, and back pain in amputees: results of a national survey. Arch. Phys. Med. Rehabil. 86, 1910–1919. Ergenzinger, E. R., Glasier, M. M., Hahm, J. O., and Pons, T. P. 1998. Cortically induced thalamic plasticity in the primate somatosensory system. Nat. Neurosci. 1, 226–229. Flor, H., Braun, C., Elbert, T., and Birbaumer, N. 1997. Extensive reorganization of primary somatosensory cortex in chronic back pain patients. Neurosci. Lett. 224, 5–8. Flor, H., Elbert, T., Mu¨hlnickel, W., Pantev, C., Wienbruch, C., and Taub, E. 1998. Cortical reorganization and phantom phenomena in congenital and traumatic upper-extremity amputees. Exp. Brain Res. 119, 205–212. Florence, S. L. and Kaas, J. H. 1995. Large-scale reorganization at multiple levels of the somatosensory pathway following therapeutic amputation of the hand in monkey. J. Neurosci. 15, 8083–8095. Gru¨sser, S., Winter, C., Mu¨hlnickel, W., Denke, C., Karl, A., Villringer, K., and Flor, H. 2001. The relationship of perceptual phenomena and cortical reorganization in upper extremity amputees. Neuroscience 102, 263–272.

705

Huse, E., Larbig, W., Flor, H., and Birbaumer, N. 2001. The effect of opioids on phantom limb pain and cortical reorganization. Pain 90, 47–55. Jaeger, H. and Maier, C. 1992. Calcitonin in phantom limb pain: a double-blind study. Pain 48, 21–27. Jensen, T. S., Krebs, B., Nielsen, J., and Rasmussen, P. 1985. Immediate and long-term phantom limb pain in amputees: incidence, clinical characteristics and relationship to preamputation pain. Pain 21, 267–278. Jensen, T. S., Krebs, B., Nielsen, J., and Rasmussen, P. 2000. Immediate and long-term phantom limb pain in amputees: Incidence, clinical characteristics and relationship to preamputation of somatosensory and motor cortex after peripheral nerve or spinal cord injury in primates. Prog. Brain Res. 128, 173–179. Katz, J. 1992. Pychophysical correlates of phantom limb experience. J. Neurol. Neurosurg. Psychiatry 55, 811–821. Katz, J. and Melzack, R. A. 1991. Auricular transcutaneous electrical nerve stimulation (TENS) reduces phantom limb pain. J. Pain Sympt. Manage 6, 77–83. Karl, A., Birbaumer, N., Lutzenberger, W., Cohen, L. G., and Flor, H. 2001. Reorganization of motor and somatosensory cortex in upper extremity amputees with phantom limb pain. J. Neurosci. 21, 3609–3618. Kooijman, C. M., Dijkstra, P. U., Geertzen, J. H. B., Elzinga, A., and van der Schans, C. P. 2000. Phantom pain and phantom sensations in upper limb amputees: an epidemiological study. Pain 87, 33–41. Krane, E. J. and Heller, L. B. 1995. The prevalence of phantom sensation and pain in pediatric amputees. J. Pain Sympt. Manage 10, 21–29. Lotze, M., Grodd, W., Birbaumer, N., Erb, M., Huse, E., Larbig, W., and Flor, H. 1999. Does use of a myoelectric prosthesis prevent cortical reorganization and phantom limb pain? Nat. Neurosci. 2, 501–502. Mackenzie, N. 1983. Phantom limb pain during spinal anaesthesia. Recurrence in amputees. Anaesthesia 38, 886–887. MacLachlan, M., McDonald, D., and Waloch, J. 2004. Mirror treatment of lower limb phantom pain: a case study. Disabil. Rehabil. 26, 901–904. Nathan, P. W. 1983. Pain and the sympathetic system. J. Auton. Nerv. Syst. 7, 363–370. Nikolajsen, L. and Jensen, T. S. 2001. Phantom limb pain. Br. J. Anaesth. 87, 107–116. Nikolajsen, L., Gottrup, H., Kristensen, A. G., and Jensen, T. S. 2000. Memantine (a N-methyl-D-aspartate receptor antagonist) in the treatment of neuropathic pain after amputation or surgery: a randomized, double-blinded, cross-over study. Anesth. Analg. 91, 960–966. Nikolajsen, L., Hansen, C. L., Nielsen, J., Keller, J., Arendt-Nielsen, L., et al., 1996. The effect of ketamine on phantom limb pain: a central neuropathic disorder maintained by peripheral input. Pain 67, 69–77. Nikolajsen, L., Ilkjaer, S., Christensen, J. H., Kroner, K., and Jensen, T. S. 1997a. Randomised trials of epidural bupivacaine and morphine in prevention of stump and phantom pain in lower-limb amputation. Lancet 350, 1353–1357. Nikolajsen, L., Ilkjaer, S., and Jensen, T. S. 2000. Relationship between mechanical sensitivity and post-amputation pain: a perspective study. Eur. J. Pain 4, 327–334. Nikolajsen, L., Ilkjaer, S., Kroner, K., Christensen, J. H., and Jensen, T. S. 1997b. The influence of preamputation pain on postamputation stump and phantom pain. Pain 72, 393–405. Ramachandran, V. S., Rogers-Ramachandran, D. C., and Stewart, M. 1992. Perceptual correlates of massive cortical reorganization. Science 258, 1159–1160.

706 Phantom Limb Pain Sherman, R. A. 1989. Stump and phantom limb pain. Neurol. Clin. 7, 249–264. Sherman, R. A. and Sherman, C. J. 1983. Prevalence and characteristics of chronic phantom limb pain. Results of a trial survey. Am. J. Phys. Med. 62, 227–238. Soros, P., Knecht, S., Bantel, C., Imai, T., Wusten, R., et al. 2000. Functional reorganization of the human primary somatosensory cortex after acute pain demonstrated by magnetoencephalography. Neurosci. Lett. 298, 195–198.

Wei, F. and Zhuo, M. 2001. Potentiation of sensory responses in the anterior cingulate cortex following digit amputation in the anaesthetised rat. J. Physiol. 532, 823–833. Wiech, K., Preissl, H., Kiefer, T., To¨pfner, S., Pauli, P., et al. 2001. Prevention of phantom limb pain and cortical reorganization in the early phase after amputation in humans. Soc. Neurosci. Abstr. 28, 163. Wilkins, K. L., McGrath, P. J., Finley, G. A., and Katz, J. 1998. Phantom limb sensations and phantom limb pain in child and adolescent amputees. Pain 78, 7–12.

47 Human Insular Recording and Stimulation F Mauguie`re, Lyon I University and INSERM U879, Bron, France M Frot, INSERM U879, Bron France J Isnard, Lyon I University and INSERM U879, Bron, France ª 2009 Elsevier Inc. All rights reserved.

47.1 47.1.1 47.1.2 47.1.3 47.1.4 47.2 47.2.1 47.2.2 47.2.3 47.2.4 47.2.5 47.3 47.3.1 47.3.2 47.3.3 47.3.4 47.3.5 47.3.6 47.4 47.4.1 47.4.2 47.4.3 References

Anatomy, Connections, and Physiology of the Insula in Primates The Insula as the Fifth Lobe of the Brain The Insula as a Node in a Distributed Cortical Network The Insula as a Polymodal Area The Insula as Part of the Mirror-Neuron System Rational, Ethical Limitations and Procedure of Insular Recording and Stimulations in Humans Recording and Stimulation of the Human Insula Are Justified only in the Context of Presurgical Evaluation of Epilepsy Depth Intracortical Electrodes Are Needed to Explore the Insula The Number of Electrodes Is Limited by Ethical Issues The Site of Electrode Implantation Is Guided by Diagnostic Purposes Only Data Recorded in Nonepileptogenic Cortex are Physiologically Relevant Insular Recordings of Pain Evoked Responses in Humans The Laser Stimulus Cortical Surface Recordings (Electrocorticography) Intracortical S2 Recordings Intracortical Insular Recordings Topographic Specificity of Insular Laser-Evoked Potentials Interhemispheric Transmission of S2 and Insular Laser-Evoked Potentials Insular Stimulation The Challenge of Insular Stimulation Pain Evoked by Insular Stimulation Anatomical Location of the Insular Pain Area

708 708 709 710 710 710 710 711 711 711 711 711 711 712 712 712 714 714 714 714 715 715 715

Glossary cytoarchitectony (cytoarchitectonic) Anatomical method based on microscopic observation of brain slices used to delineate cortical areas according to the organization of the different types of gray matter cells (neurons). This technique permits the drawing of cytoarchitectonic maps of the cortex, of which the most widely used is that of Korbinian Brodmann, first described in 1909, which counts 52 distinct areas in the human brain. The thickness of two different types of cortical cells layers (granule and pyramidal cells) and the number of layers are the two main parameters used for cytoarchitectonic mapping. Granule cells are over-represented in

primary sensory (visual, auditory, and somatosensory) cortical areas (granular cortex), while large pyramidal cells are characteristic of the primary motor cortex (agranular cortex). deep-brain stimulation Technique involving stimulating the brain with electric current pulses of low intensity using depth electrodes implanted through the skull. In humans, this technique can be used for therapeutic or diagnostic purposes. Highfrequency continuous (or chronic) deep-brain stimulation is used as a treatment in various neurological diseases, e.g., Parkinson’s disease. For diagnosis purposes, single pulses or trains of pulses are used mostly in presurgical assessment

707

708 Human Insular Recording and Stimulation

of patients with drug-resistant focal epileptic seizures in order to map the seizure focus (or epileptogenic zone) and the functional areas surrounding the focus. Chronically implanted electrodes are painless; they also permit the recording of ongoing brain activity and evoked potentials. discharge (epileptic discharge, afterdischarge) Abnormal electroencephalographic (EEG) activity with abrupt onset and termination lasting at least several seconds seen during an epileptic seizure; discharges can be recorded either by scalp or by depth electrodes. They can occur spontaneously or be triggered by deep-brain stimulation and then named after-discharges. electroencephalography (EEG) The record of electrical activity of the brain taken by means of electrodes placed on the surface of the scalp. First applied to study the activity of the human brain by Hans Berger in 1924, this noninvasive technique is still used routinely for the diagnosis of epilepsy. evoked potentials (EPs) Brain electric response (wave or complex of waves) elicited by and timelocked to a physiological or nonphysiological stimulus, the timing of which can be reliably assessed, e.g., a short duration. Laser beam applied to the skin surface. Because of their low voltage most of EPs are not evident from the ongoing electroencephalographic (EEG) activity after a single stimulation. Repeated stimulations and computer summation techniques are thus needed for their detection. The number of single responses to be summated is a function of the signal-to-noise ratio (ratio between the EP and ongoing EEG activity voltages); this number is higher for scalp than for depth intracerebral recordings.

47.1 Anatomy, Connections, and Physiology of the Insula in Primates 47.1.1 The Insula as the Fifth Lobe of the Brain In an article published in 1896 that was devoted to the comparative anatomy of the insula Clark T. E. (1896) quoted 39 synonyms used in anatomical literature to name the fifth lobe of the brain buried in the lateral sulcus and covered by the opercular parts of the frontal, parietal, and temporal lobes, among which the term insula, first proposed by Reil in 1804, has prevailed.

somatotopy (somatotopic) Representation maps of peripheral skin areas and joints in the somatosensory cortex that were first described in the human brain by Wilder Penfield using electric stimulation of parietal cortex. The even existence of such maps demonstrates that granule cells receiving inputs from the same peripheral areas are grouped together in the somatosensory cortex. Microelectrode recordings in mammalian brain including monkeys have shown that separate somatotopic maps of the peripheral skin and joint receptors can be drawn in the somatosensory cortical areas. somatosensory areas (S1, S2) Cortical areas containing a full somatotopic map of the contralateral body half that have been identified in mammals and human brain by means of electric cortical stimulation, evoked potentials, brain imaging (functional magnetic resonance imaging), and unit or multiple cell responses. The human primary sensory area (S1) is located in the postcentral parietal gyrus and the second somatosensory area (S2) is located in the upper bank of the sylvian fissure (parietal operculum). stereotaxy (stereotactic) The stereotactic space first described by Jean Talairach is a three-dimensional representation of the human brain in which each point in the brain can be located according to its coordinates (x, y, and z) in a Cartesian space. The space is defined by the intersection of the midsagittal plane and the plane perpendicular to midsagittal plane passing through the anterior and posterior commissure of the brain (AC–PC). Using depth electrodes implanted perpendicular to the mid-sagittal plane, any given recording or stimulation site can be localized by its stereotactic coordinates.

Due to its anatomical situation in depth of brain lateral fissure (see Figure 1 and Tanriover, N. et al., 2004), and its cytoarchitectonic organization the insula has long be considered by anatomists as a rather isolated lobe of the brain mostly devoted to the processing of body and visceral sensation including gustation, pain, and other emotions, as well as to visceromotor and autonomic control. In primates including humans, the insula shows a caudorostral sequence of three distinct cytoarchitectonic areas namely; (1) a large area of granular cortex, at its upper and posterior part, whose structure is very similar to that of the second

Human Insular Recording and Stimulation

(a)

709

(b)

CS A

ec

cn ic p

30 mm

SF

gp c

ac

T1

ot

t1 CS ph

T2 t2

SF

phig

T3

B

a

C

fg Figure 1 Anatomy of the human insular lobe (frontal slices). A) Anatomical fontal brain section showing the deep location of the insula (in yellow) in the sylvian fissure (SF, white arrow), which separates the frontal and parietal lobes (above) from the temporal lobe (below). The second somatosensory area (S2 in green), which occupies the superior bank of the SF, has common borders with the lower part of the primary somatosensory area (S1 in purple), and the insula. The circular sulcus (CS) separates the insula from the parietal operculum S2 and the first temporal gyrus (T1). The dashed red lines indicates the trajectory of depth electrodes used for insular, parietal, and temporal lobes recordings in patients with epilepsy of the temporal lobe and perisylvian cortex (see Isnard, J. et al., 2004). See also Figure 4 for sagittal view of the insula. B) Magnetic resonance imaging (MRI) slice showing the projection of the recording electrodes implanted horizontally perpendicular to the midline sagittal plane (dashed vertical white line). Recording contacts appears as small white segments along the electrodes trajectory. The deepest contacts of electrodes A and B are located in the insular cortex. The depths coordinates (x) of each contact is calculated from the midline sagittal plane in the human brain stereotactic space of Talairach. The x coordinates of insular recording sites vary from 27 mm to 36 mm from midline. Electrode A (red circle) contacts explore from depth to surface: the insula (yellow arrow), the S2 area (green arrow; 38 < x < 46 mm) and the lower part of the S1 area (purple arrow; 48 < x < 63 mm). Electrode B contacts explore the insula and the first temporal gyrus (T1 in Figure 1A). Electrode C contacts explore the second temporal gyrus (T2 in Figure 1B) and hippocampus. a, amygdala; ac, anterior commissure; c, claustrum; CS, circular sulcus; cn, caudate nucleus; ec, external capsule; fg, fusiform grus; gp, globus pallidus; ic, internal capsule; ot, optic tract; phig, parahippocamplal gyrus; SF, sylvian fissure; T1, first temporal gyrus; t1, first temporal sulcus; T2, second temporal gyrus; t2, second temporal sulcus; T3, third temporal gyrus.

somatosensory (S2) cortical area, which is involved mostly in the processing of somatosensory and pain sensation; (2) a transitional dysgranular field localized in its anterosuperior part involved in gustation and visceral sensation; and (3) an anteroventral agranular field, which is in continuity with the temporal pole and olfactory proisocortex, and related to olfactory and autonomic functions (see Tanriover, N. et al., 2004 for a review). 47.1.2 The Insula as a Node in a Distributed Cortical Network The insula is characterized by anatomical borders that are defined by a limiting sulcus (the circuminsular

fissure) but also by fuzzy cytoarchitectonic borders with neighboring cortical areas and by a dense network of corticocortical connections with adjacent or more distant cortical areas. Therefore its function cannot be sketched as an isolated functional center, as suggested by the term insula. A complete description of insular connections is given in the review by Augustine J. R. (1996) showing that the insula is connected to the limbic areas, amygdalar nucleus, basal ganglia, and all of the cortical lobes, except the occipital lobe. Several attempts have been made to identify functional networks in which the insula could play the role of a functional node. Among these networks the perisylvian–insular, the temporo– limbic–insular and the mesial–orbitofrontal–insular

710 Human Insular Recording and Stimulation

networks (Mesulam, M. M. and Mufson, E. J., 1982) deserve the attention of pain physiologists because they are involved in pain localization and intensity encoding, as well as in emotional and behavioral reaction to pain. 47.1.3

The Insula as a Polymodal Area

The question of insular physiology has been addressed by studies using neuroimaging, evoked potentials (EPs), and direct stimulation in humans as well microelectrode studies in monkeys (Augustine, J. R., 1996). These studies have confirmed that the insula is involved in somatosensory and pain sensation as assessed by numerous functional imaging studies in humans (see Peyron, R. et al., 2002 for a review), as well as by the somatosensory and pain-evoked response recordings and direct electric stimulations of the insular cortex that are detailed below in this chapter. However, the insula also proved to be a highly organized lobe with multiple specific functions other than pain including in particular: Visceral sensation, visceromotor control. Cardiovascular function as demonstrated by insular stimulation in epileptic patients that produces changes in heart rate or blood pressure in 50% of cases (Oppenheimer, S. M. et al., 1992), thus leading to suspect a role of insular discharges in cardiac arrhythmias causing sudden death during epileptic seizures. Gustation as assessed first by the stimulation studies of Penfield W. and Faulk M. E. (1955) and further confirmed by neuroimaging studies and microelectrode recordings of insular neurons in monkeys. These physiological findings are consistent with the altered taste perception observed in patients with insular lesions. Audition and language, in particular allocation of auditory attention, tuning in to novel auditory stimuli, temporal, and phonological processing of auditory stimuli. Furthermore several studies suggest that both right and left insulas are involved in the control of speech production. 47.1.4 The Insula as Part of the Mirror-Neuron System Some recent studies suggest that the insular lobe could belong to the mirror-neuron system that characterizes regions of the brain that are able to respond when the subject performs an action and when the subject observes another individual doing a similar action

(see Rizzolatti, G. and Craighero, L., 2004 for a review). The concept also refers to regions of the brain that are able to encode for a sensation (or emotion) perceived by the subject and to respond to the observation of others experiencing that sensation (or emotion). In the human insula, the regions involved in visceral sensation or visceromotor responses are also responding to faces expressing disgust (KrolakSalmon, P. et al., 2003). Similarly the human insula respond to both pain perception and empathy for others’ pain ( Jackson, P. L. et al., 2005).

47.2 Rational, Ethical Limitations and Procedure of Insular Recording and Stimulations in Humans 47.2.1 Recording and Stimulation of the Human Insula Are Justified only in the Context of Presurgical Evaluation of Epilepsy In humans, electrical stimulation of the cortex, as well as invasive intracranial recordings of the cerebral activity, including surface recordings using electrodes placed on the cortex (electrocorticography) and depth recordings using electrodes implanted directly in the cortex (stereotactic electroencephalography or SEEG), aims at localizing the area that produces focal epileptic seizures. This area, referred to as the epileptogenic zone (EZ; Rosenow, F. and Luders, H. O., 2001), is that which is surgically removed to obtain seizure freedom in patients whose epilepsy cannot be controlled by conventional drug treatment. Ethically such recordings are justified only when the EZ cannot be localized noninvasively either by scalp recordings or neuroimaging techniques. In this context, invasive explorations aim mostly at recording spontaneous seizures. They are also used to perform a functional mapping of the cortex located in, or in the vicinity of, the EZ, in order to predict the functional consequences of the surgical treatment, which consists of removing the EZ cortex. This procedure, named cortectomy, is possible provided that the EZ is not located in an eloquent area involved in essential cortical functions such as language, memory, motor control, and vision. Both the recording of responses evoked by sensory stimulations and direct electrical stimulation of the cortex are commonly used to achieve this functional mapping in epilepsy surgery centers around the world. This context obviously entails some limitations in the use of depth cortical

Human Insular Recording and Stimulation

711

recordings and stimulation in studies of human brain physiology.

47.2.5 Only Data Recorded in Nonepileptogenic Cortex are Physiologically Relevant

47.2.2 Depth Intracortical Electrodes Are Needed to Explore the Insula

Data from cortical recordings or stimulations can be considered as reflecting the normal physiology of the brain on the condition that they have been obtained in cortical areas that are not involved in the epileptogenic process and do not show increased excitability to peripheral inputs or local electric fields produced by stimulation. Two criteria are commonly used to check this, which are first the absence of insular epileptic discharge in the insula during spontaneous seizures and, second, the absence of sustained afterdischarge after electrical stimulation of the insular cortex.

Due to its deep location in the lateral fissure the insula can be explored either by electrocorticography during surgery in patients whose frontoparietal or temporal operculum has been removed by a previous cortectomy, as was the case in the few patients first explored in Montreal by Penfield W. and Faulk M. E. (1955), or by depth SEEG electrodes implanted perpendicular to the mid-sagittal plane through the opercular cortex (Figure 1). These electrodes usually have five to ten contacts, each of 2 mm in length separated by 1.5 mm and can be left in place chronically up to 15 days (Isnard, J. et al., 2000; 2004). Only the deepest contacts of such electrodes reach the insular cortex while the superficial ones explore the frontoparietal or temporal opercular cortex. Therefore, concerning somatosensory responsive areas located close to the lateral fissure, it must be checked on individual brain magnetic resonance imaging (MRI) whether contacts are located in the suprasylvian external parietal cortex (area S1), in the parietal operculum cortex (area S2), or in the insula. Oblique electrodes trajectories can also been used to explore the insula, thus increasing the number of contacts located in the insular cortex. 47.2.3 The Number of Electrodes Is Limited by Ethical Issues Only the minimal number of electrodes that are useful to diagnosis can be implanted. Consequently the spatial resolution of the mapping in each individual is low, and pooling interindividual data is necessary to draw topographic functional maps of the human insula based on depth electrode data. 47.2.4 The Site of Electrode Implantation Is Guided by Diagnostic Purposes Implantation sites are guided by the hypothesis issued from noninvasive investigations concerning the most probable EZ location. Furthermore the trajectory of electrode tracts is restricted by the anatomy of blood vessels that are particularly dense in the lateral fissure. Therefore, some parts of the insula are rarely or never explored.

47.3 Insular Recordings of Pain Evoked Responses in Humans In what follows we will describe responses to pain and nonpainful cutaneous stimuli because the same contact in the insula most often detects both types of responses. Moreover pain intensity rating is subjective and corresponds to various levels of stimulus intensity between subjects. In complement to insular responses we will also describe responses recorded in the second somatosensory (S2) area (Figure 1), which is located in the superior bank of the lateral fissure, because it has a blurred anatomical border with the granular insular cortex and is also involved in building up pain sensation. 47.3.1

The Laser Stimulus

Most of the studies on pain-EPs in normal subjects and patients use a laser beam (mostly CO2) applied on the skin surface as a stimulus. The laser beam is known to stimulate the endings of small diameters fibers and mostly those of A delta fibers. When the power output is fixed, the amount of thermal energy delivered depends on the duration of the pulse, which is in the order of a few milliseconds and, thus, permits an accurate timing for the analysis of the electrophysiologic response. The energy density of the laser beam is expressed in milli-Joules per mm2 of skin surface (mJ mm2). Threshold values for pain show large interindividual variations between 30 and 40 mJ mm2 using a CO2 laser beam. In most studies, the sensation perceived by the subject is that of sharp pinprick, without poststimulus pain, considered as

712 Human Insular Recording and Stimulation

Depth Coordinates Talairach (mm)

characteristic of the sensations produced by the stimulation of A delta fibers. Although they are able to rate it on a visual analog scale of pain (usually at 4–7 on a 10 level scale), the subjects do not identify this sensation as a pain comparable to what they might have experienced in the past. Indeed no natural pain is provoked by selective activation of the A delta fibers, and this must be kept in mind when using laser stimulation in pain studies. In particular, the laser stimulus can be considered as adequate to assess the intensity coding of a pain stimulus, but is suboptimal for studying of the emotional reaction to pain. AC-PC

47.3.2 Cortical Surface Recordings (Electrocorticography) Lenz F. A. et al. (1998) were the first to record cortical surface recordings by means of a subdural grid of electrodes placed on the surface of the parietal operculum with CO2-laser-evoked potentials (LEPs) peaking between 160 and 340 ms after the stimulus. The spatial distribution of this response over the cortical surface of the perisylvian cortex was considered as compatible with generators located in the parietal operculum and/or in the insular cortices. However subdural electrodes placed over the sylvian area do not allow direct recording neither in the deep aspect of the frontoparietal opercular cortex nor in the insula.

47.3.3

Intracortical S2 Recordings

In humans, LEPs at stimulus intensities below and above pain threshold are recorded in the suprasylvian opercular cortex corresponding to the human S2 area (Frot, M. et al., 2001). These responses are not picked up in the other areas most often explored in presurgical assessment of epilepsy including the amygdala, hippocampus, and orbitofrontal cortex. They show a biphasic negative–positive waveform peaking at 137 13 ms (N140) and 172 11 ms (P170), respectively, after stimulation of opposite hand (Figure 2). Similar responses are equally recorded in the homologous cortex, ipsilateral to the painful stimulus with a delay of 10–17 ms. The LEP voltage in S2 shows a significant increase as soon as the stimulus intensity reaches the sensory threshold as well as between sensory and pain thresholds while it rapidly reaches a plateau for intensities above pain threshold (Frot, M. et al., 2007; Figure 3).

P230 31

Insula

34 N180

38

P170

SII

41 45 –

48 N140 100 ms

50 μv +

E AC-PC

Figure 2 Pain laser-evoked potentials (LEPs) to skin laser stimulation of the dorsum of the hand. The lower part of the figure shows frontal magnetic resonance imaging slices of the right insula with projection of the contacts of a recording electrode exploring the insula (red) and S2 (blue). The vertical dashed blue line represent the midline sagittal plane, and the horizontal dashed blue line the anterior commissure–posterior commissure (AC–PC) horizontal plane used for stereotactic implantation of depth electrodes. Evoked potentials illustrated in the upper part of the figure are obtained by averaging responses to repeated stimulations of the left hand by a CO2 laser beam. Figures along the vertical axis are the depth coordinates (x) in mm from midline of each recording contact. Note that distinct responses are obtained in both areas, which are separated by a delay of 50 ms.

47.3.4

Intracortical Insular Recordings

LEPs contralateral to stimulation recorded in the insular cortex itself (Frot, M. and Mauguie`re, F., 2003) consist in a N180 negative response (mean latency: 180 16.5 ms) followed by a P230 positivity (mean latency: 226 16 ms; Figure 2). As for S2, insular LEPs ipsilateral to stimulation peak 10–17 ms later than contralateral ones. LEP amplitudes increase between sensory and pain threshold intensities but, contrary to what is observed in S2, continue to increase significantly at intensities over the pain threshold (Figure 3). The reason for the delay of  50 ms (50 16 ms between S2 N140 and insular N180 peaking latencies) observed between S2 and insular pain responses remains questionable. It is too long for a monosynaptic transmission from S2 to the insula, the two areas being interconnected through direct projections. Alternatively, knowing that both S2 and the insula

Human Insular Recording and Stimulation

(a)

SII

713

Insula

–50 –40 –30 –20 –10 μV 0 10 20 30 40 50 –100 0 100 200 300 400 500 600 700 ms

13 12 11 10

800 900

–25 –20 –15 –10 –5 μV 0 5 10 15 20 25 –100 0 100 200 300 400 500 600 700 800 900 ms

N_P peak amplitudes (μV)

(b) 90 80 70

SII Insula SE

60 50 40 30 20 10

I0

I1

I2

I3

Figure 3 Effects of stimulus intensity on laser-evoked potential (LEP) amplitude in S2 and insula. A) LEP traces in S2 and insula to four different stimulus intensities are superimposed. CO2 Laser pulses were applied at four different intensities in each subject. The power output being fixed, the amount of thermal energy delivered depends on the duration of the pulse. Pulse duration is set up according to subjects’ subjective reports, rated on a visual analog scale (VAS) with an anchor point corresponding to the pain threshold. The printed scales consist of 10-cm horizontal lines where the left extreme is labeled no sensation and the right extreme maximal pain, and an anchored level 4 was at pain threshold (Lickert-type scale). The different stimuli and related subjective sensation are as follows: I0: below sensory threshold (pulse duration: 5–15 ms, mean energy density: 7 mJ mm2, no sensation); I1: above sensory threshold (pulse duration: 15–45 ms, mean energy density: 19 mJ mm2, producing a detectable nonpainful sensation reported for more than 90% of stimulations; For one-third of patients this sensation is a warmth sensation and for the others two-thirds a slight nonpainful pinprick sensation; VAS: 1.6 1.09); I2: pain threshold (pulse duration: 25–80 ms, mean energy density: 33 mJ mm2, producing a pricking sensation, like a hair pulling or a drop of hot boiling water on the skin; VAS: 3.9 1.46); I3: 20% above pain threshold (pulse duration: 35– 110 ms, mean energy density: 46 mJ mm2, producing a pricking sensation described as clearly painful; VAS: 5.4 1.6). In S2, a significant increase of the LEP is observed as soon as the stimulus intensity reaches the sensory threshold (between I0 and I1, P < 0.001), as well as between sensory and pain thresholds (I1 to I2, P < 0.001) while amplitudes rapidly reach a plateau for intensities above pain threshold (no significant amplitude difference between I2 and I3). In the insula, no significant amplitude increase is observed for low-stimulation intensities between I0 and I1, LEP amplitudes also increase between sensory and pain threshold intensities (P < 0.05 between I1 and I2) and continue to increase significantly at higher intensities over pain threshold (P < 0.001 between I2 and I3). B) Insula and S2 LEPs peaking amplitudes as a function of stimulus intensity. In these polynomial regression curves of the stimulus–response functions S2 LEPs amplitudes show a S-shaped profile with increasing stimulus intensities that reaches a plateau above pain threshold, while insular LEP amplitudes show an exponential profile. Laser stimuli above pain threshold trigger a maximal response in S2 and a pain level-related response in the insula (Modified from Frot, M., Magnin, M., Mauguie`re, F., and Garcia-Larrea, L. 2007. Human SII and posterior insula differently encode thermal laser stimuli. Cereb. Cortex 17, 610–620).

714 Human Insular Recording and Stimulation

receive direct projections from the thalamus (see for a review Augustine, J. R., 1996) the explanation could be that the latter are triggered via thalamocortical fibers with a slower conduction than that of thalamic projections to the S2 area. To our knowledge, however, no electrophysiological demonstration of this hypothesis is hitherto available. A third hypothesis could be that the suprasylvian cortex and the insula are activated by inputs conveyed by peripheral fibers with different conduction velocities. Some studies have estimated the A delta conduction velocity in a large range of 7–20 m s1 suggesting the existence of different A delta fiber subpopulations, with different conduction velocities. One can hypothesize that these different subpopulations of peripheral fibers could project in distinct cortical regions. However, to our knowledge, no electrophysiological study has been devoted to the identification of separate subpopulations of fibers with different conduction velocities in the spinothalamic tract or thalamocortical projections. 47.3.5 Topographic Specificity of Insular Laser-Evoked Potentials Due to the anatomical proximity between the S2 area and the granular part of the insula the question arises whether insular responses might reflect the diffusion of S2 LEPs with a polarity reversal across the sylvian fissure, which is almost virtual in that region. The fact that when two contacts, or more, explore the insular cortex there is an amplitude increase from surface to depth of the N180–P230 response suggests that this is not so (see Frot, M. and Mauguie`re, F. 2003 for a complete discussion). However, the absolute proof that the N180–P230 is generated in the insular cortex would be its polarity reversal between the surface and the depth of the insular gray matter; unfortunately usual stereotactic recordings in patients do not have enough spatial resolution (2 mm interval between two neighboring contacts of 1.5 mm) to assess the distribution of potentials perpendicular to the cortical surface. 47.3.6 Interhemispheric Transmission of S2 and Insular Laser-Evoked Potentials Insular and S2 responses to pain are bilateral; ipsilateral potentials peaking with a delay of 10–20 ms after contralateral ones. This delay is compatible with the interhemispheric transmission time through fibers of the corpus callosum as estimated by numerous

studies (e.g., 15 ms between primary visual areas); it is in the same range as that measured between ipsiand contralateral S2 magnetic fields evoked by electrical stimulation of the median nerve. The possibility remains, however, that responses ipsilateral to the stimulus could be triggered via ipsilateral thalamic fibers with slower conduction velocities. Only intracortical recordings of S2 or insular EPs to ipsilateral stimuli in patients with a lesion of the homologous areas in the opposite hemisphere could address this question directly.

47.4 Insular Stimulation 47.4.1 The Challenge of Insular Stimulation In humans, it has long been a challenge to stimulate the insular cortex. Thus, only a few studies have reported nonnociceptive somesthetic symptoms, cardiovascular effects as well as visceromotor and viscerosensitive sensations consecutive to direct electrical stimulation of the insular cortex. Truly painful responses have not been reported during stimulation of any area of the cerebral cortex in humans by Penfield W. and Faulk M. E. (1955), who extensively stimulated the surface of all cortical areas of the human brain, including the insula, using surface electrodes. However, they did not explore the posterior part of the insula where electric stimulation evokes painful sensations. Electric stimulations are produced by a currentregulated neurostimulator designed for a safe diagnostic stimulation of the human brain. Square pulses of current are applied between two adjacent contacts (bipolar stimulation) at a frequency of 50 Hz, pulse duration of 0.5 ms, train duration of 5 s, and intensity of 0.8– 6.0 mA. These parameters are used to avoid any tissue injury (charge density per square pulse 3 months) and mechanical tenderness in at least 11 out of 18 tender points (TP; Wolfe, F. et al., 1990). Most 775

776 Fibromyalgia

TP sites are located at tendon insertion areas and have shown few detectable tissue abnormalities. Besides musculoskeletal pain and mechanical tenderness most FM patients also complain of insomnia, fatigue, and distress. In addition FM coaggregates with major mood disorders (Raphael, K. G. et al., 2004).

51.2 Pathogenesis of Fibromyalgia FM can be characterized as a pain amplification syndrome of patients who often display widespread hyperalgesia and allodynia to mechanical, thermal, and chemical stimuli. However, the hypersensitivity of FM patients is not limited to pain, but also includes light, sound, and smell. The cause for this heightened sensitivity is unknown, but central nervous system (CNS) sensory processing abnormalities have been reported in several studies (Desmeules, J. A. et al., 2003; Staud, R., 2004). Most of these studies found evidence of central sensitization of dorsal horn neurons of the spinal cord and the brain including those that are related to pain. The pathogenesis of central sensitization in FM is unclear but may be related to prior stressors, including infections and traumas. Because most FM patients relate their pain to deep tissues, particularly muscles, these structures may play an important role in the initiation and maintenance of central sensitization and pain. No consistent tissue abnormalities have been reported in FM patients that would explain persistent pain. However, focal muscle areas, like trigger points (TrPs), may play an important role for FM pain because little nociceptive input from peripheral tissues is required for the maintenance of central sensitization (Bengtsson, M. et al., 1989).

51.3 Muscle Nociception Nociceptive input from muscle may be particularly relevant for FM pain. Muscle pain travels in myelinated A-delta fibers (group III) and in unmyelinated type C fibers (group IV). Pain receptors are mostly located at free nerve endings which are concentrated around small arterioles and capillaries between the muscle fibers. The cell bodies for these nerves are found in the dorsal root ganglion and synapse in lamina I and IV–V of the dorsal horn of the spinal cord. Activation of peripheral nociceptors leads to a release of neurotransmitters in the spinal cord,

mostly substance P and calcitonin gene-related peptide (CGRP). There is also a retrograde migration of substance P from cell bodies which is then released in the region of the free nerve endings. This retrograde flow can sensitize tissues and increase their responsiveness to less intense stimuli. Muscle nociceptors are activated by mechanical stimuli (stretching or pressure), bradykinin, serotonin, and potassium ions, but are not activated by normal muscle movements or even increased muscle tension. Sensory input from muscle, as opposed to skin, is a much more potent effector of central sensitization and this may be particularly relevant for FM (Wall, P. D. and Woolf, C. J., 1984).

51.4 Triggering Events for Fibromyalgia The onset of FM has frequently been associated with certain triggers or stressors include physical trauma, infections, emotional distress, endocrine disorders, and immune activation (Greenfield, S. et al., 1992; Middleton, G. D. et al., 1994; Waylonis, G. W. and Perkins, R. H., 1994). These stressors have been associated with the degree of pain, disability, life interference, and affective distress of FM patients (Turk, D. C. et al., 1996). Strong evidence for trauma as a trigger of FM symptoms comes from studies of patients with acute injuries who developed chronic widespread pain at much higher rates than controls (Al Allaf, A. W. et al., 2002; Buskila, D. and Neumann, L., 2002). Additional evidence for such an association include postinjury reported sleep abnormalities (Berglund, A. et al., 2001), local injury sites as a source of chronic distant regional pain (Arendt-Nielsen, L. and Svensson, P., 2001), and recent evidence of injury-related CNS neuroplasticity in FM (Carli, G., 2000). Further prospective studies, however, are needed to confirm these associations and to identify the mechanisms that are relevant for posttraumatic FM pain (White, K. P. et al., 2000).

51.5 Abnormal Response to Stressors The biological response to stressors appears predictable in animals and humans. Particularly, events that are perceived as inescapable or unavoidable, or which appear unpredictable, evoke the strongest adverse biological responses (Gold, P. W. et al., 1988a;

Fibromyalgia

1988b; Chrousos, G. P. and Gold, P. W., 1992; Viau, V. et al., 1993; Sapolsky, R. M. et al., 2000). This may explain why victims of trauma appear to develop much higher rates of FM than persons with self-inflicted injuries (Greenfield, S. et al., 1992). In addition, early life stressors can have a permanent and profound impact on subsequent biological responses to stress in animals and humans. Studies in rodents have demonstrated that exposure to multiple stressors including trauma or separation in the neonatal period can lead to permanent changes in the biological response to stress (Sapolsky, R. M., 1996; McNamara, R. K. et al., 2002). This permanent effect of early stressors could explain the higher than expected incidence of traumatic childhood events in individuals who later develop chronic pain (Anderberg, U. M. et al., 2000; Bailey, B. E. et al., 2003).

777

51.7 Fibromyalgia and Affective Spectrum Disorders Several studies have reported that FM is comorbid with major depressive disorder (MDD; Arnold, L. M. et al., 2000; White, K. P. et al., 2002). In addition, anxiety is very prevalent in patients with FM (Thieme, K. et al., 2004). The outcome of a recent large family study of FM probands was consistent with the hypothesis that FM and MDD are characterized by shared, genetically mediated risk factors (Raphael, K. G. et al., 2004). Although the findings of this study should not be interpreted that MDD and FM represent different forms of the same syndrome, they strongly suggest that FM and MDD share important CNS mechanisms.

51.8 Central Sensitization in Fibromyalgia 51.6 Posttraumatic Stress Disorder and Fibromyalgia Posttraumatic stress disorder (PTSD) often occurs after a significant traumatic event and is characterized by behavioral, emotional, functional, and physiological symptoms. Relevant traumatic events related to PTSD are usually perceived as threatening one’s life or physical integrity and can lead to emotional responses including horror, helplessness, or intense fear. The psychological symptoms of PTSD include re-experience of the traumatic event, avoidance, and increased arousal. It has been shown that the experience of trauma is associated with increased somatic and physical complaints, including pain (Beckham, J. C. et al., 1997; 1998). More than 50% of patients with FM suffer from PTSD in the USA and Israel (Sherman, J. J. et al., 2000; Cohen, H. et al., 2002). Compared to the prevalence of PTSD in the general population (6%), FM patients show greatly increased rates similar to Vietnam veterans and victims of natural disasters (Shore, J. H. et al., 1986; Green, M. M. et al., 1993). Not surprisingly, the incidence of FM is also increased in patients with PTSD (21%) and often associated with increased pain ratings, more distress, and higher functional impairment (Amir, M. et al., 1997). As with several other disorders, however, it is unclear whether PTSD is the cause or consequence for FM.

Whereas peripheral sensitization is related to changes of primary nociceptive afferent properties, central sensitization requires functional changes in the CNS (neuroplasticity). Behaviorally, centrally sensitized patients, like FM sufferers report abnormal or heightened pain sensitivity with spreading of hypersensitivity to uninjured sites and the generation of pain by low threshold mechanoreceptors that are normally silent in pain processing (Torebjork, H. E. et al., 1992). Thus, tissue injury may not only cause pain but also an expansion of dorsal horn receptive fields and central sensitization.

51.9 Temporal Summation of Second Pain (Wind-Up) In 1965, Mendell and Wall described for the first time, that repetitive C-fiber stimulation can result in a progressive increase of electrical discharges from second-order neurons in the spinal cord (Mendell, L. M. and Wall, P. D., 1965). This important mechanism of pain amplification in the dorsal horn neurons of the spinal cord is related to temporal summation of second pain or wind-up (WU) and has been used in FM patients for the evaluation of central sensitization (Staud, R. et al., 2001). This technique reveals sensitivity to input from unmyelinated (C) afferents and the status of the N-methyl-D-aspartate (NMDA) receptor systems that are implicated in a

778 Fibromyalgia

variety of chronic pain conditions. Temporal summation depends upon activation of NMDA transmitter systems by C nociceptors, and chronic central pain states like FM can result from excessive temporal summation of pain (Staud, R. and Smitherman, M. L., 2002).

51.10 Abnormal Wind-Up of Fibromyalgia Patients Several recent studies have demonstrated psychophysical evidence that input to central nociceptive pathways is abnormally processed in patients with FM (Staud, R. and Domingo, M., 2001a; 2001b; Staud, R. et al., 2001; Vierck, C. J. et al., 2001; Price, D. D. et al., 2002; Staud, R., 2002). When WU pain is evoked both in normal controls and FM patients, the perceived magnitude of the experimental stimuli (heat, cold, pressure, electricity) is greater for FM patients compared to controls, as is the amount of temporal summation within a series of stimuli. Following a series of stimuli, after-sensations are greater in magnitude, last longer, and are more frequently painful in FM subjects. These results indicate both augmentation and prolonged decay of nociceptive input in FM patients and provide convincing evidence for the presence of central sensitization.

51.11 Wind-Up Measures as Predictors of Clinical Pain Intensity in Fibromyalgia Patients The important role of central pain mechanisms, like WU, for FM patients is also supported by their ability to predict clinical pain intensity. Thermal WU ratings correlate with clinical pain intensity (Pearson’s r ¼ 0.529), thus emphasizing the important role of these pain mechanisms for FM. In addition, statistical prediction models that includes TP count, painrelated negative affect, and WU ratings have been shown to account for nearly 50% of the variance in FM clinical pain intensity (Staud, R. et al., 2003; 2004).

51.12 Fibromyalgia and Other Chronic Pain Conditions Many systemic illnesses can also present with diffuse pain similar to FM, including polymyalgia rheumatica (Gowin, K. M., 2000), rheumatoid arthritis,

Sjogren’s syndrome, inflammatory myopathies (Sultan, S. M. et al., 2002), systemic lupus erythematosus (Tench, C. et al., 2002), multiple sclerosis, and joint hypermobility syndrome (Nef, W. and Gerber, N. J., 1998). Furthermore, several infectious diseases including hepatitis C, Lyme disease, coxsackie B infection, HIV, and parvovirus infection, frequently result in chronic pain states (Barkhuizen, A., 2002). Although the majority of FM patients report the insidious onset of pain and fatigue, approximately half of all patients describe the start of chronic pain after a traumatic or infectious event.

51.13 Myofascial Pain Syndrome Myofascial pain or regional musculoskeletal pain is one of the most common pain syndromes encountered in clinical practice. Myofascial pain represents the most common cause of chronic pain, including neck and shoulder pain, tension headaches, and lower back pain (Granges, G. and Littlejohn, G., 1993; Fricton, J. R., 1994; Macfarlane, G. J. et al., 1996; Borg-Stein, J. and Simons, D. G., 2002). The term myofascial pain was introduced in the early 1950s by Janet Travell. She also defined the term myofascial TrP and demonstrated with David Simons that individual muscles have specific nondermatomal patterns of TrP pain referral (Simons, D. G. et al., 1999). In 1983, both authors first described the clinical picture and pathophysiology of a new syndrome which they named myofascial pain syndrome (MPS; Long, S. P. and Kephart, W., 1998; Simons, D. G. et al., 1999). MPS has been defined as a chronic pain syndrome accompanied by TrPs in one or more muscles or groups of muscles. Similar to FM, it is more frequently found in women compared to men. Besides the presence of TrPs and referred pain, MPS is frequently associated with limitation of movement, weakness, and autonomic dysfunction (Long, S. P. and Kephart, W., 1998) similar to FM.

51.14 Trigger Points TrPs represent areas of local mechanical hyperalgesia that can be found in MPS and several chronic pain conditions, including FM, osteoarthritis, and rheumatoid arthritis. They are defined as specific areas of hyperirritability in muscle, but can also be detected in ligaments, tendons, periosteum, scar tissue, or skin (Han, S. C. and Harrison, P., 1997; Simons, D. G. et al.,

Fibromyalgia

1999). TrPs are located in palpable taut bands and produce local and referred pain, which is specific for the particular muscle. When TrPs are mechanically stimulated, so-called taut bands within a muscle, rather than the entire muscle, will contract (Chu, J., 1998). They are often associated with a local muscle twitch response, which can easily be elicited by needling or palpation of the TrP (Chu, J., 1998; 1999). Latent TrPs are similar to active TrPs, but they are not associated with spontaneous pain and no referral of pain occurs. However, latent TrPs are painful when palpated.

51.15 Relationship between Myofascial Pain and Fibromyalgia Approximately 70% of patients with FM have TrPs (Granges, G. and Littlejohn, G., 1993). A TP is considered to be different from a TrP because of the absence of referred pain, local twitch response, and a taut band in the muscle. The distinction between TPs and TrPs requires careful physical examination. TrPs are frequently located in areas of muscular TPs of patients with FM (Wolfe, F. et al., 1992; Borg-Stein, J. and Stein, J., 1996) suggesting that some muscular TPs in patients with FM may actually be TrPs (Inanici, F. et al., 1999). The presence of TrPs in most if not all FM patients represents evidence for local muscle abnormalities in this chronic musculoskeletal pain syndrome. Although it is unclear if TrPs are the cause or effect of muscle injury, they represent abnormally contracted muscle fibers. This muscle contraction can lead to accumulation of histamine, serotonin, tachykinins, and prostaglandins, which may result in the activation of local nociceptors. Prolonged muscle contractions may also result in local hypoxemia and energy depletion (Simons, D. G. et al., 1999).

51.16 Inflammatory Connective Tissue Diseases Many patients (up to 25%) with chronic arthritis have also wide-spread pain similar to FM. These patients may also present with symptoms of chronic fatigue, impaired memory and concentration, and mood abnormalities. Most of these patients, however, will have findings suggestive of inflammation, including joint pain/swelling, rashes, muscle weakness, as well as laboratory abnormalities, like

779

elevated erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), anemia, autoantibodies (rheumatoid factor, cyclic citrullinated peptide antibodies, anti-nuclear antibodies (ANA)), etc.

51.17 Treatment of Fibromyalgia Treatment of patients with chronic widespread pain like FM needs to be individually tailored to each patient’s needs. This includes the assessment of biopsychosocial abnormalities which are readily detectable in most FM patients. Importantly the identification of pain generators is essential for an effective treatment plan. Thus patients with arthritis, particularly osteoarthritis of the spine will benefit from muscle relaxants, physical therapy, and massage. In addition, these patients may respond well to therapy with cyclo-oxygenase (COX) inhibitors. Identification and treatment of mood abnormalities is crucial because affective spectrum disorders seem to share important mechanisms with FM. Pharmacotherapy for FM has been most successful with antidepressant, muscle relaxant, or anticonvulsant drugs. These drugs affect the release of various neurochemicals (e.g., serotonin, norepinephrine, substance P) that have a broad range of activities in the brain and spinal cord, including modulation of pain sensation and tolerance. None of these drugs, however, is currently approved by the US Food and Drug Administration for the treatment of FM. Most FM patients will respond to low-dose tricyclic medications, such as amitriptyline and cyclobenzaprine, as well as cardiovascular exercise, cognitive behavioral therapy (CBT), patient education, or a combination of these for the management of FM. Also tramadol, selective serotonin reuptake inhibitors (SSRI), selective norepinephrine re-uptake inhibitors (SNRI), and anticonvulsants have been found to be moderately effective. There is some evidence for the efficacy of strength training exercise, acupuncture, hypnotherapy, biofeedback, massage, and warm water baths. However, many commonly used FM therapies like guaifenesine have been found to be ineffective. The efficacy of FM patients to manage their pain seems to correlate with their functional status. Brain imaging and psychological profiles have identified at least three FM subgroups, that is, patients who are highly dysfunctional, interpersonally distressed, or are effective copers (Giesecke, T. et al., 2003). Such

780 Fibromyalgia

studies provide an explanation why some treatments seem to be differentially effective in individual patients. Thus optimal FM management will require a combination of pharmacological and nonpharmacological therapies with patients and healthcare professionals working as a team.

51.18 Prognosis of Fibromyalgia FM can be mild or disabling, but often has substantial emotional and social consequences. About 50% of all patients have difficulty with or are unable to perform routine daily activities. Estimates of patients who have had to stop working or change jobs range from 30% to 40%. Patients with FM suffer job losses and social abandonment more often than people with other conditions that cause pain and fatigue. Although FM symptoms seem to remain stable, several long-term studies indicate that physical function and pain worsen over time (Forseth, K. O. et al., 1999; Baumgartner, E., 2002). Significant life stressors often result in a poor outcome, including diminished capacity to work, poor self-efficacy, increased pain sensations, disturbed sleep, fatigue, and depression. A recent study reported increased mortality in patients with widespread pain compared to those without chronic pain (McBeth, J. et al., 2003). Although this study did not specifically evaluate FM, these findings may be relevant for FM patients. The higher mortality was mostly associated with malignancies, although the cause for this association is currently unknown.

51.19 Conclusions The pathogenesis of FM pain is currently unknown, but up to 50% of the variance can be explained by central sensitization and distress. However, additional mechanisms like tonic peripheral nociceptive input may play an important role for the initiation and maintenance of the increased pain sensitivity of FM patients. FM, like many other chronic pain syndromes, is treatable, and remission can occur in many patients who actively participate in effective disease management programs. New treatment strategies, however, may benefit from interventions that improve peripheral and central pain sensitization as well as the affective disorders of FM patients.

References Al Allaf, A. W., Dunbar, K. L., Hallum, N. S., Nosratzadeh, B., Templeton, K. D., and Pullar, T. 2002. A case-control study examining the role of physical trauma in the onset of fibromyalgia syndrome. Rheumatology 41, 450–453. Amir, M., Kaplan, Z., Neumann, L., Sharabani, R., Shani, N., and Buskila, D. 1997. Posttraumatic stress disorder, tenderness and fibromyalgia. J. Psychosom. Res. 42, 607–613. Anderberg, U. M., Marteinsdottir, I., Theorell, T., and von Knorring, L. 2000. The impact of life events in female patients with fibromyalgia and in female healthy controls. Eur. Psychiatry 15, 295–301. Arendt-Nielsen, L. and Svensson, P. 2001. Referred muscle pain: basic and clinical findings. Clin. J. Pain 17, 11–19. Arnold, L. M., Keck, P. E., Jr., and Welge, J. A. 2000. Antidepressant treatment of fibromyalgia: a meta-analysis and review. Psychosomatics 41, 104–113. Bailey, B. E., Freedenfeld, R. N., Kiser, R. S., and Gatchel, R. J. 2003. Lifetime physical and sexual abuse in chronic pain patients: psychosocial correlates and treatment outcomes. Disabil. Rehabil. 25, 331–342. Barkhuizen, A. 2002. Rational and targeted pharmacologic treatment of fibromyalgia. Rheum. Dis. Clin. North Am. 28, 261–290. Baumgartner, E., Finckh, A., Cedraschi, C., and Vischer, T. L. 2002. A six year prospective study of a cohort of patients with fibromyalgia. Ann. Rheum. Dis. 61, 644–645. Beckham, J. C., Crawford, A. L., Feldman, M. E., Kirby, A. C., Hertzberg, M. A., Davidson, J. R., and Moore, S. D. 1997. Chronic posttraumatic stress disorder and chronic pain in Vietnam combat veterans. J. Psychosom. Res. 43, 379–389. Beckham, J. C., Moore, S. D., Feldman, M. E., Hertzberg, M. A., Kirby, A. C., and Fairbank, J. A. 1998. Health status, somatization, and severity of posttraumatic stress disorder in Vietnam combat veterans with posttraumatic stress disorder. Am. J. Psychiatry 155, 1565–1569. Bengtsson, M., Bengtsson, A., and Jorfeldt, L. 1989. Diagnostic epidural opioid blockade in primary fibromyalgia at rest and during exercise. Pain 39, 171–180. Berglund, A., Alfredsson, L., Jensen, I., Cassidy, J. D., and Nygren, A. 2001. The association between exposure to a rear-end collision and future health complaints. J. Clin. Epidemiol. 54, 851–856. Borg-Stein, J. and Simons, D. G. 2002. Myofascial pain. Arch. Phys. Med. Rehabil. 83, S40–S47. Borg-Stein, J. and Stein, J. 1996. Trigger points and tender points: one and the same? Does injection treatment help? Rheum. Dis. Clin. North Am. 22, 305–322. Buskila, D. and Neumann, L. 2002. The development of widespread pain after injuries. J. Musculoskel. Pain 10, 261–267. Carli, G. 2000. Neuroplasticity and clinical pain. Prog. Brain Res. 129, 325–330. Chrousos, G. P. and Gold, P. W. 1992. The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. JAMA 267, 1244–1252. Chu, J. 1998. Twitch response in myofascial trigger points. J. Musculoskel. Pain 6, 99–116. Chu, J. 1999. Twitch-obtaining intramuscular stimulation: observations in the management of radiculopathic chronic low back pain. J. Musculosket. Pain 7, 131–146. Cohen, H., Neumann, L., Haiman, Y., Matar, M. A., Press, J., and Buskila, D. 2002. Prevalence of post-traumatic stress disorder in fibromyalgia patients: overlapping syndromes or post-traumatic fibromyalgia syndrome? Semin. Arthritis Rheum. 32, 38–50. Croft, P., Rigby, A. S., Boswell, R., Schollum, J., and Silman, A. 1993. The prevalence of chronic widespread pain in the general population. J. Rheumatol. 20, 710–713.

Fibromyalgia Desmeules, J. A., Cedraschi, C., Rapiti, E., Baumgartner, E., Finckh, A., Cohen, P., Dayer, P., and Vischer, T. L. 2003. Neurophysiologic evidence for a central sensitization in patients with fibromyalgia. Arthritis Rheum. 48, 1420–1429. Forseth, K. O., Forre, O., and Gran, J. T. 1999. A 5.5 year prospective study of self-reported musculoskeletal pain and of fibromyalgia in a female population: significance and natural history. Clin. Rheumatol. 18, 114–121. Fricton, J. R. 1994. Myofascial pain. Clin. Rheumatol. 8, 857–880. Giesecke, T., Williams, D. A., Harris, R. E., Cupps, T. R., Tian, X., Tian, T. X., Gracely, R. H., and Clauw, D. J. 2003. Subgrouping of fibromyalgia patients on the basis of pressure-pain thresholds and psychological factors. Arthritis Rheum. 48, 2916–2922. Gold, P. W., Goodwin, F. K., and Chrousos, G. P. 1988a. Clinical and biochemical manifestations of depression. Relation to the neurobiology of stress (1). N. Engl. J. Med. 319, 348–353. Gold, P. W., Goodwin, F. K., and Chrousos, G. P. 1988b. Clinical and biochemical manifestations of depression. Relation to the neurobiology of stress (2). N. Engl. J. Med. 319, 413–420. Gowin, K. M. 2000. Diffuse pain syndromes in the elderly. Rheum. Dis. Clin. North Am. 26, 673–682. Granges, G. and Littlejohn, G. 1993. Prevalence of myofascial pain syndrome in fibromyalgia syndrome and regional pain syndrome: a comparative study. J. Musculoskel. Pain 1, 19–35. Green, M. M., McFarlane, A. C., Hunter, C. E., and Griggs, W. M. 1993. Undiagnosed post-traumatic stress disorder following motor vehicle accidents. Med. J. Aust. 159, 529–534. Greenfield, S., Fitzcharles, M. A., and Esdaile, J. M. 1992. Reactive fibromyalgia syndrome. Arthritis Rheum. 35, 678–681. Han, S. C. and Harrison, P. 1997. Myofascial pain syndrome and trigger-point management. Reg. Anesth. 22, 89–101. Inanici, F., Yunus, M. B., and Aldag, J. C. 1999. Clinical features and psychologic factors in regional soft tissue pain: comparison with fibromyalgia syndrome. J. Musculoskelet. Pain 7, 293–301. Long, S. P. and Kephart, W. 1998. Myofascial Pain Syndrome. In: The Management of Pain (eds. M. A. Ashburn and L. J. Rice), pp. 299–321. Churchill Livingstone. Macfarlane, G. J., Thomas, E., Papageorgiou, A. C., Schollum, J., Croft, P. R., and Silman, A. J. 1996. The natural history of chronic pain in the community: a better prognosis than in the clinic? J. Rheumatol. 23, 1617–1620. McBeth, J., Silman, A. J., and Macfarlane, G. J. 2003. Association of widespread body pain with an increased risk of cancer and reduced cancer survival: a prospective, population-based study. Arthritis Rheum. 48, 1686–1692. McNamara, R. K., Huot, R. L., Lenox, R. H., and Plotsky, P. M. 2002. Postnatal maternal separation elevates the expression of the postsynaptic protein kinase c substrate rc3, but not presynaptic GAP-43, in the developing rat hippocampus. Dev. Neurosci. 24, 485–494. Mendell, L. M. and Wall, P. D. 1965. Responses of single dorsal cord cells to peripheral cutaneous unmyelinated fibres. Nature 206, 97–99. Middleton, G. D., McFarlin, J. E., and Lipsky, P. E. 1994. The prevalence and clinical impact of fibromyalgia in systemic lupus erythematosus. Arthritis Rheum. 37, 1181–1188. Nef, W. and Gerber, N. J. 1998. Hypermobility syndrome. When too much activity causes pain. Schweiz. Med. Wochenschr. 128, 302–310. Price, D. D., Staud, R., Robinson, M. E., Mauderli, A. P., Cannon, R. L., and Vierck, C. J. 2002. Enhanced temporal summation of second pain and its central modulation in fibromyalgia patients. Pain 99, 49–59.

781

Raphael, K. G., Janal, M. N., Nayak, S., Schwartz, J. E., and Gallagher, R. M. 2004. Familial aggregation of depression in fibromyalgia: a community-based test of alternate hypotheses. Pain 110, 449–460. Sapolsky, R. M. 1996. Why stress is bad for your brain. Science 273, 749–750. Sapolsky, R. M., Romero, L. M., and Munck, A. U. 2000. How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr. Rev. 21, 55–89. Sherman, J. J., Turk, D. C., and Okifuji, A. 2000. Prevalence and impact of posttraumatic stress disorder-like symptoms on patients with fibromyalgia syndrome. Clin. J. Pain 16, 127–134. Shore, J. H., Tatum, E. L., and Vollmer, W. M. 1986. Psychiatric reactions to disaster: the Mount St. Helens experience. Am. J. Psychiatry 143, 590–595. Simons, D. G., Travell, J. G., Simons, L. S., and Cummings, B. D. 1999. Myofascial Pain and Dysfunction: The Trigger Point Manual. Upper Half of the Body. 2nd edn. Lippincott Williams & Wilkins. Staud, R. 2002. Evidence of involvement of central neural mechanisms in generating fibromyalgia pain. Curr. Rheumatol. Rep. 4, 299–305. Staud, R. 2004. New evidence for central sensitization in patients with fibromyalgia. Curr. Rheumatol. Rep. 6, 259. Staud, R. and Domingo, M. 2001a. Evidence for abnormal pain processing in fibromyalgia syndrome. Pain Med. 2, 208–215. Staud, R. and Domingo, M. 2001b. New insights into the pathogenesis of fibromyalgia syndrome. Med. Aspects Hum. Sex. 1, 51–57. Staud, R. and Smitherman, M. L. 2002. Peripheral and central sensitization in fibromyalgia: pathogenetic role. Curr. Pain Headache Rep. 6, 259–266. Staud, R., Price, D. D., Robinson, M. E., and Vierck, C. J. 2004. Body pain area and pain-related negative affect predict clinical pain intensity in patients with fibromyalgia. J. Pain 5, 338–343. Staud, R., Robinson, M. E., Vierck, C. J., Cannon, R. L., Mauderli, A. P., and Price, D. D. 2003. Ratings of experimental pain and pain-related negative affect predict clinical pain in patients with fibromyalgia syndrome. Pain 105, 215–222. Staud, R., Vierck, C. J., Cannon, R. L., Mauderli, A. P., and Price, D. D. 2001. Abnormal sensitization and temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome. Pain 91, 165–175. Sultan, S. M., Ioannou, Y., Moss, K., and Isenberg, D. A. 2002. Outcome in patients with idiopathic inflammatory myositis: morbidity and mortality. Rheumatology (Oxf.) 41, 22–26. Tench, C., Bentley, D., Vleck, V., McCurdie, I., White, P., and D’Cruz, D. 2002. Aerobic fitness, fatigue, and physical disability in systemic lupus erythematosus. J. Rheumatol. 29, 474–481. Thieme, K., Turk, D. C., and Flor, H. 2004. Comorbid depression and anxiety in fibromyalgia syndrome: relationship to somatic and psychosocial variables. Psychosom. Med. 66, 837–844. Torebjork, H. E., Lundberg, L. E., and LaMotte, R. H. 1992. Central changes in processing of mechanoreceptive input in capsaicin-induced secondary hyperalgesia in humans. J. Physiol. 448, 765–780. Turk, D. C., Okifuji, A., Starz, T. W., and Sinclair, J. D. 1996. Effects of type of symptom onset on psychological distress and disability in fibromyalgia syndrome patients. Pain 68, 423–430. Viau, V., Sharma, S., Plotsky, P. M., and Meaney, M. J. 1993. Increased plasma ACTH responses to stress in nonhandled compared with handled rats require basal levels of

782 Fibromyalgia corticosterone and are associated with increased levels of ACTH secretagogues in the median eminence. J. Neurosci. 13, 1097–1105. Vierck, C. J., Staud, R., Price, D. D., Cannon, R. L., Mauderli, A. P., and Martin, A. D. 2001. The effect of maximal exercise on temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome. J. Pain 2, 334–344. Wall, P. D. and Woolf, C. J. 1984. Muscle but not cutaneous C-afferent input produces prolonged increases in the excitability of the flexion reflex in the rat. J. Physiol. Lond. 356, 443–458. Waylonis, G. W. and Perkins, R. H. 1994. Post-traumatic fibromyalgia. A long-term follow-up. Am. J. Phys. Med. Rehabil. 73, 403–412. White, K. P., Harth, M., Speechley, M., and Ostbye, T. 2000. A general population study of fibromyalgia tender points in noninstitutionalized adults with chronic widespread pain. J. Rheumatol. 27, 2677–2682.

White, K. P., Nielson, W. R., Harth, M., Ostbye, T., and Speechley, M. 2002. Chronic widespread musculoskeletal pain with or without fibromyalgia: psychological distress in a representative community adult sample. J. Rheumatol. 29, 588–594. Wolfe, F., Simons, D. G., Fricton, J. R., Bennett, R. M., Goldenberg, D. L., Gerwin, R., Hathaway, D., McCain, G. A., Russell, I. J., and Sanders, H. O. 1992. The fibromyalgia and myofascial pain syndromes: a preliminary study of tender points and trigger points in persons with fibromyalgia, myofascial pain syndrome and no disease. J. Rheumatol. 19, 944–951. Wolfe, F., Smythe, H. A., Yunus, M. B., Bennett, R. M., Bombardier, C., Goldenberg, D. L., Tugwell, P., Campbell, S. M., Abeles, M., and Clark, P. 1990. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum. 33, 160–172.

52 Pain Perception – Nociception during Sleep G J Lavigne, Universite´ de Montre´al, Montreal, QC, Canada K Okura, Tokushima Graduate School, Tokushima, Japan M T Smith, John Hopkins Medical School, Baltimore, MD, USA ª 2009 Elsevier Inc. All rights reserved.

52.1 52.1.1 52.1.2 52.1.3 52.1.4 52.2 52.2.1 52.2.2 52.3

Pain in Relation to Sleep Definition, Epidemiology, and Relevance Cognitive Disturbances Sleep Fragmentation and Deprivation Circadian Variation in Pain Perception Perception of Pain during Sleep: Nociception or Sleep Arousal Nociception – Pain Perception during Sleep Sleep Arousal: Brain and Autonomic Activation Circular Relation between Pain and Poor Sleep and Putative Consequence on Health Cost

References

784 784 785 785 786 786 786 789 790 791

Glossary alpha EEG wave intrusion The intrusion of fastfrequency electroencephalographic (EEG) alpha (7.5–11 Hz) activity into slow wave sleep (SWS) or into deep sleep (stages 3 and 4). SWS is dominated by large and slow EEG waves of delta type (0.5–4.0 or 0.75–4.5 Hz); it also characterizes sleep stages 3 and 4. SWS is not a specific biological marker of pain during sleep. sleep awakening (major arousal) A sudden increase in EEG and heart rate frequency with a rise in muscle tone that lasts more than 10 or 15 s. Subject is not usually aware of external influences. An excessive number of major arousals during sleep is frequently followed by a complaint of unrefreshing sleep and cognitive impairment the following day. cyclic alternating pattern Repetition of microarousals every 20–60 s as a sentinel that allows for a reset of physiological functions (e.g., heart rate, respiration, muscle tone) or prepares the body for an appropriate response in relation to potential disrupting events. micro-arousal A sudden increase, during sleep, in EEG activity and heart rate frequency under a cardiac sympathetic dominance with a possible rise in muscle tone. It should last more than 3 s but less than 10 or 15 s depending on scoring method. A sleeping subject is normally unaware of this

physiological activity; it tends to be repeated 8–15 times per hour of sleep. nociception The receiving and transmitting of noxious sensory signals from the periphery to the central nervous system. pain An unpleasant and sensory, cognitive, and emotional experience normally associated or not with tissue damage, which usually requires a minimal level of consciousness for expression. pain threshold The lowest experimental stimulation perceived as being painful by a conscious subject in 50% of the trials. sleep A natural physiological and behavioral state usually characterized by a partial isolation from the environment except when an unpleasant or potentially harmful or life-threatening event is present. sleep stage A division of the specific sleep period into sleep stages (St): light sleep (St 1 or 2), deep sleep (St 3 and 4) are both described as non-REM sleep, and the REM or paradoxical sleep. Most body movements occur in light non-REM sleep (periodic limb movement, sleep bruxism). Sleep apnea (cessation of breathing for more than 10 s) is dominant in deep sleep and in REM sleep. REM behavior disorder (RBD) is characterized by sudden movement in REM sleep that is normally associated with muscle hypotonia (behaviorally described as motor paralysis).

783

784 Pain Perception – Nociception during Sleep

sleep fragmentation Interruption of any sleep stage by isolated or repetitive events such as sleep stage shifts (deeper to lighter), micro-arousals, frank awakenings, with or without low duration of

52.1 Pain in Relation to Sleep 52.1.1 Definition, Epidemiology, and Relevance Pain is a sensation that usually requires a certain level of consciousness before it is interpreted as an unpleasant sensory experience. Most persistent pain states can trigger complaints of poor sleep quality. Poor sleep quality is reported in 50–90% of patients with the following chronic pain conditions: arthritis, cervical and orofacial pain, low back pain, cancer pain, fibromyalgia. (Atkinson, J. H. et al., 1988; Dao, T. T. T. et al., 1994; Morin, C. M. et al., 1998; Smith, M. T. et al., 2000; Dauvilliers, Y. and Touchon, J., 2001; Riley, J. L. III et al. 2001; Roizenblatt, S. et al., 2001; McCracken, L. M. and Iverson, G. L., 2002). Sleep quality is also impaired in the presence of other medical conditions of which pain is a common symptom, including: headaches, irritable bowel syndrome, spinal cord injury, and metastatic breast cancer (Cohen, M. et al., 2000; Menefee, L. A. et al., 2000; Moldofsky, H., 2001; Widerstrom-Noga, E. G. et al., 2001; Rains, J. C. and Penzien, D. B., 2002; Koopman, C. et al., 2002; Okifuji, A. and Turk, D. C., 2002; Lavigne, G. J. et al., 2005). According to a recent survey from the National Sleep Foundation (USA), up to 20% of the adult population reports that their sleep is disrupted by somatic discomfort and pain. The interaction between pain and poor sleep is supported by cohort and case control studies. Patients with orofacial pain are 3.7 more times at risk of reporting poor sleep (Macfarlane, T. V. and Worthington, H. V., 2004). In a survey done in the USA with 1506 community women and men aged between 55 and 84, it was found that bodily pain was associated with a risk for complaints of insomnia (e.g., difficulty falling asleep, middle of the night/ early morning awakenings, or nonrestorative sleep). Odds ratios for insomnia among those reporting bodily pain were estimated to be between 1.88 and 2.68 (Foley, D. et al., 2004). It has also been reported that the prevalence of insomnia is 2 times higher in Canadian chronic pain patients in comparison to the general population without pain (Sutton, D. A. et al.,

deep St 3 and 4 sleep and possible alpha EEG wave intrusion. As a result, sleep continuity may be impaired and poor sleep quality (e.g., unrefreshing) is frequently reported upon awakening.

2001; Moldofsky, H., 2001). A cross-sectional study done in Hungary with over 12 643 adults showed that insomnia-related complaints were 3 times higher in chronic pain patients than in nonpain subjects (Novak, M. et al., 2004). Finally, the concomitance of sleep disorders and pain may modify the subjective sensation related to sleep quality (e.g., refreshing) since 50% of insomnia patients with pain reported that pain interfered with daily activities (Novak, M. et al., 2004). Moreover, in the presence of bodily pain there is an increase (OR of 1.73) in self-reports of daytime sleepiness (Foley, D. et al., 2004) a topic further described in the next section. In explorations of the interaction between high pain intensity and poor sleep, it is important to consider that chronic pain is frequently concomitant with anxiety, fatigue, mood disturbance, depression, and poor physical fitness (Menefee, L. A. et al., 2000b; Riley, III. J. L. et al., 2001; Smith, M. T. et al., 2000; McCraken, L. M. and Iverson, G. L. 2002b; Nicassio, P. M. et al., 2002; Sayar, K. et al., 2002; Yatani, H. et al., 2002). For example, fatigue is frequently reported in chronic pain patients and can explain 6.5% of the variability between pain intensity and complaints of poor sleep. Depression may further explain up to 40% of this variability. The presence of frank sleep apnea, a major risk for fatigue and daytime sleepiness, seems to be relatively low in chronic pain patients, as reported in a recent review (Dauvilliers, Y. and Touchon, J. 2001; Donald, F. et al., 1996). However, the cumulative effect of poor sleep over a given night and possibly over several nights also needs to be considered. While it is recognized that daytime sleepiness may result from long interruptions of respiration (more than 10 s is defined as sleep apnea), less information is available on the cumulative consequence of several briefer hypoxic events, which may alter cognitive function and brain metabolism (Bonnet, M. H. 1985; Wesenten, N. J. et al., 1999; Stepanski, E. J., 2002; Martin, S. E. et al 1996; Van Dogen, H. P. et al., 2003; Gozal, D. and O’Brien, L. M., 2004). Recent work in fibromyalgia, for instance, suggests the possibility of a high rate of sleep-related upper airway resistance syndrome that

Pain Perception – Nociception during Sleep

when reversed by continuous positive airway pressure therapy, may improve daytime function (Gold, A. R. et al., 2004). The impact of the above-mentioned variables on pain and sleep interaction and their reversal by continuous positive airway pressure (CPAP) needs to be further assessed in controlled and blind studies. 52.1.2

Cognitive Disturbances

Very few studies have investigated the effect of pain on cognitive functions such as memory and attention. Three studies using chronic musculoskeletal pain and fibromyalgia patients suggest a causative association (Kewman, D. G. et al., 1991; Landro, N. I. et al., 1997; Coˆte´, K. A. and Moldofsky, H., 1997). The impact of cognitive deficits and their potential aggravation by disturbed sleep needs to be further studied. The potential impact of several classes of pain medication (e.g., opioids, anticonvulsants, muscle relaxants, antidepressants) on sleep and daytime alertness is also a particularly important line of research with real-life consequences ranging from sleep-related industrial accidents to impaired driving ability (George, C .F. P., 2003; Chapman, S., 2001). A recent experimental study done in normal volunteers showed that a one night infusion of morphine during sleep time can alter sleep quality by reducing deep-sleep duration and increasing sleep stage 2 duration (Shaw, I. R., et al., 2005). Evidence-based data on long-term use of morphine on sleep homeostasis are missing. 52.1.3 Sleep Fragmentation and Deprivation Sleep fragmentation is usually characterized by a rapid shift from a deeper sleep stage to a lighter one or by an increase in the number of brief arousals up to longer awakenings during the night (see Glossary for definitions). The number of body movements and respiratory disturbance events, which are often associated with arousals, seems to have an additive effect on daytime functioning over the following day or days. Sleep deprivation is a more general term that either characterizes the absence or very short duration of a given sleep stage and/or the near absence or reduction of sleep as tested by experimental manipulations. As recently demonstrated, measures of the impact of chronic sleep loss fall into a clear hierarchy: mood measures being more sensitive than cognitive tasks, which are in turn more sensitive than performance of motor tasks (Bonnet, M. H., 2005).

785

The increase in sleep fragmentation in normal subjects or in patients with sleep apnea seems to be clearly associated with a reduction in next-day performance, sleepiness, and impaired alertness (Bonnet, M. H., 1985; Wesenten, N. J. et al., 1999; Stepanski, E. J., 2002; Martin, S. E. et al., 1996; Van Dogen, H. P. et al., 2003). A minimum of 5–6 h of sleep seems to be the threshold below which daytime performance is altered and, interestingly, several days are required before a return to baseline levels (Van Dogen, H. P. et al., 2003). There is still no definitive evidence indicating that lack of deep sleep (St 3 and 4) or of slow wave EEG activity (SWA) increases pain sensitivity, although some animal and human experimental studies suggest such a link (see review from Kundermann, B. et al., 2004a; Kundermann, B. and Lautenbacher, S., 2007). To our knowledge only one study has compared deep-sleep deprivation with other sleep stages or total sleep deprivation (Onen, A. H. et al., 2001). Moreover, the absence of deep sleep is a feature of all chronic-pain conditions (Okura, K. et al., 2004). Before summarizing the studies on sleep deprivation and changes in pain perception, it is important to reiterate that study design and data analysis need to control for: (1) the differences between groups for age, since after 40 years of age, slow wave density, a dominant feature of deep sleep, tends to decline; (2) presence of respiratory disturbances during sleep, since patients with fibromyalgia who complain of daytime hypersomnolence tend to present with more micro-arousals, a higher number of short respiratory disturbances and longer oxygen desaturation periods than matched normal controls, an effect reversed by CPAP (Sergi, M. et al., 1999; Gold, A. R. et al., 2004); (3) the concomitant effect of fatigue, mood depression, anxiety, poor lifestyle habits, etc., as described above. In addition to the above issues, it is also important to note that the literature of sleep deprivation and pain is generally limited by experimental studies done with small sample sizes and a lack of adequate control groups. Several studies have been conducted in normal subjects to assess the effect of deep-sleep deprivation on next-day pain perception. The disruption of sleep stage 4 or SWS by sound was associated with an increase in muscle tenderness and a reduction in pain threshold (mechanical pressure) the next morning, but this effect was less dominant when studies controlled for concomitant influences of fatigue (Moldofsky, H. and Scarisbrick, P., 1976; Lentz, M. J. et al., 1999; Older, S. A. et al., 1998). Negative findings have been reported by others (Drewes, A. M. et al., 1997; Kundermann, B.

786 Pain Perception – Nociception during Sleep

et al., 2004a; Older, S. A. et al., 1998; Arima, T. et al., 2001; Smith, M. T., et al., 2007). Surprisingly, when normal subjects were deprived of SWA sleep, REM sleep or total sleep duration, no change in thermal pain threshold was noted during any of the sleep interruptions (Onen, A. H. et al., 2001). In this study, however, total sleep deprivation slightly reduced mechanical pain tolerance scores (8%) and in the period after sleep recovery, a significant rebound effect was noted, such that mechanical pain tolerance was 15% higher. A recent study done in normal volunteers showed that two nights of total sleep deprivation reduced both heat and cold pain thresholds, but had no effect on warmth and cold detection threshold; results suggested that change in pain threshold was not specific to alterations in somatosensory function (Kundermann, B. et al., 2004b). Kundermann and colleagues also suggested, in a comprehensive review, that the role of stress and changes in endogenous serotonin and opioid activity can also play an important role in arousal and changes in pain perception (Kundermann, B. et al., 2004a). It is important to clarify that experimental sleep deprivation, which has been induced in the above studies, is an extreme manipulation that may be different from the natural ongoing sleep disruption experienced by chronic pain patients. As described above, fragmentation or deprivation, not necessarily limited to St 3 and 4, seems to alter cognitive function and memory consolidation; all sleep stages seem to be equally important for the preservation and maintenance of daytime functions (Stickgold, R. et al., 2000; Mednick, S. et al., 2003; Gais, S. et al., 2000). 52.1.4 Circadian Variation in Pain Perception Surprisingly, most studies using normal nonpain subjects without mood alteration have failed to demonstrate a clear circadian variation in experimental pain threshold or pain intensity reports over a 24 h schedule or when comparing evening and morning data (Rogers, E. J. and Vilkin, B. 1978; Strian, F. et al., 1989; Koltyn, K. F. et al., 1999; Lavigne, G. J. et al., 2000; Bentley, A. J. et al., 2003; Lavigne, G. J. et al., 2004). In patients with chronic pain, however, symptom presentation often has a typical circadian pattern. Arthritic pain is often worse in the morning, while pain levels related to fibromyalgia, myofascial orofacial pain, and some headache conditions are typically higher in the afternoon (Bellamy, N. et al., 1991; Reilly, P. A. and Littlejohn, G. O., 1993; Dao, T. T. T. et al., 1994). Furthermore, not all pain conditions

involve pain that directly interferes with sleep; in patients with torticolis, pain is rapidly reduced by adopting the supine posture (Lobbezoo, F. et al., 1996; Bentley, A. J., 2007).

52.2 Perception of Pain during Sleep: Nociception or Sleep Arousal 52.2.1 Nociception – Pain Perception during Sleep While awake, tactile and thermal sensory input of sufficient intensity can activate A delta, A beta, and C sensory fibres projecting to the thalamus and several cortical areas (Bromm, B. and Lorenz, J. 1998; Coghill, R.C. et al., 1994; Le Pera, D. et al., 2000; Peyron, R. et al., 2000). The long duration of painful hypertonic saline infusions seems to activate A delta and C afferent fibers that in the wake state reach the thalamus, amygdale, and other cortical areas associated with pain processing (Le Pera, D. et al., 2000; Zubieta, J. K. et al., 2001). During sleep, however, a putative gating process of somatosensory inputs is thought to prevent awakening resulting from irrelevant input or non-life-threatening events. Several studies suggest that sleep-preserving sensory gating mechanisms are likely to be located at the upper brain stem area (see Figure 1) in the so-called reticular activating system (Pompeiano, O. and Swett, J. E. 1963; Hernandez-Peon, R. et al., 1965; Soja, P. J. et al., 2001; Soja, P. J., 2007; Nofzinger, E. and Derbyshire, S. W. G., 2007). However, the balance between wakefulness system(s) and sleep-promoting neuronal network(s) in relation to sensory discrimination and pain during sleep is poorly understood and requires further investigation. Regarding sensory perception during sleep, it is crucial to discriminate between studies made using sound and those using tactile stimulations. The results of sound studies have made it apparent that acoustic stimulation triggers more sleep arousals and awakenings in non-REM light sleep stages (St 1 and 2) than in deep sleep (St 3 and 4) or in REM sleep (Rechstaffen, A. and Kales, A., 1968; Carley, D. W. et al., 1997; Kato, T. et al., 2004). Sound is a different sensory modality from pain: its main function with respect to sleep is to alert the individual to wake up (alarm clock) or to parental duties (a baby’s cry). Tactile stimulation, however, is more likely to be interpreted as a touch to the body, which may or may not enforce the awakening process and is likely to be interpreted differently than sound by a sleeping

Pain Perception – Nociception during Sleep

Wake

787

Sleep

Cortex

Cortex

Thalamus

Hypothalamus

Thalamus

Brainstem reticular formation

Stimulus

Hypothalamus

Brainstem reticular formation

Stimulus

Figure 1 During wake state, there is a free flow in neuronal activity from spinal cord or/and brainstem to and from thalamus and cortical networks. During sleep, a gating mechanism seems to isolate the upper brain from most incoming inputs originating at somatosensory level. However, some circuits, for example, auditory processing, remain fully active. The exact anatomical site of the separation (see dashed line) between spinal and brainstem networks and thalamo-cortical pathways remain to be demonstrated.

brain (Velluti, R. A. et al., 2000; Kato, T. et al., 2004; Soja, P. J. et al., 2001) Moreover, during sleep the term nociception is probably more accurate to describe the process of potentially harmful inputs, interpreted in conscious and awake subjects as pain (Bromm, B. and Lorenz, J., 1998; Lavigne, G. J. et al., 2000). Studies done in the 1960s, using tactile-cutaneous sensory stimulations during wake/sleep states, are a rich source of information (Pompeiano, O. and Swett, J. E., 1963; Hernandez-Peon, R. et al., 1965) It was suggested that a filtering mechanism is active during synchronized or non-REM sleep at the first relay of neurons in the brainstem mesencephalic-reticular formation and in the trigeminal sensory nucleus. More recent work lends further support to the concept that sleep involves a selective isolation from the external milieu. Recordings of ascending spinoreticular and trigemino-thalamic tract neurons show that a gating mechanism seems to be present during sleep when brief sensory or pain stimulations are applied to the skin of the animal. Furthermore, the neurons behaved differently across sleep stages, that is, during non REM or REM sleep: air puff activated trigemino-thalamic tract neurons during REM sleep whereas neuronal activity following tooth pulp stimulation was

suppressed (Cairns, B. E. et al., 1996; Soja, P. J. et al., 2001). It was further suggested that the serotoninergic and nonserotoninergic brainstem raphe magnus cells are involved to an important extent in the sensory modulation of pain inputs (Foo, H. and Mason, P., 2003). Interestingly, recording of thalamic cells in one human has confirmed previous animal findings suggesting that thalamic neurons discharge differently during states of waking and sleeping. It was observed that the discharge of thalamic neurons was in a tonic mode while the patient was awake and in a bursting mode when the patient was in light sleep; nevertheless none of these cells had a clear sensory receptive field in the periphery (Tsoukatos, J. et al., 1997). These findings are similar to those from animal studies showing that thalamic neurons are under a global inhibition during sleep while cortical neurons, by contrast, are highly active (Steriade, M. and Timofeev, I., 2003). The exact location of the mechanism(s) supporting the somatosensory dissociation during sleep remains under investigation (see Figure 1). The balance between mechanisms that maintain vigilance or promote sleep continuity, however, seems to be statedependent and related to the modulation of neuronal networks at the level of the reticular activating system.

788 Pain Perception – Nociception during Sleep

The initiation of an awakening and conscious reaction during sleep may be secondary to a decrease in the sensory gating in sleep resulting in the recovery of the free flow between ascending and descending brainstem, thalamus and cortical activities (Siegel, J., 2004; Skinner, R. D. et al., 2004). In other words, it is as if the reptilian brain maintains basic survival function during sleep, and interaction with thalamo-cortical networks depends on the nature (sound, touch, and harmful stimulus), magnitude, and duration of the stimulation. Obviously, this hypothesis needs to be supported by further evidence. A recent paper summarizing the evidence on brain activation during sleep provides relevant information (Peigneux, P. et al., 2003). During light sleep, pontine tegmentum and thalamus are deactivated while mesencephalic regions remain active. In deep sleep, all three structures are relatively deactivated while activity is largely maintained at the cortical temporal and insular lobe levels. Paradoxically, all the above structures are activated during REM sleep, although a strong dissociation is present: there is no peripheral efferent activity (e.g., the motor cortex does not trigger a movement except in the presence of sleep pathology: the REM behaviour disorder). There is little evidence strongly supporting a clear-cut gating of sensory information at the lower brain level, to prevent awakening from irrelevant sensory inputs. However, the role of the amygdala and the hypothalamus is discussed in the interpretation of sensory gating outside the higher thalamocortical levels (Morrison, A. R. et al., 2000; Lee, R. S. et al., 2001). A review of behavioral animal and human studies is also useful for a better understanding of the modulation of sensory inputs during sleep. The interaction between the pain system and vigilance versus sleep is further supported by a cat study using the classical tail flick sensory motor reflex (Kshatri, A. M. et al., 1998). It was suggested that the gating of sensory inputs during sleep depends on the integrity of the cholinergic system at the medial pontine–reticular level. This work also clearly showed, in comparison to the wake state and in the absence of any medication, that the reflex latency was 3 times longer in non-REM sleep (quiet sleep in animal) and 5 times longer in REM sleep. This finding again supports the concept of higher responsiveness to brief sensory inputs during non-REM in comparison to REM sleep. However, another cat study revealed that under tonic sensory nociceptive influences (formalin injection in the foot) the animals tended to remain awake with delayed sleep onset for

the first 2 days, and a reduction in duration of deep sleep (St 3 and 4 in humans) and REM sleep stages (Carli, G. et al., 1987) Interestingly, after 2 days, the animals recovered, exhibiting total sleep time and deep sleep of longer duration; a typical pattern seen after sleep deprivation (Onen, A. H. et al., 2001; Kundermann, B. et al., 2004a). Another sleep and pain study in rats, using the experimental adjuvant arthritis model in both hind paws, also showed fragmentation of the typical sleep and wake pattern (Landis, C. A. et al., 1988). The number of brief sleep periods was increased over the circadian rhythm; total sleep time and deep sleep duration were also shorter in rats with arthritis. The abovementioned animal studies suggest that a sleeping brain is not completely isolated from the external milieu and that pain-nociception can activate networks related to vigilance and body protection. This activation appears to be related to the type (phasic versus tonic, intensity, etc.) and duration of the painful stimuli (Velluti R. A. et al., 2000; Soja, P. J. et al., 2001; Kato, T. et al., 2004; Lavigne, G. J. et al., 2004). In humans, the perception of pain during sleep also depends on the duration and type of stimulus used; brief sensory nerve-related or mild duration thermal or long duration chemical or mechanical stimulations initiate different types of responses that need to be interpreted accordingly. In a study using the spinal motor responses, following brief stimulation of the leg sural nerve to evoke a flexion reflex, it was noted that the reflex latency was prolonged during sleep in comparison to wake state (Sandrini, G. et al., 2001). In parallel, the threshold was 60% higher in non-REM and 200% higher in REM sleep than during wake state. This study supports the abovementioned animal findings, suggesting that during sleep lower brain neurons modulate pain inputs in such a way that a hypoalgesic response seems to be present. In contrast, when sensory processing from periphery to cortex was estimated with extremely brief (100 s). A similar procedure has been used by others during sleep (Drewes, A. M. et al., 1997). Interestingly, we found that micro-arousal responses were also more dominant in light sleep in comparison to deep and REM sleep, and a clear and dominant sleep awakening response was present with an equipotent response rate in all sleep stages (Lavigne, G. J. et al., 2004). This evidence suggests that when a painful stimulus or a clinical pain episode lasts long enough, the protective mechanism that maintains sleep continuity (the gating barrier to irrelevant input) is released and a clear behavioral response may occur with a potential return to consciousness. Recent clinical evidence for impaired somatosensory gating during sleep in chronic pain conditions has been suggested by findings of decreased sleep spindle activity in chronic low back pain and fibromyalgia patients (Harman, K. et al., 2002; Landis, C. A. et al., 2004). Thus it can be hypothesized that brief sensory stimuli, such as electrical or thermal pain, are too brief to be processed by a sleeping brain as potentially harmful, whereas longer-lasting or tonic painful stimuli akin to clinical pain states are more likely to elicit a full-blown arousal response. 52.2.2 Sleep Arousal: Brain and Autonomic Activation The above arousal and awakening responses observed with thermal and deep muscle infusion are not only restricted to a cortical activation as seen on electroencephalogram. They are also associated with a clear increase in heart rate and a change in respiration that is frequently interrupted with the onset of the pain stimulation (Lavigne, G. J. et al., 2000;

789

Lavigne, G. J. et al., 2001; Bentley, A. J. et al., 2003; Lavigne, G. J. et al., 2004). It is interesting to note that the so-called fast alpha EEG intrusion, which for a long time was believed to be a marker of pain in relation to sleep, is not considered to provide the sole explanation for poor sleep in pain patients (Moldofsky, H., 2001; Mahowald, M. L. and Mahowald M. W., 2000; Roizenblat, S. et al., 2001; Rains, J. C. and Penzien, D. B., 2003). More recent thinking conceptualizes pain as a disruptor of sleep homeostasis that may increase sleep arousal instability, described as an augmentation in the normal cyclical alternating pattern in which brain and cardiac activation tends to recur in clusters (Staedt, J. et al., 1993; Moldofsky, H., 2001; Roizenblatt, S. et al., 2001; Parrino, L., Zucconi, M. and Terzano, M. G., 2007). Cardiac activation during sleep is used as an indirect estimate of sympathetic (e.g., accelerator) and parasympathetic (decelerator or brake) balance during wake and sleep states. During wake state, a sympathetic dominance predominates, maintaining a high level of vigilance. Sympathetic-cardiac dominance is also present during REM sleep, a state with high cortical and cardiac activity but with a behavioral muscle paralysis. Conversely, during nonREM sleep, parasympathetic-cardiac activity is dominant and this may provide a recuperative function since there is an inverse coupling: a low sympathetic dominance is inversely coupled with a high degree of SWA in each consecutive non-REM to REM cycle (Brandenberger, G. et al., 2001). Interestingly, in insomnia and fibromyalgia patients, a sympathetic dominance persists across NREM sleep cycles at levels similar to wake and REM sleep states (Bonnet, M. H. and Arand D. L., 1998; Martı´nezLavı´n, M. et al., 1998). It has been hypothesized that enhanced sympathetic activity during sleep may over-facilitate arousal mechanisms and cyclical patterns of brain activation. However, this hypothesis was not supported in a study of medication-free women suffering from fibromyalgia in comparison to women with efficient sleep and no pain (McMillan, D. et al., 2004). By contrast, when patients with chronic fibromyalgia (widespread pain) and pain (low back, etc.) presenting with poor sleep efficiency were matched for age and gender to normal sleepers, we found (see Figure 2) that the normal parasympathetic and sympathetic balance was lost in both pain groups during non-REM sleep with an inverse coupling of SWA, that is, a lower density of SWA was observed during consecutive sleep stages compared to control

790 Pain Perception – Nociception during Sleep

500

SWA power (amplitude μV)

500 400

p = 0.03

FM

400

300

300

200

200

100

100

0

NREM REM NREM REM NREM REM

0

1st sleep cycle 2nd sleep cycle 3rd sleep cycle

LF/(HF + LF)

NREM REM NREM REM NREM REM 1st sleep cycle 2nd sleep cycle 3rd sleep cycle

FM

0.8

0.7

0.7

0.6

0.6

0.5

0.5

0.4

Pain

0.9

0.9 0.8

p = 0.09

n = 10

0.4

Pain

n = 10 Normal FM Pain

Figure 2 Dynamics of SWA and HRV over three consecutive sleep cycles. In normal subjects, SWA shows an inverse coupling with sympathetic activity (low-frequency divided by high-frequency plus low-frequency. One of the heart rate variability: HRV). During non-REM sleep, SWA was high when the sympathetic cardiac activity was low, and, conversely, SWA was low when HRV was high in REM sleep. In comparison to normal subjects, fibromyalgia (FM) chronic widespread pain patients showed a significant reduction in SWA for the first sleep cycle only (t-test: p ¼ 0.03). Chronic pain patients (PAIN) also presented a similar trend in SWA, but not statistically significant (t-test: p ¼ 0.09). PAIN patients did not show a rise in sympathetic activity during REM sleep (p ¼ NS: repeated ANOVA); FM patients showed a trend toward no rise in REM sleep.

subjects (Okura, K. et al., 2005). Furthermore, like previous studies of men with fibromyalgia in a wake state, our preliminary analysis suggests that men maintain a high sympathetic activity across all sleep stages (Cohen, H. et al., 2001). Women, however, do not show the usual rise in sympathetic activity during REM sleep. Our data differ from those of (MartinezLavin, M., et al., 1998) since we separated data into consecutive non-REM and REM cycles. Caution is needed when interpreting the above-mentioned observations since parasympathetic and sympathetic balance tends to be altered with age and acute stress in relation to sleep (Brandenberger, G. et al., 2003; Hall, M. et al., 2004).

52.3 Circular Relation between Pain and Poor Sleep and Putative Consequence on Health Cost The initiation of pain (e.g., acute post-op or trauma) usually precedes or coincides with the onset of poor sleep in close to 53–89% of patients (Morin, C. M. et al.,

1998; Smith, M. T. et al., 2000; Riley, J. L., III et al., 2001). In other words, in retrospective accounts, sleep disturbance is generally not considered a major problem for many patients until an injury is experienced; then pain and sleep become salient interacting issues. Intensive, time-series diary studies using multilevel modeling statistical techniques consistently show that over time, a day with intense pain is frequently followed by a poor sleep quality and subsequent ratings of poor sleep are in turn linked to next-day increases in clinical pain. This circular relationship, also described as a vicious circle, has been observed in patients with fibromyalgia, severe skin burns, and rheumatoid arthritis (Affleck, G. et al., 1996; Raymond, I. et al., 2001; Stone, A. A. et al., 1997; Nicassio, P. M. et al., 2002; Lavigne, G. J. et al., 2005). As has been mentioned above, the influences of fatigue, mood alteration, other sleep disorders (such as sleep apnea or periodic limb movement), and medication use have not been well controlled for in these studies. No direct data, to our knowledge, reports on the cost of pain and its interaction with poor sleep. However, an extensive study done in a Canadian

Pain Perception – Nociception during Sleep

population (125 574 respondents) estimated that for every four patients seen by a family physician, three will report chronic pain (Meana, M. et al., 2004). When the potential cognitive disruption of pain medications is considered together with the rates at which analgesic, antidepressant, codeine, and hypnotics medications are used (3–4 times more often by women with chronic pain), it becomes apparent that the reduced ability of chronic pain patients with poor sleep to perform daily tasks is a societal burden (Meana, M. et al., 2004b). Moreover, given the aging population and the high prevalence of chronic pain (reported by over 50% of elderly of both genders), it is clear that health managers have a major challenge in planning service use (Harstall, C. and Ospina, M., 2003; Meana, M. et al., 2004). The economic cost of chronic pain can probably be estimated in the order of billion dollars from headaches to pelvic pain; obviously specific estimation needs to be done. The large range of costs, for various pain symptoms and syndromes, reflects a lack of reliable information, although it is clear that chronic pain conditions are extremely costly (Latham, J. and Davis B. D., 1994). To date, an approximate estimate of the additional burden that poor sleep places on chronic pain costs can be only derived from cost studies of insomnia, which have yielded estimates ranging from 77 to 92 billion dollars (Stoller, M. K., 1994). If we agree that the suggested prevalence of chronic pain in adult population stands at 11% (Harstall, C. and Ospina, M., 2003) and that insomnia (defined as difficulties in sleep onset or in maintaining sleep and/or perception of nonrestorative sleep) is reported conservatively at a similar prevalence (Martin, S. A. et al., 2004) we can extrapolate, based on the assumption that one chronic pain patient in two will report similar insomnia complaints, that the overall direct cost is probably over 1 billion dollars. Indirect costs arising from as sick leave, hospitalization, and vehicular accident also need to be estimated, as has been done for other sleep disorders (Barbe´, F. et al., 1998; George, C. F. P., 2003). There is an obvious need for prospective and systematic studies of pain and economics that will estimate cost of health care, corrected for concomitant conditions such as aging, diabetes, obesity, cardiovascular problems, sleep disorders, depression, and anxiety (Lavigne, G. and Manzini, C., 2007). Moreover, indirect cost of absenteeism, low working performance, accident, reduced familial activities and risk of divorce also need to be factored into estimates of the cost of pain in relation to poor sleep.

791

References Affleck, G., Urrows, S., and Tennen, H. 1996. Sequential daily relations of sleep, pain intensity, and attention to pain among women with fibromyalgia. Pain 68, 363–368. Arima, T., Arendt-Nielsen, L., and Svensson, P. 2001. Effect of jaw muscle pain and soreness evoked by capsaicin before sleep on orofacial motor activity during sleep. J. Orofac. Pain 15(3), 245–256. Atkinson, J. H., Ancoli-Israel, S., and Slater, M. A. 1988. Subjective sleep disturbance in chronic back pain. Clin. J. Pain 4, 225–232. Barbe´, F., Pericas, J., Munoz, A., Findley, L., Anto, J. M., and Agusti, A. G. N. 1998. Automobile accidents in patients with sleep apnea syndrome. Am. J. Respir. Crit. Care Med. 158, 18–22. Bedyoun, A., Morrow, T. J., and Shen, J. 1993. Variability of laser-evoked potentials: attention, arousal and laterizes differences. Electroenceph Clin Neurophysiol 88, 173–181. Bentley, A. J. 2007. Pain Perception during Sleep and Circadian Influences: The Experimental Evidence. In: Sleep and Pain (eds. G. Lavigne, B. J. Sessle, M. Choinie`re, P. J. Soja), pp. 123–136. IASP Press.. Bellamy, N., Sothern, R. B., and Campbell, J. 1991. Circadian rhythm in pain, stiffness, and manual dexterity in rheumatoid arthritis: relation between discomfort and disability. Annals. Rheum Dis 50, 243–248. Bentley, A. J., Newton, S., and Zio, C. D. 2003. Sensitivity of sleep stages to painful thermal stimuli. J. Sleep Res. 12, 143–147. Bonnet, M. H. 2005. Acute Sleep Deprivation. In: Principles and Practice Sleep of Medicine (eds. M. H. Kryger, T. Roth, W. C. Dement), 5, pp. 51–66. Elsevier Saunders. Bonnet, M. H. 1985. Effect of sleep disruption on sleep, performance, and mood. Sleep 8(1), 11–19. Bonnet, M. H. and Arand, D. L 1998. Heart rate variability in insomniacs and matched normal sleepers. Psychosom. Med. 60, 610–615. Brandenberger, G., Ehrhart, J., Piquard, F., and Simon, C. 2001. Inverse coupling between ultradian oscillations in delta wave activity and heart rate variability during sleep. Clin. Neurophysiol. 112, 992–996. Brandenberger, G., Viola, A. U., Ehrhart, J., Charloux, A., Geny, B., Piquard, F., and Simon, C. 2003. Age related changes in cardiac autonomic control during sleep. J. Sleep Res. 12, 173–180. Bromm, B. and Lorenz, J. 1998. Neurophysiological evaluation of pain. Electroenceph. Clin. Neurophysiol. 107, 227–253. Cairns, B. E., McErlane, S. A., and Fragoso, M. C. 1996. Spontaneous discharge and peripherally evoked orofacial responses of trigemino-thalamic tract neurons during wakefulness and sleep. J. Neurosci. 16, 8149–8159. Carley, D. W., Applebaum, R., Basner, R. C., Onal, E., and Lopata, M. 1997. Respiratory and arousal responses to acoustic stimulation. Chest 112(6), 1567–1571. Carli, G., Montesano, A., Rapezzi, S., and Paluffi, G. 1987. Differential effects of persistent nociceptive stimulation on sleep stages. Behav. Brain Res. 26, 89–98. Chapman, S. 2001. The effects of opioids on driving ability in patients with chronic pain. APS Bull. 11, 5–9. Coghill, R. C., Talbot, J. D., Evans, A. C., Meyer, E., Gjedde, A., Bushnell, M. C., and Duncan, G. H. 1994. Distributed processing of pain and vibration by the human brain. J. Neurosci. 14, 4095–4108. Cohen, M., Menefee, L. A., and Doghramji, K. 2000. Sleep in chronic pain: problems and treatments. Int. Rev. Psychiat 12, 115–126.

792 Pain Perception – Nociception during Sleep Cohen, H., Neumann, L., Alhosshle, A., Kotler, A., AbuShakra, M., and Buskila, D. 2001. Abnormal sympathovagal balance in men with fibromyalgia. J. Rheumatol. 28, 581–589. Coˆte´, K. A and Moldofsky, H. 1997. Sleep, daytime symptoms, and cognitive performance in patients with fibromyalgia. J. Rheumatol. 24, 2014–2023. Dao, T. T. T., Lund, J. P., and Lavigne, G. J. 1994. Comparison of pain and quality of life in bruxers and patients with myofascial pain of the masticatory muscles. Orofac. Pain. 8, 350–356. Dauvilliers, Y. and Touchon, J. 2001. Le sommeil du fibromyalgique: revue des donne´es cliniques et polygraphiques. Neurophysiol. Clin. 2001 31, 18–33. Donald, F., Esdaile, J. M., Kimoff, J. R., and Fitzcharles, M. A. 1996. Musculoskeletal complaints and fibromyalgia in patients attending a respiratory sleep disorders clinic. J. Rheumatol. 23(9), 1612–1616. Drewes, A. M., Nielsen, K. M., and Arendt-Nielsen, L. 1997. The effect of cutaneous and deep pain on the electroencephalogram during sleep – An experimental study. Sleep 20, 623–640. Foley, D., Ancoli-Israel, S., Britz, P., and Walsh, J. 2004. Sleep disturbances and chronic disease in older adults: results of the 2003 National Sleep Foundation Sleep in America Survey. J. Psychosom. Res. 56(5), 497–502. Foo, H. and Mason, P. 2003. Brainstem modulation of pain during sleep and waking. Sleep Med. Rev. 7, 145–154. Gais, S., Plihal, W., and Wagner, U. 2000. Early sleep triggers memory for early visual discrimination skills. Nature Neurosci 3, 1335–1339. George, C. F. P. 2003. Driving simulators in clinical practice. Sleep Med. Rev. 7, 311–320. Gold, A. R., Dipalo, F., Gold, M. S., and Broderick, J. 2004. Inspiratory airflow dynamics during sleep in women with fibromyalgia. Sleep 27(3), 459–466. Gozal, D. and O’Brien, L. M. 2004. Snoring and obstructive sleep apnoea in children: why should we treat? Paediatr. Respir. Rev. 5 (Suppl A), S371–S376. Hall, M., Vasko, R., Buysse, D., Ombao, H., Chen, Q., Cashmere, J. D., Kupper, D., and Thayer, J. F. 2004. Acute stress affects heart rate variability during sleep. Psychosomatic Med 66, 56–62. Harstall, C. and Ospina, M. 2003. How prevalent is chronic pain. Pain Clin. Update 11(2), 1–4. Harman, K., Pivik, R. T., D’Eon, J. L., Wilson, K. G., Swenson, J. R., and Matsunaga, L. 2002. Sleep in depressed and nondepressed participants with chronic low back Pain: electroencephalographic and behavior findings. Sleep 25(7), 775–783. Hernandez-Peon, R., O’Flaherty, J. J., and MazzuchelliO’Flaherty, A. L. 1965. Modifications of tactile evoked potentials at the spinal trigeminal sensory nucleus during wakefulness and sleep. Experimental Neurol. 13, 40–57. Kato, T., Guitard, F., Rompre´, P. H., Lund, J. P., Montplaisir, J. Y., and Lavigne, G. J. 2004. Experimentally induced arousals during sleep: a cross-modality matching paradigm. 2004. J. Sleep Res. 13, 1–10. Kewman, D. G., Vaishampayan, N., and Zald, D. 1991. Cognitive impairment in musculoskeletal pain patients. Int’l. J. Psychiat. Med. 21, 253–262. Koltyn, K. F., Focht, B. C., and Ancker, J. M. 1999. Experimentally induced pain perception in men and women in the morning and evening. Int. J. Neurosci. 98, 1–11. Koopman, C., Nouriani, B., and Erickson, V. E. 2002. Sleep disturbances in women with metastatic breast cancer. Breast Journal 6, 362–370. Kshatri, A. M., Baghdoyan, H. A., and Lydic, R. 1998. Cholinomimetics, but not morphine, increase

antinociceptive behavior from pontine reticular regions regulating rapid eye movement sleep. Sleep 21(7), 677–685. Kundermann, B. and Lautenbacher, S. 2007. Effects of Impaired Sleep Quality and Sleep Deprivation on Diurnal Pain Perception. In: Sleep and Pain (eds. C. Lavigne, B. J. Sessle, M. Choinie`re, P. J. Soja), Seattle IASP Press. Kundermann, B., Krieg, J. C., Schreiber, W., and Lautenbacher, S. 2004a. The effect of sleep deprivation on pain. Pain Res. Manage. 39(1), 25–32. Kundermann, B., Spernal, J., Huber, M. T., Krieg, J. C., and Lautenbacher, S. 2004b. Sleep deprivation affects thermal pain thresholds but not somato-sensory thresholds in healthy volunteers. Psychosomatic. Med. 66, 932–937. Landis, C. A., Robinson, C. R., and Levine, J. D. 1988. Sleep fragmentation in the arthritic rat. Pain 34, 93–99. Landis, C. A., Lentz, M. J., Rothermel, J., Buchwald, D., and Shaver, J. L. 2004. Decreased sleep spindles and spindle activity in midlife women with fibromyalgia and pain. Sleep 27(4), 741–750. Landro, N. I., Stiles, T. C., and Sletvold, H. 1997. Memory functioning in patients with primary fibromyalgia and major depression and healthy controls. J. Psychosom Res. 42, 297–306. Latham, J. and Davis, B. D. 1994. The socioeconomic impact of chronic pain. Disabil. Rehabil. 16(1), 39–44. Lavigne, G. J. and Manzini, C. 2007. Pain and Poor Sleep: Impact on Public Health. In: The Public Health Impact of Sleep Disorders (eds. S. R. Pandi-Perumal and D. Leger), pp. 193–208. Lavigne, G. J., Brousseau, M., Kato, T., Mayer, P., Manzini, C., Guitard, F., and Montplaisir, J. Y. 2004. Experimental pain perception remains equally active over all sleep stages. Pain 110, 646–655. Lavigne, G. J., McMillan, D., and Zucconi, M. 2005. Pain and Sleep. In: principles and practice sleep of medicine (eds. M. H. Kryger, T. Roth, W. C. Dement), Vol. 106, pp. 1246–1255. Elsevier Saunders. Lavigne, G. J., Zucconi, M., and Castronovo, C. 2000. Sleep arousal response to experimental thermal stimulation during sleep in human subjects free of pain and sleep problems. Pain 84, 283–290. Lavigne, G. J., Zucconi, M., Castronovo, C., Manzini, C., Veglia, F., Smirne, S., and Ferini-Strambi, L. 2001. Heart rate changes during sleep in response to experimental thermal (nociceptive) stimulations in healthy subjects. Clin. Neurophysiol. 112, 532–535. Lee, R. S., Steffenson, S. C., and Henriksen, S. J. 2001. Discharge profiles of ventral tegmental area GABA neurons during movement, anesthesia, and the sleep-wake cycle. J. Neurosci. 21(5), 1757–1766. Lentz, M. J., Landis, C. A., and Rothermel, J. 1999. Effects of selective slow wave sleep disruption on musculoskeletal pain and fatigue in middle aged women. J. Rheumatol. 26, 1586–1592. Le Pera, D., Svensson, P., Valeriani, M., Watanabe, I., ArendtNielsen, L., and Chen, A. C. 2000. Long-lasting effect evoked by tonic muscle pain on parietal EEG activity in humans. Clin. Neurophysiol. 111(12), 2130–2137. Lobbezoo, F., Thu Thon, M., and Montplaisir, J. 1996. Relationship between sleep, neck muscle activity, and pain in cervical dystonia. Can. J. Neurol. Sci. 23, 285–290. Macfarlane, T. V. and Worthington, H. V. 2004. Association between orofacial pain and other symptoms: a population based study. Oral. Biosci and Med. 1, 45–54. Mahowald, M. L. and Mahowald, M. W. 2000. Nighttime sleep and daytime functioning (sleepiness and fatigue) in less welldefined chronic rheumatic diseases with particular reference

Pain Perception – Nociception during Sleep to the ‘alpha-delta NREM sleep anomaly’. Sleep Med. 1, 195–207. Martin, S. A., Aikens, J. E., and Chervin, R. D. 2004. Toward cost-effectiveness analysis in the diagnosis and treatment of insomnia. S. Med. Rev. 8(1), 63–72. Martin, S. E., Engleman, M. H., Deary, I. J., and Douglas, N. J. 1996. The effect of sleep fragmentation on daytime function. Am. J. Respir. Crit. Care Med. 153, 1328–1332. Martı´nez-Lavı´n, M., Hermosillo, A. G., and Rosas, M. 1998. Circadian studies of autonomic nervous balance in patients with fibromyalgia: a heart rate variability analysis. Arthri. Rheum. 41, 1966–1971. McCracken, L. M. and Iverson, G. L. 2002. Disrupted sleep patterns and daily functioning in patients with chronic pain. Pain Res. Manage. 7, 75–79. McMillan, D., Landis, C., Lentz, M., Shaver, J., Heitkemper, M., Rothermel, J., Blunden, P., and Buchwald, D. 2004. Hearth rate variability during sleep in women with fibromyalgia. Sleep. 27, A324 (abstract Suppl.). Meana, M., Cho, R., and DesMeules, M. 2004. Chronic pain: the extra burden on Canadian women. BMC Women’s Health 4 (Suppl 1), S17. Mednick, S., Nakayama, K., and Stickgold, R. 2003. Sleep dependent learning: a nap is as good as a night. Nature Neurosci. 6, 697–698. Menefee, L. A., Cohen, M., and Anderson, W. R. 2000. Sleep disturbance and nonmalignant chronic pain: a comprehensive review of the literature. Pain Med 1, 156–172. Moldofsky, H. 2001. Sleep and pain: clinical review. Sleep Med. Rev. 5, 387–398. Moldofsky, H. and Scarisbrick, P. 1976. Induction of neurasthenic musculoskeletal pain syndrome by selective sleep stage deprivation. Psychosom. Med. 38, 35–44. Morin, C. M., Gibson, D., and Wade, J. 1998. Self-reported sleep and mood disturbance in chronic pain patients. Clin. J. Pain. 14, 311–314. Morrison, A. R., Sanford, L. D., and Ross, R. J. 2000. The amygdale: A critical modulator of sensory influence on sleep. Biol. Signals Recept. 9, 283–296. Nicassio, P. M., Moxham, E. G., and Schuman, C. E. 2002. The contribution of pain, reported sleep quality, and depressive symptoms to fatigue in fibromyalgia. Pain. 100, 271–279. Nofzinger, E. A. and Derbyshire, S. W. G. 2007. Pain Imaging in Relation to Sleep. In: Sleep and Pain (eds. G. Lavigne, B. J. Sessle, M. Choinie`re, P. J. Soja), pp. 153–173. IASP Press. Novak, M., Mucsi, I., Shapiro, C. M., Rethelyi, J., and Kopp, M. S. 2004. Increased Utilization of health services by insomniacs – an epidemiological perspective. J. Psychosom. Res. 56, 527–536. Okifuji, A. and Turk, D. C. 2002. Stress and psychophysiological dysregulation in patients with fibromyalgia syndrome. Appl. Psychophysiol. Biofeed 27(2), 129–141. Okura, K., Lavigne, G. J., Montplaisir, J. Y., Rompre´, P. H., Huynh, N., and Lafranchi, P. 2005. Slow wave activity and heart rate variation are less dominant in fibromyalgia and chronic pain patients than in controls. Sleep 28, 0894. Okura, K., Rompre´, S., Manzini, C., Rompre´, P. H., Huynh, N., Montplaisir, J. Y., and Lavigne, G. J. 2004. Sleep duration and quality in chronic pain patients in comparison to the sleep of fibromyalgia, insomnia, RLS and control subjects. Sleep. 27: (abstract Suppl.) A329 No. 736. Older, S. A., Battafarano, D. F., and Danning, C. L. 1998. The effects of delta wave sleep interruption on pain thresholds and fibromyalgia like symptoms in healthy subjects; correlations with insulin like growth factor 1. J. Rheum. 25, 1180–1186. Onen, A. H., Alloui, A., and Gross, A. 2001. The effects of total sleep deprivation, selective sleep interruption and sleep

793

recovery on pain tolerance thresholds in healthy subjects. J. Sleep Res. 10, 35–42. Parrino, L., Zucconi, M., and Terzano, M. G. Sleep Fragmentation and Arousal in the Pain Patient. In: Sleep and Pain (eds G. Lavigne, B. J. Sessle, M. Choinie`re, P. J. Soja,) pp. 213–231. IASP Press. Peigneux, P., Laureys, S., Cleeremans, A., and Maquet, P. 2003. Cerebral Correlates of Memory Consolidation during Human Sleep : Contribution of Functional Neuroimaging. In: Sleep and Brain Plasticity. (eds. P. Maquet, C. Smith, R. Stickgold), Chap. 11,209–224. Peyron, R., Laurent, B., and Garcia-Larrea, L. 2000. Functionnal imaging of brain responses to pain. A review and metaanalysis. Neurophysiol. Clin. 30, 263–288. Pompeiano, O. and Swett, J. E. 1963. Actions of grated cutaneous and muscular afferent volleys on brain stem units in the decerebrate, cerebellectomized cat. Arch. Ital. Biol. 101, 552–583. Rains, J. C. and Penzien, D. B. 2002. Chronic headache and sleep disturbance. Curr. Pain Headache Rep. 6, 498–504. Rains, J. C. and Penzien, D. B. 2003. Sleep and chronic pain ~ challenges to the  EEG sleep pattern as a pain specific sleep anormaly. J. Psychosom. Res. 54, 77–83. Raymond, I., Nielsen, T. A., and Lavigne, G. J. 2001. Quality of sleep and its daily relationship to pain intensity in hospitalized adult burn patients. Pain 92, 381–388. Rechtschaffen, A. and Kales, A. 1968. A manual of standardized terminology, techniques and scoring techniques for sleep stages of human subjects. Brain Res. Inst., University of California. Reilly, P. A. and Littlejohn, G. O. 1993. Diurnal variation in the symptoms and signs of the fibromyalgia syndrome (FS). J. Musculoskel. Pain 1, 237–243. Riley, III, J. L., Benson, M. B., and Gremillion, H. A. 2001. Sleep disturbances in orofacial pain patients: pain-related or emotional distress? J. Craniomandib. Pract. 19, 106–113. Rogers, E. J. and Vilkin, B. 1978. Diurnal variation in sensory and pain thresholds correlated with mood states. J. Clin. Psychiat. 39(5), 431–438. Roizenblatt, S., Moldofsky, H., and Benedito-Silva, A. A. 2001. Alpha sleep characteristics in fibromyalgia. Arthritis. Rheum. 44, 222–230. Sandrini, G., Milanov, I., and Rossi, B. 2001. Effects of sleep on spinal nociceptive reflexes in humans. Sleep 24, 13–17. Sayar, K., Arikan, M., and Yontem, T. 2002. Sleep quality in chronic pain patients. Can. J. Psychiatry. 47, 844–848. Sergi, M., Rizzi, M., Braghiroli, A., Puttini, P. S., Greco, M., Cazzola, M., and Andreoli, A. 1999. Periodic breathing during sleep in patients affected by fibromyalgia syndrome. Eur. Respir. J. 14, 203–208. Shaw, I. R., Lavigne, G., Mayer, P., and Choinie`re, M. 2005. Acute intravenous administration of morphine perturbs sleep architecture in healthy pain-free young adults: a preliminary study. Sleep. 28(6), 677–682. Siegel, J. 2004. Brain mechanisms that control sleep and waking. Naturwissens Chaften 91, 355–365. Skinner, R. D., Homma, Y., and Garcia-Rill, E. 2004. Arousal mechanisms related to posture and locomotion. 2. Ascending modulation. Prog. Brain Res. 143, 291–298. Smith, M. T. and Haythornthwaite, J. A. 2007. CognitiveBehavioral Treatment for Insomnia and Pain. In: Sleep and Pain (eds. G. Lavigne, B. J. Sessle, M. Choinie`re, P. J. Soja), pp. 439–457. IASP Press. Smith, M. T., Perlis, M. L., and Smith, M. S. 2000. Sleep quality and presleep arousal in chronic pain. J. Behav. Med. 23, 1–13. Soja, P. J. 2007. Modulation of Prethalamic Sensory Inflow during sleep versus Wakefulness. In: Sleep and Pain (eds. G. Lavigne, B. J. Sessle, M. Choinie`re, P. J. Soja), pp. 45–76. IASP Press.

794 Pain Perception – Nociception during Sleep Soja, P. J., Pang, W., Taepavarapruk, N., and McErlane, S. A. 2001. Spontaneous spike activity of spinoreticular tract neurons during sleep and wakefulness. Sleep 24, 18–25. Staedt, J., Windt, H., and Hajak, G. 1993. Cluster arousal analysis in chronic pain- disturbed sleep. J. Sleep Res. 2, 134–137. Stepanski, E. J. 2002. The effect of sleep fragmentation on daytime function. Sleep 25(3), 268–276. Steriade, M. and Timofeev, I. 2003. Neuronal Plasticity during Sleep Oscillations in Corticothalamic Systems. In: Sleep and Brain Plasticity (eds. P. Maquet, C. Smith, and R. Stickgold), Chap. 14,270–291. Stickgold, R., James, L. T., and Hobson, J. A. 2000. Visual discrimination learning requires sleep after training. Nature Neurosci. 3(12), 1237–1238. Stoller, M. K. 1994. Economic effects of insomnia. Clini. Ther. 16(5), 873–897. Stone, A. A., Brokerick, J. E., Porter, L. S., and Kaell, A. T. 1997. The experience of rheumatoid arthritis pain and fatigue: examining momentary reports and correlates over one week. Arthritis. Care Res. 10(3), 185–193. Strian, F., Lautenbacher, S., and Galfe, G. 1989. Diurnal variations in pain perception and thermal sensitivity. Pain 36, 125–131. Sutton, D. A., Moldofsky, H., and Badley, E. M. 2001. Insomnia and health problems in Canadians. Sleep 24, 665–670. Tsoukatos, J., Kiss, Z. H. T., Davis, K. D., Tasker, R. R., and Dostrovsky, J. O. 1997. Patterns of neuronal firing in the human lateral thalamus during sleep and wakefulness. Exp. Brain Res. 113, 273–282. Van Dongen, H. P., Maislin, P., Mullington, J. M., and Dinges, D. F. 2003. The cumulative cost of additional wakefulness: dose–response effects on neurobehavioral

functions and sleep physiology from chronic sleep restriction and total sleep deprivation. Sleep 26(2), 117–126. Velluti, R. A., Pena, J. L., and Pedemonte, M. 2000. Reciprocal actions between sensory signals and sleep. Biol. Signals Recept. 9, 297–308. Wang, X., Inui, K., Qiu, Y., Hoshiyama, M., Tran, T. D., and Kakigi, R. 2003. Effects of sleep on pain related somato sensory evoked potentials in humans. Neurosci. Res. 45, 53–57. Wesenten, N. J., Balkin, T. J., and Belenky, G. 1999. Does sleep fragmentation impact recuperation? A review and reanalysis. J. Sleep Res. 8, 237–245. Widerstrom-Noga, E. G., Felipe-Cuervo, E., and Yezierski, R. P. 2001. Chronic pain after spinal injury: interference with sleep and daily activities. Arch. Phys. Med. Rehabil. 82, 1571–1577. Yatani, H., Studts, J., and Cordova, M. 2002. Comparison of sleep quality and clinical and psychologic characteristics in patients with temporomandibular disorders. J. Orofac. Pain 16, 221–228. Zubieta, J. K., Smith, Y. R., Bueller, J. A., Xu, Y., Kilbourn, M. R., Jewett, D. M., Meyer, C. R., Koeppe, R. A., and Stohler, C. S. 2001. Regional Mu opioid receptor regulation of sensory and affective dimensions of pain. Science 293, 311–315.

Relevant Website http://www.sleepfoundation.org – National Sleep Foundation.

53 Pharmacological Modulation of Pain A Dray, AstraZeneca Research and Development, Montreal, PQ, Canada ª 2009 Elsevier Inc. All rights reserved.

53.1 53.2 53.3 53.4 53.5 53.6 53.7 53.8 53.9 53.10 53.11 53.12 53.13 53.13.1 53.14 53.14.1 53.14.2 53.15 53.16 53.17 53.18 53.19 53.20 53.21 References

Introduction G-Protein-Coupled Receptors Opioids and Their Receptors Kinins and Their Receptors Protease-Activated Receptors Cannabinoids and Their Receptors Mrg-Related GPCR and Their Ligands Prostanoids and Receptors Cytokines, Chemokines, and Their Receptors Adrenoceptors Glutamate Regulation and Glutamate Receptors Gamma-Aminobutyric Acid Receptors Ion Channels Ligand-Gated Channels Purinergic Receptors P2X Receptors Acid-Sensing Channels Sodium Channels Calcium Channels Neurotrophins and Their Receptors Kinases Botulinum Toxin Nitric Oxide Summary and Conclusions

53.1 Introduction Chronic pain is a complex integration of sensory, affective, and cognitive processes encompassing a variety of clinical conditions that have been generalized as nociceptive (rheumatoid and osteoarthritis (OA)), neuropathic (postdiabetic neuropathy, posttraumatic neuralgia), or etiologically mixed (low back pain, cancer pain; for references see Merskey, H. et al., 2005; Campbell, J. N. et al., 2006). Pain conditions are etiologically diverse and there is limited understanding of clinical pain mechanisms and of environmental and social factors that aggravate pain such as stress and anxiety. In addition, it has been difficult to provide a unifying linkage of pain symptoms with the cellular mechanistic processes underlying these symptoms that would rationalize chronic pain therapy. The complexity of chronic pain is further reflected in the diversity of molecular targets considered to drive pain

795 796 796 798 799 799 801 801 802 803 804 805 805 805 806 806 807 807 808 809 810 810 811 811 811

processes. Furthermore there is the evolving view that the pharmacology of pain may alter with timedependent expression of targets, in the initiation versus the maintenance phases of pain, and that target expression is state-dependent (related to relative activity of the pain process or pathway). Thus poor understanding of pain pharmacology has seriously hampered the introduction of new drugs as there have been few drugs introduced with a new mechanism of action within living memory. A recent step to building rational pain therapy has embraced a mechanism-based approach guided by advances in pain pharmacology. Thus major symptoms such as hyperalgesia, allodynia, and spontaneous pain have been linked with some of the identifiable, and often overlapping, neural cellular processes. The key processes are considered to be sensitization (reduced threshold for stimulation of pain pathways), hyperexcitability (amplification or 795

796 Pharmacological Modulation of Pain

prolongation of nerve discharges in pain pathways), and spontaneous nerve activity (ectopic and/or spontaneous discharges in pain pathways). These processes or mechanisms are driven by molecular changes that provide the targets for pharmacological characterization and analgesia intervention (summarized in Figure 1). It is important to remember that for the most part these neural mechanisms and their molecular drivers have been explored in animal models and rarely consolidated to the same degree in human studies. There have been a number of excellent reviews of pain mechanisms and molecules (Hunt, S. P. and Mantyh, P., 2001; Scholz, J. and Woolf, C. J., 2002; Watkins, L. R. and Maier, S., 2002) in the peripheral nervous system and central nervous system (CNS). Causative factors for pain are inflammatory mediators, factors released and made in response to nerve injury, phenotypic changes in neural pathways as well as supporting glial cells, structural modifications including nerve sprouting (sympathetic and sensory fibers), nerve rewiring (sensory and CNS fibers), and neurodegeneration of specific neurons in the CNS resulting in a hyperexcitable nervous system. Specific molecular interactions that drive the aforementioned excitability changes may differ according to the specific injury and consequent chemical environments that are created. The molecular interactions involve all major families of regulatory proteins (Gprotein-coupled receptors (GPCRs), ion channels, regulatory enzymes, neurotrophins, kinases), offering an abundance of analgesic targets and therapeutic opportunities. The pharmacology of these targets is evolving and is dependent on the availability of reliable chemical and biopharmaceutical tools.

Central sensitization and hyper-excitability

Brain

Opioids, NMDA, mGluR5 GABA,

Skin/Joint/GI

Spinal cord DRG

Spontaneous activity NaVs, CaVs, TRPV1, CB1, NGF/TrKA

Peripheral sensitization and hyper-excitability COX, mPGES, NOS CB1, B1/2, TRPV1, NaVs, CaVs, P2X3 NGF/TrKA

Figure 1 Mechanistic processes in chronic pain and key molecular drivers.

In this chapter I have selected from the emerging pharmacology of pain molecular approaches (summarized in Table 1) that will provide direction for future pain treatments.

53.2 G-Protein-Coupled Receptors GPCRs have been a relatively tractable family of drug targets in a number of therapeutic arenas. A variety of GPCRs are involved in regulating neural excitability in pain pathways, often through the action of a variety of inflammatory mediators. These mediators act peripherally or centrally, via an equally large variety of specific membrane receptors (Scholz, J. and Woolf, C. J., 2002). In general, GPCRs signal via the production of second messengers (cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), diacylglycerol (DAG), phospholipase C (PLC)) coupled with intracellular protein kinases and phosphatases (protein kinase A, several isotypes of protein kinase C (PKC)) which in their turn, phosphorylate and dephosphorylate specific cellular proteins including ligand- (e.g., TRPV1) and voltage-gated membrane ion channels (e.g., NaV1.8) which are important in regulating nerve excitability.

53.3 Opioids and Their Receptors Opioids, and morphine in particular, are among the most effective pain medications. They act at peripheral, spinal, and supraspinal sites through a variety of opioid receptors (-, -, and -opioid receptors). These receptors are considered to be targets for an endogenous opioid system that has been extensively reviewed (Yaksh, T. L., 1997). -Opioid receptor activation commonly causes a variety of well-documented, targetrelated, CNS side effects including sedation, dysphoria, respiratory depression, and constipation. Thus there has been a vigorous attempt to exploit the peripheral antinociceptive actions of opioids as a means of avoiding CNS side effects. In support of this approach, sensory neurons express and transport opioid receptors to both the central and peripheral terminals. At central terminals, opioids reduce transmitter release from primary afferent nociceptors, thus blocking synaptic transmission while in the periphery opioid receptor activation directly hyperpolarize sensory neurons and attenuate nerve sensitization or hyperexcitability induced by inflammation or injury (Hurley, R. W. and Hammond, D. L., 2000; Sawynok, J., 2003).

Pharmacological Modulation of Pain Table 1

797

Pharmacological modulators of pain and emerging mechanisms of action and clinical indications. Pharmacological tools

Molecular Target

Analgesia mechanism and targeted tissue

Agonist

Antagonist

-Opioid receptors

Morphine, fentanyl

Naloxone, naltrexone

-Opioid receptor B1 receptor

Enkephalin, DPDPE, SNC80 Des Arg9 bradykinin

Naltrindole

B2 receptor

Bradykinin

Icatibant, bradyzide

PAR2

Proteases

Unknown

CB1

THC, anandamide, 2-arachidonylglycerol, palmitoylethanolamide, WIN55, 212-2, ajulemic acid THC, anandamide, 2-arachidonylglycerol, palmitoylethanolamide, WIN55, 212-2, ajulemic acid, GW405833, HU308, AM 1241 BAM8-22, 2-MSH

SR141716A (rimonabant), SR147778,

Agonist: Pain pathways PNS and CNS

Nociceptive and inflammatory Nociceptive and neuropathic

SR144428

Agonist: Pain pathways PNS and CNS

Nociceptive and neuropathic

Unknown Ibuprofen, naproxene

Antagonist: PNS Inhibition of PG synthesis Inhibition of PG synthesis in PNS and CNS Inhibition of PG synthesis in PNS and CNS Antibody versus ligand

Nociceptive Nociceptive and inflammatory Nociceptive and inflammatory

CB2

SNSR COX-1 constitutive COX-2 induced

des Arg10, HOE-140; SSR240612, NVPSAA 164

Ibuprofen, naproxene, celecoxib, rofecoxib

mPGES

Unknown

IL-1

IL-1

Unknown

TNF-

TNF-

Anti-TNF, etanercept, adalimumab

-2

Clonidine, dexmedetomidine

iGluR

Glutamate, kainate, AMPA, NMDA

mGluR (5)

Glutamate

LY293558, GV196771, ifenprodil, CP-101, 606 MPEP, SIB1757

GABAA

Muscimol

Bicuculline

GABAB

Baclofen

CGP35348

TRPV1

Capsaicin

TRPA1

Cinnamaldehyde

Capsazepine, DD161515, SB705498 Unknown

Agonist: reduced peripheral and CNS excitability Agonist: Modulation of CNS pathways Antagonist: inflammatory tissue: pain pathway: PNS, CNS Antagonist: inflammatory tissue: pain pathway: PNS, CNS Antagonist: PNS

Antibody versus ligand Inhibition of neuroexcitability in PNS and CNS Antagonist: CNS pathways

Pain indications Acute and chronic pain states Nociceptive and inflammatory Nociceptive and inflammatory

Nociceptive and inflammatory

Nociceptive and inflammatory Nociceptive and neuropathic Nociceptive and neuropathic Nociceptive and neuropathic Nociceptive and neuropathic

Antagonist: CNS pathways Agonist: reduced CNS excitability Agonist: reduced CNS excitability Antagonist: PNS excitability

Nociceptive and neuropathic Nociceptive and neuropathic Nociceptive and neuropathic Nociceptive and neuropathic

Antagonist: PNS

Neuropathic (Continued )

798 Pharmacological Modulation of Pain Table 1

(Continued) Pharmacological tools

Molecular Target

Agonist

Antagonist

TRPM1 P2X3 P2X4 P2X7

Menthol, icilin ATP, , -methy ATP ATP ATP

Unknown A-3174919 TNP-ATP Unknown

ASIC1-3 NaV1.3, NaV1.8, NaV1.7, NaV1.9 CaV2.2

Low pH

A-317567 Lidocaine, mexiletine, lamotrigine SNX-111, NMED-160

CaV3.2 NGF

NGF

P38-kinase

ATP

iNOS

Ethosuximide ALE0540, PD90780, RN624 (mAb) SB203580, CNI-14930 L-NAME, GW27415

Analgesia mechanism and targeted tissue

Pain indications

Antagonist: PNS Antagonist: PNS Antagonist: CNS Antagonist: CNS and PNS excitability Antagonist: PNS Blocker: PNS excitability

Neuropathic Nociceptive Neuropathic Nociceptive and neuropathic Nociceptive Nociceptive and neuropathic

Blockers: PNS and CNS excitability Blocker: PNS Antiligand: PNS excitability Blocker: PNS and CNS excitability Blocker: PNS and CNS excitability

Nociceptive and neuropathic Neuropathic Nociceptive and neuropathic Nociceptive and neuropathic Nociceptive and neuropathic

AMPA, -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; ATP, adenosine triphosphate; B, bradykinin; CaV, voltage-gated calcium channels; CB, cannabinoid; CNS, central nervous system; COX, cyclo-oxygenase; DPDPE, [D-Pen2,D-Pen5]-enkephalin; GABA, gammaaminobutyric acid; iNOS, inducible nitric oxide synthase; L-NAME, L-N-nitro-L-arginine methyl ester; mGluR, metabotropic glutamate receptor; MPEP, 2-methyl-6-(phenylethynyl)-pyridine; mPGES, microsomal-associated prostaglandin E synthase; NaV, voltage-gated sodium channel; NGF, nerve growth factor; NMDA, N-methyl-D-aspartic acid; PAR, protease-activated receptor; PG, prostaglandin; PNS, peripheral nervous system; SNSR, sensory neuron specific receptor; THC, tetrahydrocannabinol; mAb, monoclonal antibody; TNP-ATP, 29,39-O-(2,4,6-trinitrophenyl) adenosine 59-triphosphate.

In addition peripherally mediated opioid analgesia may be enhanced because -opioid receptor expression is increased by inflammation and nerve injury (Stein, C. et al., 2003). This is also accompanied by a peripheral increase in the expression of opioids peptides. Novel opioids such as [8-(3,3-diphenyl-propyl)4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-3-yl]-acetic acid (DiPOA) and the antidiarrheal drug loperamide, whose distribution is peripherally restricted, have shown efficacy in a number of post-operative, inflammatory, and neuropathic pain models (Whiteside, G. T. et al., 2005a; Shidoda, K. et al., 2006). The pharmacology and analgesic efficacy of -opioid receptors (DOR) have also been explored since there is a potential for analgesic efficacy without the confounding side effects of other opioid ( and ) receptor therapies. A variety of studies have supported the concept that -selective ligands produce analgesia without notable sedation, respiratory depression, or inhibition of gastrointestinal motility. These studies have used genetic methods ranging from the knockdown of receptors to deletion of the DOR gene as well as pharmacological tools such as selective peptides and nonpeptide agonists ([DPen2,D-Pen5]-enkephalin (DPDPE), SNC80, AM-

390) and antagonists (e.g., naltrindole; see Dray, A., 1999 for references).  Ligands may provide less analgesic efficacy than morphine but their effectiveness appears to depend on the pain stimulus, the type of injury, and the influence of their neurochemical environment. Thus, systemically administered  ligands have low analgesic efficacy in acute pain models but show robust analgesia efficacy in a variety of chronic pain conditions accompanies by inflammation (Cahill, C. M. et al., 2001). Enhanced activity has been attributed to stimulus-induced trafficking of DOR from the cytoplasm to nerve membranes in CNS neurons (Cahill, C. M. et al., 2001). Activity and environment-dependent receptor trafficking also appears as an important regulatory mechanism in sensory neurons (Bao, L. et al., 2003) but further studies are required to understand the significance of this in clinical pain and analgesia.

53.4 Kinins and Their Receptors Bradykinin is an important peptidic mediator of inflammatory pain causing nociceptor activation and sensitization via constitutively expressed bradykinin B2

Pharmacological Modulation of Pain

receptors (BK2) on peripheral nociceptors (Dray, A., 1997). It also stimulates the production and release of prostaglandin (PGs) cytokines and nitric oxide (NO). The abundant metabolite of bradykinin, des Arg9 bradykinin (kallidin), activates BK1 receptors which also occur constitutively, but in low abundance, in the periphery (Dray, A. and Perkins, M. N., 1993; Wotherspoon, G. and Winter, J., 2000) and in the primate CNS (Shughrue, P. J. et al., 2003). Both receptors are coupled to similar transduction mechanism including G-i and G-q causing stimulation of DAG, PLC, and the release of intracellular calcium. BK2 receptors are considered to undergo desensitization following prolonged kinin exposure, whereas BK1 receptors do not desensitize rapidly and thus may promote more prolonged pain and inflammation. In keeping with this, BK1 receptors are dramatically unregulated in many tissues, including sensory neurons (Levy, D. and Zochodne, D. W., 2000) and spinal cord (Fox, A. et al., 2003; Ferreira, J. et al., 2005), following tissue or ultraviolet injury (Eisenbarth, H. et al., 2004) or traumatic nerve injury and by mediators such as interleukin (IL)-1 or the neurotrophin glial cell line-derived neurotrophic factor (GDNF; Fox, A. et al., 2003; Valleni, V. et al., 2004). These kinins cause a cascade of secondary changes, including prostanoid production, phosphorylation of signaling proteins such as PKC, and the sensitization of sensory transducers such as the TRPV1 receptor (Marceau, F. et al., 1998). These events are linked with heat and mechanical hyperalgesia (Liang, Y. F. et al., 2001; Fox, A. et al., 2003). There is an abundance of evidence supporting the analgesic potential of BK2 receptor antagonists (Stewart, J. M., 2004). For example, BK2 antagonists (icatibant [HOE-140], bradyzide) and BK1 antagonist (des Arg10 HOE-140; SSR240612) produce robust antihyperalgesic effects in a variety of animal models of inflammatory hyperalgesia (Burgess, G. M. et al., 2000; Fox, A. et al., 2003, Gougat, J. et al., 2004) as well as in models of nerve injury-induced hyperalgesia (Gabra, B. H. and Sirois, P., 2003). In keeping with this deletion of the BK receptor genes reduces immune cell chemotaxis, spinal sensitization, as well as heat and mechanical allodynia following traumatic and diabetic nerve lesions (Pesquero, J. B. et al., 2000; Ferreira, J. et al., 2005; Gabra, B. H. et al., 2005). To strengthen the translation of BK1 receptor therapy to humans, transgenic mice expressing human BK1 receptors, show robust inflammatory pain that was attenuated by the oral administration of the human-selective BK1 antagonist NVP-SAA 164 (Fox, A. et al., 2005).

799

Kinin antagonists have not been extensively evaluated in clinical pain although they inhibit other kinin-mediated changes in humans, for example, cancer, allergy, and vasodilatation. However, recent clinical study using a single dose intra-articular joint administration of Icatibant (Flechtenmacher, J. et al., 2004) produced long-lasting (up to 1 week) relief of movement-related pain in patients suffering from OA. This study highlights a strong proof of principle for BK2 involvement in OA and that localized monotherapy with a selective antagonist can produce significant pain relief.

53.5 Protease-Activated Receptors Several proteases, from circulating inflammatory cells and vascular epithelium, cleave a variety of protease-activated receptors (PARs) that are associated with sensory neurons (Vergnolle, N. et al., 2003). PAR2 in particular has been highlighted as a regulator of sensory nerve excitability and plays an important role in inflammatory hyperalgesia. Thus PAR2 agonists contribute to neurogenic inflammation through the stimulation of peripheral substance P and calcitonin gene-related peptide (CGRP) release and to spinal hyperexcitability via release of these neuropeptides in the spinal cord. PAR2 receptor activation directly increases dorsal root ganglion (DRG) excitability and sensitizes TRPV1 receptors via a PKC mechanism (Amadesi, S. et al., 2004); thus contributing to inflammation-induced hyperalgesia. In keeping with this, deletion of the TRPVR1 gene or pretreatment with the TRPV1 antagonist capsazepine, abolished PAR2-induced thermal hyperalgesia, suggesting that TRPV1 is required for PAR2-induced hyperalgesia. PAR1 is also coexpressed on peptide-containing DRGs, and although PAR1 agonists induce neurogenic inflammation they do not sensitize TRPV1 receptors, nor do they induce hyperalgesia. Overall these data suggest that PAR2 antagonists would have antihyperalgesic activity (Mantyh, P. W. and Yaksh, T. L., 2001)

53.6 Cannabinoids and Their Receptors Two major cannabinoid receptor subtypes, CB1 and CB2 are associated with pain modulation and have received much attention in recent years (reviewed by Fox, A. and Bevan, S., 2005). These receptors are

800 Pharmacological Modulation of Pain

widely distributed in the nervous system but CB1 receptors are located in greatest abundance in the CNS and on peripheral sensory neurons. CB2 receptors have been found mainly in peripheral tissues including immune tissues and keratinocytes (Hohmann, A. G. and Herkenham, M., 1999; Rice, A. S. C. et al., 2002) but more recently on some sensory and CNS cells. Several fatty acids, for example, anandamide, 2-arachidonylglycerol, and palmitoylethanolamide, have been identified as endogenous ligands for these receptors and are termed endocannabinoids. They are released from postsynaptic nerve terminals to modulate postsynaptic excitability and transmitter release at presynaptic elements via Gi/Go-coupled activity. Specific antagonists such as SR141716A and SR147778 for CB1 and SR144428 for CB2 have been used to characterize receptor functions. For the most part CB1 receptors are located on neurons where activation causes attenuation of presynaptic N-calcium channel activity and inhibition of transmitter release (Kreitzer, A. C. and Regeher, W. G., 2002). In contrast, activation of neuroglia (astrocytes, microglia) is accompanied by de novo expression of both CB1 and CB2 and increased release of endocannabinoids (Stella, N. 2004). Specifically CB2 receptors are expressed in spinal microglia following peripheral nerve lesions but not by peripheral inflammation (Zhang, J. M. et al., 2003). The significance of this is presently unclear although prolonged CB receptor activation has been associated with increased expression of neuroprotective modulators such as brain-derived neurotrophic factor (BDNF; Marsicano, G. et al., 2003). Both CB1 and CB2 receptor types have been shown to have a key role in the modulation of nociceptors. Although CB1 effects have been best characterized, the mechanism and sites of action are incompletely understood. It is likely that an interplay of several CB1-driven systems occurs during acute or chronic pain. Brainstem structures appear to be important. For example, CB1-induced local activation of the periaqueductal gray (PAG; by stressinduced release of endocannabinoids) has been suggested to be involved in aversive responses and acute stress-induced analgesia (Finn, D. P. et al., 2004; Hohmann, A. G. et al., 2005). This was blocked by SR141716A (rimonabant, the CB1 antagonist) but not by naltrexone (-opioid antagonist). Paradoxically, recent data suggest that deletion of the CB1 receptor in mice is associated with a greater vulnerability to stress (Fride, E. et al., 2005). Finally CB1-induced

analgesia has been proposed to be driven by activation of descending inhibitory mechanisms. In keeping with this, block of the descending noradrenergic systems (Gutierrez, T. et al., 2003) has been proposed to account, in part, for CB1-induced antinociception. Several studies have now shown that CB2 agonists modulation acute pain, for example, AM1241 and GW405833 (incision model) (LaBuda, C. J. et al., 2005) while GW405833 has been reported to exhibit efficacy in neuropathic and inflammatory pain models (Valenzano, K. J. et al., 2005). Interestingly another CB2 agonist, JWH-133 shows antihyperalgesia as well as anti-inflammatory activity (Elmes, S. J. R. et al., 2005). The effects of CB2 agonists appear not to be due to the release of endogenous opioids as actions were unaffected by naltrexone (Whiteside, G. T. et al., 2005b). Several clinical studies have supported the use of cannabinoids, such as tetrahydrocannabinol (THC), to reduce pain. However this action is commonly accompanied by adverse effect such as euphoria, dizziness, and sedation (Campbell, F. A. et al., 2001; Wade, D. T. et al., 2003; Svenden, K. B. et al., 2004). The reduction of CNS side effects has been approached through targeting peripheral CB receptors, since both CB1 and CB2 receptor activation produce antinociception. In support of this approach, the systemic administration of WIN55,212-2, a nonselective CB agonist, attenuated inflammatory hyperalgesia and this action was reversed by peripheral (intraplantar) but not spinal administration of a CB1 antagonist (Fox, A. and Bevan, S., 2005). Moreover a peripherally restricted CB1 agonist (e.g., NVP-001, personal communication) was shown to reduced inflammatory hyperalgesia by directly reducing nociceptor excitability (Richardson, J. D. et al., 1998). Finally, CT-3 (ajulemic acid) a nonspecific CB1 and CB2 agonist, with limited CNS availability produced analgesia in a number of inflammatory and neuropathic pain models (Burstein, S. H. et al., 2004; Dyson, A. et al., 2005) as well as in human neuropathic pain, at doses which cause minimal CNS side effects (Karst, M. et al., 2003). The mechanism of action of CT-3 appears to involve mainly CB1 receptors and a number of other indirect actions including activation of peroxisome proliferator-activated receptor (PPAR)- receptors and inhibition of inflammatory cell activity and mediator release (Liu, J. et al., 2003). Selective CB2 ligands (HU-308, AM-1241, and GW405833) as well as nonselective compounds (HU-210 and CP55940) have shown antinociceptive effects in a variety of inflammatory and neuropathic

Pharmacological Modulation of Pain

pain models (Malan, T. P. et al., 2003, Valenzano, K. J. et al., 2005). These effects are still present in CB1knockout (KO) mice, absent in CB2-KO animals, can be revered by CB2 antagonist such as SR144528, and occur without major CNS side effects (sedation, catalepsy, or motor impairments). It is unclear how these effects are produced since CB2 receptors have not been found on sensory neurons (Sokal, D. M. et al., 2003). Rather an indirect effect via immune cell modulation and the naloxone-reversible release of -endorphin from keratinocytes has been proposed (Ibrahim, M. M. et al., 2005). In contrast, a number of reports have suggested that CB2 agonists, for example, JWH-133, may reduce C-fiber excitability directly (Ross, R. A. et al., 2001; Sagar, D. R. et al., 2005). There is also a possibility that CB2 agonists cause antinociception via the CNS as CB2 receptors are expressed in spinal microglia after nerve injury (Zhang, J. M. et al., 2003), and CB2 activation may modulate microglial activity (Water, L. et al., 2003). Indeed the direct spinal administration of JWH-133 attenuated mechanical allodynia (Sagar, D. R. et al., 2005). Clearly greater understanding is still required with respect to the mechanisms of CB2mediated analgesia. Other approaches to address the role of endogenous cannabinoid systems in pain and analgesia have targeted fatty acid amide hydrolysis (FAAH), the major degradation pathway for endogenous cannabinoids (Cravatt, B. F. and Lichtman, A. H., 2004). Thus in mice lacking this enzyme (Cravatt, B. J. et al., 2001), or treatment of naı¨ve mice with a novel FAAH inhibitor such as OL135 (Lichtman, A. H. et al., 2004), increases the analgesic efficacy of anandamide and significantly elevated brain anandamide levels were measured. In addition, OL135 increased pain threshold in acute pain models, decreased the mechanical allodynia of neuropathic pain, and decreased thermal hyperalgesia in models of persistent pain (Chang, L. et al., 2006). Surprisingly a CB2 rather than CB1 antagonist attenuated the effect of OL135 in the persistent pain models and its effects appeared to be mediated by a naloxone-reversible mechanism. In this latter respect several reports have indicated analgesic synergy, between -opioid and CB receptors. Thus combinations of these agonist have been shown to provide pain reduction with minimal side effects in acute pain models (Cichewicz, D. L. and McCarthy, E. A., 2003). However, it is still unclear whether such synergy can be exploited in chronic pain treatment.

801

53.7 Mrg-Related GPCR and Their Ligands The mas-related gene (Mrg) family is a large family of GPCRs which vary in numbers depending on species, are rather exclusively expressed in subsets of small sensory neurons (Dong, X. et al., 2001), and may be co-localized with markers for nociceptive neurons such as TRPV1 (Lembo, P. M. C. et al., 2002). Selective manipulations of individual Mrgs have provided exquisite markers for subsets of small sensory neurons showing selective epidermal and spinal innervation, suggesting a close anatomical and functional relationship (Zylka, M. J. et al., 2005). Focus on the human mrgX subfamily (six genes in humans), also called sensory neuron-specific receptors (SNSR), has revealed a complex pharmacology. The endogenous ligand for SNSR is unconfirmed, but several mammalian peptide ligands have been identified with high affinity for this receptor. These peptides include bovine adrenal medullary peptide 22 (BAM22), and its fragment BAM8-22 derived from the endogenous opioid precursor pro-enkephalin A, as well as two unrelated peptides 2-melanocytostimulating hormone (MSH) and CT-2-MSH. Apart from BAM22, these substances do not activate opioid receptors, rather they increase peripheral and spinal excitability to potentiate thermal and mechanical nociception (Grazzini, E. et al., 2004). This suggests that the same gene products can facilitate as well as inhibit sensory neurons and that an SNSR antagonist should be sought to inhibit hyperalgesia. Although these data strongly support a role for SNSRs in the modulation of pain, the endogenous ligand for this receptor has not been confirmed and there is little direct evidence linking SNSRs in the etiology of acute or chronic pain.

53.8 Prostanoids and Receptors A variety of prostanoid cyclo-oxygenase (COX) enzyme products (PGE2, PGD2, PGF2, thromboxane, PGI2) occur during inflammation but PGE2 is considered to be the major contributor to inflammatory pain. Thus blocking the major synthetic enzymes, COX-1 (constitutive) and COX-2 (inducible), or inhibition of prostanoid receptors continue to be important approaches for reducing inflammatory pain (Flower, R. J., 2003). Experience with selective inhibitors of COX-2 (celecoxib, rofecoxib) shows

802 Pharmacological Modulation of Pain

improved gastrointestinal tract safety but little improvement in analgesic efficacy. A relatively infrequent though increased cardiovascular risk (coronary constriction) has been observed with some COX inhibitors. The mechanism is not understood but has led to Vioxx (rofecoxib) being withdrawn from therapy and considerable clinical debate about the safety of future approaches to COX inhibition. An alternative approach for the clinical improvement of COX inhibitors has been to combine COX inhibition with NO donation (CINOD). Such molecules (NO-naproxene, NO-ibuprofen) have been claimed to show improved efficacy and safety over the parent nonsteroidal anti-inflammatory drugs (NSAIDs) due to actions (improved side effects and efficacy) of cleaved NO (Fiorucci, S. et al., 2001). Recently a splice variants of COX-1 has been identified, COX-3 (Chandrasekharan, N. V. et al., 2002). However it has low enzymic capability and its distribution and low abundance in the CNS and in periphery does not make this a compelling target for analgesia. However several NSAIDs (acetaminophen, diclofenac, phenacetin) show low efficacy but some degree of selectivity for COX-3. Overall however the analgesic efficacy of acetaminophen is poorly correlated with COX inhibition. Interestingly endogenous acetaminophen metabolism produces a conjugated arachidonic acid derivative (AM404) that shows cannabinoidlike analgesia properties (Hogestatt, E. D. et al., 2005; Ottani, A. et al., 2006). Furthermore gene deletion studies suggested that COX-3 inhibition may be linked with the antipyretic and analgesia properties of NSAIDs. Clearly further studies are needed to link this enzyme to inflammatory pain pathophysiology. Another route of inhibiting PGE2 synthesis is via the blockade of PGE synthase (PGES), a major route of conversion of PGH2 to PGE2. Two isoforms of the enzyme have been identified, membrane or microsomal-associated PGES (mPGES-1) and a cytosolic enzyme (cPGES/p23) which are linked with COX2- and COX-1-dependent PGE2 production, respectively (Jakobsson, P. J. et al., 1999; Claveau, D. et al., 2003). Both isoforms are upregulated by inflammatory mediators and gene deletion studies in mice indicate an important role for mPGES in acute and chronic inflammation and inflammatory pain (Trebino, C. E. et al., 2003). Apart from prominent roles in regulating peripheral excitability during inflammatory pain, COX-1 (glia) and COX-2 (ventral horn cells) are constitutively present in spinal cord and are increased by

inflammation, peripheral nerve injury, or by administration of cytokines, leading to increased production of spinal PGE2. In keeping with this, several NSAIDs have been shown to reduce inflammatory hyperalgesia via inhibition of spinal COX activity (Yaksh, T. L. et al., 2001). Several mechanisms have been proposed for the PGE2-induced increase in spinal excitability. Prominent are the contribution of EP1 receptors and spinal release of glutamate. Recently however the spinal effects of PGE2 have been linked with a glycine receptor. Thus deletion of the GlyR3 subunit gene, reduced pain sensitivity caused by PGE2 administration or inflammation (Harvey, R. J. et al., 2004). Finally, PGE2 exerts its effects via a variety of EP receptors (EP1, 2, 3 4) present both in peripheral sensory neurons and in the spinal cord. Activation of these receptors produces a complexity of effects, ranging from Ca2þ influx to cAMP activation or inhibition. In the periphery, sensitization by PGE2 as been shown to be cAMP mediated causing the enhancement of tetrodotoxin-resistant (TTX-r) sodium currents in nociceptors via channel phosphorylation (England, S. et al., 1996; Gold, M. S. et al., 1998). However in the spinal cord, excitability was enhanced by EP1 receptors but reduced by an EP3 agonist (ONO-AE-248) suggesting further complexity in the prostanoid regulation of pain mechanisms (Bar, K. J. et al., 2004).

53.9 Cytokines, Chemokines, and Their Receptors Cytokines are produced by a variety of immune cells as well as brain neuroglial cells in response to injury and inflammation. They are powerful mediators of hyperalgesia (see Abbadie, C., 2005). Probably the most characterized are IL-1 and tumor necrosis factor (TNF)- that act via specific receptors on sensory neurons. Their effects can be attenuated by receptor antagonists (IL-1-r) that sequester the ligand as well as by neutralizing antibodies. Indeed the TNF antibody, etanercept, has been developed for the treatment of chronic inflammation and the presence of TNF- has been correlated with a number of painful inflammatory clinical conditions (Lindenlaub, T. and Sommer, C., 2003). Cytokines induce hyperalgesia by a number of direct and indirect actions. Thus IL-1 activates nociceptors directly and produces heat sensitization via intracellular kinase activation, but it may also

Pharmacological Modulation of Pain

cause indirect nociceptor sensitization via the production of kinins and prostanoids (Sommer, C. and Kress, M., 2004). TNF- also activates sensory neurons directly via TNFR1 and TNFR2 receptors, (Pollock, J. et al., 2002; Ohtori, S. et al., 2004) and initiates a cascade of inflammatory reactions through the production of IL-1, IL-6, and IL-8. It is significant that direct TNF- application in the periphery induces neuropathic pain behavior that is blocked by ibuprofen and celecoxib (Schafers, M. et al., 2004), while nerve ligation causes increased TNF- in damaged as well as adjacent undamaged axons (Schafers, M. et al., 2003a). Interestingly anti-TNF treatment with TNF antibody, adalimumab, produced a prolonged reduction of pain symptoms in OA (Grunke, M. and Schulze-Koops, H., 2006). There appears to be a complex interplay between cytokines, and it should be noted that like other mediators of pain not all should be considered as detrimental. Thus IL-6 has been associated with potential beneficial effects after nerve injury including protection against cell death and the promotion of growth. However there is also compelling evidence of a strong association with this cytokine in several human pain conditions including herniated lumbar disc pain and pain caused by failed back surgery (De Jongh, R. F. et al., 2003). A variety of studies have demonstrated an important role for spinal inflammatory and neuroimmune processes triggered by peripheral inflammation and nerve injuries. These processes involve the regulation of a variety of receptors, channels, and enzymes with patterns that are likely to differentiate one pain state from another (Honore, P. et al., 2000). In addition, activation of spinal neuroglial cells (microglia, astrocytes, satellite cells) stimulates a cascade of secondary excitability changes (Watkins, L. R. and Maier, S., 2002). Neuroglia make close-junctional connections with other cells, providing a means of spreading excitability changes beyond the boundaries of spinal segmental input. Neuroglia also secrete a number of mediators such NO, neurotrophins, IL-1, TNF-, free radicals, and glutamate. In addition, neuroglial mediators may contribute to spinal excitability by causing dysfunction or degeneration of inhibitory spinal neurons (Moore, A. K. et al., 2002). In keeping with an important role for neuroglial mediators, treatments with anti-inflammatory agents or modulators of neuroglial activity such as propentofylline and minocycline inhibit glial activation and the release of glial products with reduced

803

behavioral signs of hyperexcitability (Watkins, L. R. and Maier, S., 2002; Raghavendra, V. et al., 2003). Chemokines are important peripheral and central mediators of inflammation. The major chemokines and their respective receptors are macrophagederived chemokine (MDC)/CCR4, regulated upon activation, normal T-cell expressed, and secreted (RANTES)/CCR5, fractalkine/CX3CR1, and SDF1/CXCR4. Receptors are located on leukocytes, on central neurons, sensory neurons, and neuroglial cells (Watkins, L. R. and Maier, S., 2002). Apart from their major chemoattractant effects, chemokines contribute directly to inflammatory hyperalgesia through G-protein-coupled activation and sensitization of sensory neurons (Oh, S. B. et al., 2001). Block of CX3CR1 by a fractalkine receptor-neutralizing antibody induces antiallodynic effects in models of peripheral nerve inflammation (Milligan, E. D. et al., 2005b). However some chemokines appear beneficial. Thus gene therapy (AV-333) has been used to increase IL-10 production through the delivery of viral and nonviral vectors by acute spinal intrathecal delivery. This experimental treatment has been shown to reverse mechanical allodynia in the chronic constriction injury (CCI) model of neuropathic pain (Milligan, E. D. et al., 2005a).

53.10 Adrenoceptors A number of chronic pain disorders termed sympathetically maintained pain have highlighted the importance of the release of sympathetic transmitters (epinephrine or norepinephrine) from sympathetic varicosities and the involvement of adrenergic receptors in pain etiology. For example following peripheral nerve injury sprouting of sympathetic nerve endings occurs at several sites. Thus sympathetic/sensory coupling at the level of the DRG (Zhang, J. M. et al., 2004), at the site of injury (neuroma), and in the periphery (Shinder, V. et al., 1999) have been demonstrated. In keeping with this some neuropathic pain symptoms have been attenuated by sympathetic blocks or surgical sympathectomy. Other studies have shown the expression of 1and 2-adrenoceptors on sensory neurons or postganglionic sympathetic terminals (Sato, J. and Perl, E. R., 1991; Tracey, D. J. et al., 1995; Lee, D. H. et al., 1999) after nerve injuries. Under these conditions sensory neurons can be directly activated by the endogenous release of sympathetic transmitters (via

804 Pharmacological Modulation of Pain

1 receptors) or in the clinic by intradermal injection of norepinephrine (Ali, Z. et al., 2000). On the other hand, transdermal applications of the 2-agonist, clonidine via transdermal patches or creams, has proven efficacious in a variety of neuropathic pain conditions (Byas-Smith, M. G. et al.,1995). Since clonidine has been shown to decrease the excitability of small sensory neurons from nerve injured animals (Ma, W. et al., 2005) the antinociceptive efficacy of clonidine is considered to be due to 2 receptor-coupled inhibition. Clonidine and other 2-agonists such as dexmedetomidine have also been used systemically to inhibit of sensory transmission in the spinal cord by block of pre- and postsynaptic membrane excitability. Unfortunately sedation and hypotension are major target-related side effects of these compounds. Great efforts have been made to identify ligands with improved 2-receptor subtype selectivity, to avoid side effects, but thus far this has not been particularly successful.

53.11 Glutamate Regulation and Glutamate Receptors Glutamate is the major excitatory neurotransmitter in the CNS with important regulatory roles for pain transmission. However there is also considerable evidence that it plays a role in pain processing in the periphery (Carlton, S. M. et al., 1995; Bahave, G., et al., 2001). Glutamate acts through receptor-coupled ligand-gated ion channels (-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA)/kinate receptors: iGluRs) and GPCR-coupled receptors (metabotropic glutamate receptors (mGluRs)). Injections of glutamate or metabolically stable receptor-selective agonists such as N-methyl-Daspartic acid (NMDA), AMPA, and kainate, cause a reduction in thermal and mechanical thresholds for pain, while application of iGluR and mGluR antagonists attenuate pain in acute models (Zhou et al.,1996; Bhave, G., et al., 2001). Building upon this has been significant progress in development of a glutamate antagonist optimized for clinic testing. For example, the AMPA-kinate receptor antagonist, LY293558 has been shown to have efficacy in models of neuropathic pain (Blackburn-Munro, G. et al., 2004) and to reduce capsaicin-induced pain in human volunteers as well as clinical dental pain with minimal side effects (Sang, C. N. et al., 1998). There has been a great deal of information linking NMDA receptors in central sensitization and CNS

excitability during chronic pain and repetitive stimulation of pain pathways. Indeed NMDA antagonists show robust attenuation of pain behaviors but provoke a number of side effects (sedation, confusion, and motor incoordination) and thus have an insufficient therapeutic window. There has been a refocus on more specific NMDA-receptor subtype blockers (NR1 and NR2) directed toward the glycine modulatory site to avoid side effects. This site actively modulates the NMDA channel only during the sustained stimulation of the receptor, which is considered to occur during chronic pain. Selective NR1-Gly antagonists have been claimed to reduce pain with reduced side effects (Danysz, W. and Parsons, C. G., 1998; Quartaroli, M. et al., 2001). However clinical experience has not yet confirmed this. GV196771 did not show efficacy against clinical pain, possible due to inadequate penetration into the CNS (Wallace, M. S. et al., 2002). Alternative initiatives have targeted other NMDA receptor subtypes such as the NR2B receptor, which has a specific distribution in sensory pathways. Blockade of this receptor has also been claimed to produce antinociception (ifenprodil, CP-101,606) with reduced side effects (Taniguchi, K. et al., 1997). This concept has yet to be evaluated in the clinic. Metabotropic glutamate receptors, particularly mGluR1 and mGluR5, have been reported to play a key role in sustaining heightened central excitability in chronic pain with minimal involvement in acute nociception. Thus spinal administration of selective agonists such as dihydroxy phenyl glycine produced allodynia, while mGluR5 was shown to be significantly overexpressed in some, but not all, chronic pain models (Hudson, L. J. et al., 2002). Furthermore antisense-oligonucleotide and antibody treatments, directed at these receptors, reduce chronic inflammatory and neuropathic pain behaviors (Fundytus, M. E. et al., 2002). In keeping with these observations, the mGluR5-selective antagonists 2-methyl-6-(phenylethynyl)-pyridine (MPEP) did not reduce acute physiological pain responses but reduced heat hyperalgesia and allodynia in models of inflammatory and neuropathic pain (Walker, K. et al., 2001; Hudson, L. J. et al., 2002; Urban, M. O. et al., 2003). Peripheral mGluR5 receptors have also been claimed to modulate pain (Jang, J. H. et al., 2004). Thus local administration of mGluR5 (MPEP, SIB1757) have been effective in reducing pain behavior (Dogrul, A. et al., 2000; Zhu, C. Z. et al., 2004) suggesting a potential for using peripheral mGlu5 antagonists in pain therapy.

Pharmacological Modulation of Pain

Metabotropic group II receptors (mGluR2 and mGluR3) also modulate pain transmission. The mGluR2 is located in sensory neurons and presynaptic nerve terminals whereas mGluR3 is found all over the brain. MGluR3 can be selectively increased in the spinal dorsal horn neurons after peripheral ultraviolet injury (Boxall, S. J. et al., 1998). mGluR2/3 receptor activation appears necessary to reduce nerve terminal excitability and modulate pain transmission since treatment with L-acetyl-carnitine reduced inflammatory hyperalgesia and mechanical allodynia and increased the expression of mGlur2/3. The effect of L-acetyl-carnitine were attenuated by LY379268, a mGlu2/3 antagonist (Chiechio, S. et al., 2002).

53.12 Gamma-Aminobutyric Acid Receptors Gamma-aminobutyric acid (GABA) receptors are emerging as important regulators of pain, particularly in the spinal cord as they are abundantly expressed both on spinal afferent nerve terminals and spinal neurons. Activation of both subtypes of GABA receptor by muscimol (GABAA agonist) or baclofen (GABAB agonist) reduced pain behavior. In contrast, GABAA (bicuculline) and GABAB (CGP35348) antagonists cause pain when injected into the spinal intrathecal space (Malan, T. P. et al., 2002). Loss of GABA (Ibuki, T. et al., 1997) and impaired GABAmediated inhibition through loss of spinal interneurons has been demonstrated in models of neuropathic pain (Moor, A. K., et al., 2002). Improvement of GABA synthesis through promotion of its synthetic enzyme, glutamic acid decarboxylase (GAD), has been achieved by gene transfer of a GAD promoter (in herpes simplex virus vector) via peripheral injection. This was taken up into sensory neurons and transported to DRGs to reduce spinal excitability, as well as mechanical and thermal allodynia caused by nerve injury (Hao, S. et al., 2005). Other important changes in ionic regulation have been highlighted to occur in chronic pain which indirectly affects GABA- and glycine-mediated inhibition and excitability in the spinal cord. In particular changes in transmembrane ion transporters have been associated with modulation of primary afferent excitability and related to neuropathic pain disorders. Thus the chloride transporter NKCC1, localized in primary sensory neurons, is responsible for maintaining the high chloride

805

ion gradient in afferent terminals. This allows the outflow of chloride ions associated with the primary afferent depolarization (PAD) and presynaptic inhibition, following GABAA receptor activation of afferent terminals. Deletion of the NKCC1 gene induced touch-evoked pain caused by light stroking. This was shown to be due to increased nerve terminal excitability caused by a reduced capability to generate presynaptic inhibition (Laird, J. M. A. et al., 2004). On the other hand increasing the expression of this cotransporter or increasing its efficacy through AMPA mediated Ca/CaM-kinase II phosphorylation has been postulated (Cervero, F. et al., 2003) to increase PAD sufficient to reach the firing threshold of the nerve terminal. This mechanism may also contribute to spinal sensitization following nerve injury and may indeed generate antidromic action potentials triggering a dorsal root reflex or the ectopic discharges in sensory nerves which cause, or contribute to spontaneous pain. Spinal sensitization that occurs following peripheral nerve injury may also arise by other mechanisms of spinal disinhibition. This has been hypothesized to involve the reduced expression of the potassiumchloride exporter KCC2, seen only in superficial spinal lamina 1 neurons after injury. In addition, knockdown of KCC2 with antisense or block of this transporter with ((dihydronindenyl)oxy) alkanoic acid (DIOA) causes a similar shift in the transmembrane ionic gradient in spinal lamina 1 neurons and a consequent behavioral hyperalgesia resembling that seen after nerve injury (Coull, J. A. M. et al., 2003). In addition, normal spinal inhibitory currents, mediated by GABA and glycine interneurons, are reversed in the absence of KCC2, so that the effects of GABA become predominant excitatory, due to the outward, rather than inward, flow of chloride ions. The emerging view suggests that a variety of changes in ionic regulation occur during chronic pain. This adds complexity to the puzzle of pain but opportunity for intervention. It will be important to learn how these disinhibitory mechanisms contribute in different chronic pain conditions and whether they are critical for pain initiation as well as its maintenance.

53.13 Ion Channels 53.13.1

Ligand-Gated Channels

Transient receptor potential (TRP) channels form a large family of sensory transducers involved in cellular calcium regulation. Many are localized to

806 Pharmacological Modulation of Pain

mammalian sensory nerves and are involved in the transduction of temperature and chemical signals that result in pain. The TRPV family has received considerable attention and is considered a good targeted for developing analgesics (Krause, J. E. et al., 2005). TRPV1, originally called the vanilloid receptor because of its selective activation by capsaicin and pungent vanilloids, has the properties of a noxious heat transducer. The effects of capsaicin on sensory neurons are complex, involving activation through ligand-operated cation channels, and the extracellular influx as well as the intracellular increase in calcium ions. Calcium-induced stimulation of phosphatase such as cacineurin then reduces excitability via inactivation voltage-gated calcium (CaV) channels as well as rapid CaV2.2 internalization (Wu, Z. Z. et al., 2005). This mechanism explains the transient and reversible analgesia effects of capsaicin either on peripheral or spinal afferent nerve terminals. TRP channel regulation of heat transduction is complex as animals with deleted TRPV1 and TRPV2 genes appear to have normal heat sensitivity (Woodbury, J. et al., 2004) whereas gene deletion of TRPV1 prevented inflammatory heat hyperalgesia (Caterina, M. J. et al., 2000). The TRPV1 receptor has assumed an increasingly prominent role in regulating sensory neuronal excitability in inflammatory pain. A variety of inflammatory agents including protons, bradykinin, adenosine triphosphate (ATP), PGE2, 12-lipoxygenase products, PAR2, anandamide, and nerve growth factor (NGF) indirectly sensitize TRPV1, or regulate its expression, to cause thermal hyperalgesia. A common mechanism appears to be GPCR-coupled stimulation of PLC, the formation of intermediates inositol triphosphate (IP3) and DAG and the activation and mobilization of PKC (Vellani, V. et al., 2001) which can phosphorylate the TRPV1 receptor. Earlier analgesia strategies, targeting TRPV1, were focused on capsaicin-like agonists that induced functional inactivation of sensory fibers by causing reversible subepidermal degeneration. This has been successfully translated into the clinic with the introduction of a number of topical capsaicin therapies for inflammatory pain. Currently there is a focus on TRPV1 channel blockers or selective antagonists against the TRPV1 receptor (Garcia-Martiez, C. et al., 2002). Supporting these approaches, competitive (AMG-9810, personal communication) and noncompetitive vanilloid receptor-1 (VR1) antagonists (DD161515; Sachez-Baez, F. et al., 2002) block chemical and thermal pain sensitivity, heralding the

emergence of a novel therapy. Indeed recent clinical studies in human volunteers have shown that oral SB705498 attenuated capsaicin and ultraviolet C (UVC)-induced pain and hyperalgesia (Chizh, B. et al., 2006). Other TRP channels (TRPV3, TRPV4, TRPA1) have been suggested to be involved in transduction. Thus TRPA1 (ANKTM1) is colocalized with TRPV1, is activated by capsaicin and mustard oil but can also be sensitized by inflammatory mediators including bradykinin to produce cold-induced burning pain (Bandell, M. et al., 2004). In addition TRPV1 can oligomerize with other TRP family members including TRPV3. TRPV3 is also a heat transducer that it sensitive in the physiological temperature range and responds to noxious heat, but is insensitive to capsaicin. This is found in keratinocytes and appears to be upregulated in inflammatory pain conditions. It is unclear how activity of TRPV3 leads to nociceptor activation. So far there are few chemical tools to help characterize the functions of these TRP receptors and support their value as analgesia targets.

53.14 Purinergic Receptors 53.14.1

P2X Receptors

The unique localization of the P2X3 receptor to small sensory fibers has highlighted its importance in pain. Large amounts of the endogenous ligand, ATP are released after tissue injury and during inflammatory injuries while both ATP and a stable analogue ,-Me ATP, induce pain and are pronociceptive when administered intradermally in human volunteers. In chronic inflammatory pain, P2X3-mediated excitability is enhanced while reduction of P2X3 receptors, by antisense oligonucleotide administrations, reduced inflammatory hyperalgesia as well as that evoked by ,-Me ATP (Honore, P. et al., 2002). In keeping with this a number of antagonists including 29,39-O-(2,4,6-trinitrophenyl) adenosine 59-triphosphate (TNP-ATP), pyridoxal-phosphate6-azophenyl-29,49-disulfonate (PPADS), and suramin, reduce pain behavior. More selective, and druglike, antagonists such as A-3174919 reduced pain in a number of acute and chronic pain models supporting the possibility for future analgesia therapy (Jarvis, M. F. et al., 2002). It should be noted that a number of other purinergic receptor subtypes, for example, P2X4 and P2X7, have also been suggested to modulate pain

Pharmacological Modulation of Pain

through altered central excitability and the release of neuroglial-cell products. Thus activated microglial, astrocytes, and satellite cells release a variety of inflammatory mediators including IL-1, TNF-, prostanoids, and NO upon ATP stimulation. Indeed increased expression of P2X4 has been shown to occur in spinal microglial after peripheral nerve lesions and this was related to painful mechanical allodynia. This behavior was blocked by spinal administrations of the selective P2X4 antagonist TNP-ATP (Tsuda, M. et al., 2003). Remarkably spinal administration of activated microglia reproduced TNP-ATP sensitive mechanical allodynia in naı¨ve animals. Increased P2X7 expression has been found in peripheral macrophages following inflammation but this receptor is also expression in spinal neurons and microglia following peripheral nerve injury (Deuchars, S. A. et al., 2001). In keeping with an important role in chronic pain both microglia and P2X7 receptors are upregulated in human chronic pain patients while deletion of the P2X7 receptor gene produced a complete absence of mechanical and thermal pain in mice (Chessell, I. P. et al., 2005). It is worth noting that other nucleotide-gated ion channels have also been shown to be important for regulating peripheral excitability. Thus the sodium/ potassium repolarizing pacemaker current, Ih, which is activated during membrane hyperpolarization is important for generation of rhythmic and spontaneous action potentials in sensory neurons following nerve injury. Ih currents are controlled by cyclic nucleotides (cAMP and cGMP) via a family (HCN1–4 channels) of ligand-gated ion channels that are constitutively expressed in sensory nerves and differentially distributed after crush or inflammatory nerve injuries (Chaplan, S. R. et al., 2003; Yao, H. et al., 2003). Nerve injury has been shown to enhance the Ih and this can be blocked with ZD7288 which also prevents repetitive firing in damaged sensory neurons and reverses touch hypersensitivity in neuropathic pain models (Chaplan, S. R. et al., 2003). This approach clearly has great potential for addressing peripheral excitability in neuropathic pain disorders. 53.14.2

Acid-Sensing Channels

Proton production is increased in inflammation and is likely to be involved in inflammatory hyperalgesia and in the sensation of muscle aching and discomfort due to the hypoxia/anoxia of muscle exercise. Indeed direct activation of nociceptors accounts for the sharp

807

stinging pain produced by intradermal injections of acidic solutions and low extracellular pH enhancing the effects of other inflammatory mediators (Krishtal, O., 2003; Mamet, J. et al., 2003). Exogenously administered acidic solutions produce a rapid but transient increase in membrane cation permeability as well as a more prolonged permeability increase in sensory neurons. This can give rise to sustained nerve activation as well as an enhanced mechanosensitivity. The mechanism of proton-induced activation of sensory neurons underlying pain has not been fully elucidated, but appears to be driven by a number of acid-sensing ion channel (ASICs) particularly ASIC1 and ASIC3 (also called DRASIC). ASIC3 has been shown to have a strong antinociceptive phenotype following deletion of this gene in KO mice (Sluka, K. A. et al., 2003). A novel blocker (A-317567) of peripheral ASIC1, ASIC2, and ASIC3 channels has been described (Dube, G. R. et al., 2005). This produces antihyperalgesia in models of inflammatory and postoperative pain but there have been no reports of therapeutic advances with more selective inhibitors.

53.15 Sodium Channels Voltage-gated sodium channels are characterized by their primary structure and sensitivity to tetrodotoxin (TTX). A variety of TTX sensitive (NaV1.1, Nav1.2, NaV1.6, and Nav1.7) and TTX insensitive (Nav1.8, NaV1.9) channels are involved in regulating sensory neural excitability (Matzner, O. and Devor, M., 1994; Eglen, R. M. et al., 1999). Changes in the expression, trafficking, and redistribution of NaVs, following inflammation or nerve injury is considered to account for the abnormal firing (ectopic generators) of afferent nerves (Devor, M., 2005). However channel redistribution appears complex as most channels appear to be downregulated in DRGs after nerve injury whereas, for example, NaV1.8 is redistributed along small axons. It has also been important to recognize that channel expression and nerve excitability are changed dramatically in uninjured axons that are closely apposed to injury (Gold, M. S. et al., 2003). The TTX-R sodium channel, NaV1.8, is uniquely expressed in all sensory neurons (IB4 positive and NGF sensitive) and appears to be an important contributor in the generation of abnormal excitability in sensory axons. Thus knockdown of NaV1.8 produces a marked reduction in abnormal pain responsiveness in pain models (Lai, J. et al., 2003).

808 Pharmacological Modulation of Pain

Inflammation also causes the overexpression of NaV1.7 in several types of sensory neurons in models of inflammatory pain (Gould, H. J. et al., 2004) and in inflamed human tooth pulp. Interestingly NaV1.7 overexpression can be prevented by pretreatment with COX-1 and COX-2 inhibitors (ibuprofen, NS398). The clinical utility of nonselective sodium channel blockade in pain treatment has been well established with the use of local anesthetics such as lidocaine. Clinical experience has confirmed that local block of abnormally active afferents reduces secondary pain in established neuropathic pain conditions (Gracely, R. et al., 1992). Interestingly this can be achieved at lower concentrations than are required for block of conduction in quiescent fibers highlighting a potential therapeutic advantage for selective fiber block (Devor, M. et al., 1992). The basis of this is due to the state-dependent increase in the affinity of channel blockers for ion channel proteins (Devor, M., 2005). An additional utility of lidocaine is that intravenous administration has been reported to produce long-lasting pain relief both in animal models (Araujo, M. C. et al., 2003) and in intractable neuropathic pain (Kastrup, J. et al., 1987). The major disadvantages of nonselective sodium channel blockers are cardiotoxicity and CNS sedation and confusion produced by NaV1.5 and NaV1.2 channel block, respectively. Thus great activity is currently focused on discovering novel but selective sodium channel blockers. In this regard novel activity-dependent sodium channel blockers (e.g., NW-1029) have been shown to reduce excitability of peripheral nerves and cause antihyperalgesia in models of inflammatory and neuropathic pain (Veneroni, O. et al., 2003). Overall however, channel blockers still appear insufficiently selective to avoid cardiac and CNS side effects. An alternative approach to selectively regulate ion channels is to block the trafficking of channels to the nerve membrane. For example the functioning of NaV1.8 may be reduced by preventing its interaction with p-11, an annexin II-related protein that tethers the channel to the nerve membrane (Okuse, K. et al., 2002). In addition, channel-associated cell surface glycoproteins such as contactin may be involved in concentrating specific channel subtypes, e.g., NaV1.8 and NaV1.9 (IB4 positive) but not NaV1.6 and NaV1.7 (IB4 negative) in DRG nerve membranes, with an associated increased in current density (Rush, A. M. et al., 2005). Although these approaches are attractive it

is unclear whether they will impact on nerve excitability associated with specific pain etiology. NaV1.3 is another ion channel that is dramatically regulated after injury. This channel has been found abundantly in fetal but not in adult tissue. However NaV1.3 is dramatically upregulated in adult sensory neurons and spinal cord following peripheral and CNS injury (Hains, B. C. et al., 2004). The expression of NaV1.3 has been suggested to make an important contribution to the sustained and high-frequency firing found in injured afferents related to neuropathic pain (Cummins, T. R. and Waxman, S. G., 1997; Kim, C. H. et al., 2002). Further it has been proposed that NaV1.3 expression may not be directly related to neural injury as it was not correlated with activating transcription factor (ATF)-3 expression, a neuronal cell death marker (Lindia, J. A. et al., 2005), but caused by a deficiency of growth factor. In this respect, GDNF administration reduced NaV1.3 expression and attenuated neuropathic pain behavior (Boucher, T. J. et al., 2000). In contrast, antisense treatments that significantly reduced sensory neuronal NaV1.3 expression in the spared nerve injury (SNI) model of neuropathic pain did not attenuate nerve injuryinduced allodynia (mechanical or cold; Lindia, J. A. et al., 2005) whereas this was reduced by the nonselective channel blockers mexiletine and lamotrigine.

53.16 Calcium Channels A variety of calcium channels (CaV) have been identified and characterized. Several have been shown to be prominently involved in pain regulation (Yaksh, T. L., 2006). The N-type calcium channel CaV2.2 is an important regulator of nerve terminal excitability and neurotransmitter release. It has been well established that there is complex chemical regulation of N-channels, particularly through GPCR signaling. For example, N-channel activity is attenuated by analgesic drugs such as opioids, with a resultant modulation of sensory transmitter release, e.g., substance P, CGRP, and glutamate, at both spinal and at peripheral sensory nerve terminals. N-channel trafficking may also be affected by GPCRs. For example, activation of the orphanin FQ receptor (ORL) by nociceptin causes channel internalization and downregulation of calcium entry (Altier, C. et al., 2005). Of additional importance is the fact that deletion of the N-channel gene reduces inflammatory and neuropathic pain (Kim, C. et al., 2001; Saegusa, H. et al., 2001). Moreover selective blockers such as ziconotide,

Pharmacological Modulation of Pain

(a naturally occurring conopeptide) and verapamil have been used to characterize channel activity while ziconitide (SNX-111, Prialt) has been used experimentally and clinically by intrathecal administration, to show utility for pain relief (Xiao, W. H. and Bennett, G. J., 1995; Snutch, T. P., 2005). Building on this concept, small molecule CaV2.2 channel blockers with oral availability are now reported to have been developed, e.g., NMED-160, showing efficacy in chronic pain models (Snutch, T. P., 2005). While it is believed that blockers of CaV2.2 exert their major analgesic effects via the spinal cord, peripheral actions are also possible. Thus N-channels expression also occurs in peripheral terminals and has been shown to increase following axotomy (Baccei, M. L. and Kocsis, J. D., 2000). This suggests that peripheral N-channels can be targeted for neuropathic pain treatments; thus avoiding potential CNS side effects such as sedation. Low-voltage-activated T channels (CaV3.1, CaV3.2, and CaV3.3) also appear important for pain transmission and as targets for pain therapy. Thus they are expressed in superficial laminas of the spinal cord and in DRG neurons (for references see Altier, C. and Zamponi, G. W., 2004; Yaksh, T. L., 2006). T-channels appear unaffected in DRGs after axotomy (Baccei, M. L. and Kocsis, J. D., 2000) but may play a more prominent role in regulating spinal excitability and spinal sensitization following repetitive C-fiber stimulation (Ikeda, H. et al., 2003). Moreover nerve injury-induced hyper-responsiveness was blocked by the T-channel blocker ethosuximide (Matthews, E. A. and Dickenson, A. H., 2001) which also attenuated mechanical allodynia in animal models of vincristineand paclitaxel-induced neuropathic pain (Flatters, S. J. and Bennett, G. J., 2004). Finally a strongly validated approach for neuropathic pain has targeted the 2,1 calcium channel subunit, the substrate for the antiallodynic drugs, gabapentin and pregabalin. This subunit is important for channel assembly, is expressed in small DRGs and in spinal neurons, and its overexpression has been associated with allodynia in a number of specific pain models (Luo, Z. D. et al., 2002).

53.17 Neurotrophins and Their Receptors The neurotrophins represent an important family of regulatory proteins essential for sensory nerve development, survival, and determination of chemical

809

phenotype including excitability (Sah, D. W. H. et al., 2003; Zweifel, L. S. et al., 2005). Several neurotrophins have been identified including NGF, brainderived growth factor (BDNF) and neurotrophins (NT) 3, neurotrophin 4/5. Each neurotrophin binds with high affinity to receptor tyrosine kinases (Trk): NGF to TrkA, BDNF and NT4/5 to TrkB, and NT3 to TrkC. NT3 also binds with TrkA and TrkB. Mature neurotrophins also bind to a structurally distinct receptor p75 which affects neuronal development through downstream signaling. Neurotrophins arise from proneurotrophin precursors following extracellular cleavage by metalloproteinases and plasmin. It should be observed that proneurotrophins also signal through the p75 receptor and may produce opposite effects from neurotrophins, e.g., apoptosis rather than cell survival (Lu, B. et al., 2005). NGF has been most studies with respect to inflammatory hyperalgesia as its production is unregulated by inflammation in macrophages, fibroblasts, and Schwann cells. NGF has emerged as a key regulator of sensory neuron excitability and as an important mediator of injury-induced nociceptive and neuropathic pain (Ro, L. S. et al., 1999; Theodosiou, M. et al., 1999; Hefti, F. F. et al., 2005). NGF acts via TrkA and p75 to activate a number of kinase pathways (e.g., p38 kinase; Ji, R. R. et al., 2002) leading to altered gene transcription and the increased synthesis of sensory neuropeptides (substance P, CGRP), ion channels (TRPV1, NaV1.8, ASIC3; Fjell, J. et al., 1999; Ji, R. R. et al., 2002; Mamet, J. et al., 2003), membrane receptors such as bradykinin and P2X3 (Petersen, M. et al., 1998; Ramer, M. S. et al., 2001), and structural molecules including neurofilament and channel anchoring proteins such as the annexin light chain p11 (Okuse, K. et al., 2002). Increased expression and release of NGF have been demonstration in several painful conditions in animal models (e.g., ultraviolet injury, surgical injury; Oddiah, D. et al., 1998; Miller, L. J. et al., 2002) and in human conditions including arthritis, cystitis, prostitis, and headache (Aloe, L. et al., 1992; Halliday, D. A. et al., 1998; Sarchielli, P. et al., 2001). Administration of exogenous NGF induces thermal and mechanical hyperalgesia in animals and humans (Andreev, N. et al., 1995; Apfel, S. C., 2002), which is considered to be due in part to mast cell degranulation and by directly increasing sensory neuronal excitability (Sah, D. W. H. et al., 2003). Few small molecule NGF antagonists are available but ALE0540, which inhibits the binding of

810 Pharmacological Modulation of Pain

NGF to TrkA and p75, and PD90780 which inhibits NGF binding to p75, have been proposed to have efficacy in chronic pain models (Owolabi, J. B. et al., 1999; Colquhoun, A. et al., 2004). In contrast, the use of TrkA-immunoglobulin G (IgG) and NGF monoclonal antisera have confirmed the importance of NGF in pain. Thus anti-NGF treatment have provided positive behavioral and biochemical readouts in several models of chronic nociceptive (including visceral) and neuropathic pain (Obata, K. et al., 2004; Hefti, F. F. et al., 2005; Sevcik, M. A. et al., 2005; Shelton, D. L. et al., 2005). These studies have also indicted a lack of effect on acute nociceptive processing or on sympathetic nerves whose phenotype is also regulated by NGF. The importance of NGF has also received clinical confirmations since RN624, a humanized anti-NGF monoclonal antibody (mAb), has been reported to be efficacious in reducing pain and improved mobility in OA (Lane, N. et al., 2005). Anti-NGF mAb therapy appears as an attractive therapeutic approach with the potential for long-lasting pain treatment, similar in efficacy to morphine, without necessarily compromising physiological nociception. NGF also induces the synthesis of another neurotrophin, BDNF, from peptide-containing sensory neurons. BDNF also accumulates in sensory neurons following painful nerve injury (see Sah, D. W. H. et al., 2003). Release of BDNF in the spinal dorsal horn increasing spinal excitability and pain sensitization via TrkB receptors. This initiates a variety of effects, including direct neural excitation, activation of a signaling cascade via the phosphorylation of NMDA receptors, and an altered regulation of the neural chloride transporter that contributes to pain hypersensitivity (Coull, J. A. M. et al., 2005). In keeping with these observations, spinal BDNF administration induces thermal and mechanical allodynia whereas anti-BNDF neutralization or TrkB IgG administration reduces inflammation or nerve injury-mediated hypersensitivity pain in a number of animal models (Kerr, B. J. et al., 1999; Theodosiou, M. et al., 1999; Deng, Y. S. et al., 2000). Finally glial cell-line-derived neurotrophic factor, GDNF represents an extensive family of ligands and membrane receptor complexes which have an important role in regulating peripheral and central neural phenotypes. GDNF-related ligands include neurturin and artemin, which act via the complex RET Trk receptor and co-receptors GFR1, GFR2, GFR3, and GFR4.

Although there appears not to be a specific role in inflammation, GDNF has been shown to have neuroprotective and restorative properties in a number of neurodegenerative and neuropathic pain states (Sah, D. W. H. et al., 2003). Specifically GDNF treatment has been shown to restore peripheral sensory neuron function, including peptide and ion channel expression patterns, following painful peripheral nerve injury accompanied by an attenuation of pain behaviors. Unfortunately clinical observations using GDNF have shown unacceptable side effects such as weight loss and allodynia, which has discouraged therapeutic developments (Nutt, J. G. et al., 2003).

53.18 Kinases As mentioned earlier inflammatory mediators also activate a number of protein kinases in sensory neurons and in the spinal cord. These include PKA, PKC, and mitogen-activated protein kinases (MAPK) considered to be important downstream regulators of excitability through altering gene transcription and posttranslational modification of target proteins (Woolf, C. J. and Salter, M. W., 2000). There are several types of MAPKs including extracellular signal-regulated kinases (ERK), cJUN, N-terminal kinase (JNK), and p38 kinase that are considered as targets for inflammatory pain. For example, several inhibitors of p38 kinase (e.g., SB203580, CNI-14930) posses antiinflammatory as well as antihyperalgesic properties in a variety of animal models (Schafers et al., 2003b).

53.19 Botulinum Toxin Another approach to pain modulation has been the use of botulinum toxins (BoTNs). This family of neurotoxins has been traditionally used as an experimental tool to study muscle nerve interactions. Recently BoTN-A has been approved for clinical use to induce muscle relaxation. The mechanism of action of BoTN is related to inhibition of transmitter release from motor fibers through proteolytic cleavage of a number of synaptosomal regulatory proteins (SNARE, syntaxin, SNAP-25, synaptobrevin). More recent studies also indicated potential for inhibition of neuropeptide transmitter release from small afferent neurons (Welch, M. J. et al., 2000; Mense, S., 2004). In keeping with this BoTN has been shown to provide long-lasting pain relief following administration into human osteoarthritic

Pharmacological Modulation of Pain

joints and improve bladder dysfunction in overactive bladder patients. This was correlated with loss of both P2X3 and VR1 receptors in the bladder (Apostolidis, A. et al., 2005).

53.20 Nitric Oxide NO induces a delayed burning pain upon intradermal injection (Holthusen, H. and Arndt, J. O., 1994) and NO donors have been postulated to activate cerebral sensory fibers directly, causing release of the sensory vasodilator CGRP (Wei, P. et al., 1992). Indeed NO has been suggested to contribute to migraine and other types of head pain (Olesen, J. et al., 1994) and there is an abundance of evidence linking NO in the etiology of a number of chronic pain conditions (Millan, M. J., 1999). Peripheral nerve injury and inflammation increases the expression of NO in sensory neurons and causes the upregulation of the nitric oxide synthase (NOS) isozymes neuronal NOS (nNOS) and inducible NOS (iNOS) in the spinal cord (Gordh, T. et al., 1998) as a result of axonal neurodegeneration, neuroglial cell activation and inflammation (Levy, D. et al., 2001). In keeping with these observations, treatment with nonspecific NOS inhibitors such as L-N-nitro-L-arginine methyl ester (L-NAME) has been shown to prevent or reduce pain hypersensitivity (Meller, S. T. et al., 1992; Hao, J. X. and Xu, X. J., 1996; Handy, R. L. and Moore, P. K., 1998). Indeed particular interest has been devoted to producing selective blockers of iNOS, to avoid side effects associated with nonspecific block of nNOS and endothelial NOS (eNOS). Recently GW27415, a selective iNOS inhibitor has been shown to partially reduce Freund’s complete adjuvant (FCA)-induced inflammatory pain as well the hypersensitivity associated with the CCI neuropathy model. This action was most likely to have been caused via a peripheral mechanism as no iNOS expression was detectable in sensory ganglia or spinal cord (Alba, J. D. et al., 2006).

53.21 Summary and Conclusions Pharmacological understanding of pain is the foundation on which new and effective therapies for pain can emerge. Great advances have been made with greater availability of improved chemical and biological tools. This has fueled greater understanding of the mechanistic and molecular substrates of pain,

811

derived for the most part from our studies of animal models (see Figure 1). The complexity and heterogeneity of chronic pain states will clearly remain an enormously challenging area for future research. There is still a great need for human data showing the regulated expression of pain molecules and clinical data that provides more rapid evaluation of emerging pharmacological concepts. This will allow the most valuable targets to be selected for analgesia development in the clinic. Clearly the improvements in our pharmacological understand of pain has also provided an abundance of opportunities for developing analgesics. Among the most comprehensively studied molecules in chronic pain are inflammatory mediators and their key receptors. These include PGE2/EP1, bradykinin/BK1 and BK2, ATP/P2X3, cytokines/ IL-1, chemokines/ CCr2 and neurotrophins/NGF/TrkA that sensitize and increase excitability in peripheral and central pain pathways. Many of these mediators act through GPCRs and there appears to be some convergence of mechanisms with changes in expression and regulation of ion channel. Key channels for pain are either ligand gated, for example, TRPV1, P2X3, P2X4, P2X7, or voltage gated, for example, NaV1.8, NaV1.7, NaV1.3, CaV2.2. A variety of additional cellular process including protein phosphorylation of membrane receptors and channels via key kinases, for example, MAPK, as well as complex phenotype change regulated by neurotrophins require further understanding. In addition, the emerging importance of neuroglia and their pharmacology needs exploration and consolidation. Finally despite the great advances in pain pharmacology, many pain molecules remain poorly validated as good targets for analgesia. Stronger clinical translation is highly likely with the progression of pharmacological opportunities into humans.

References Abbadie, C. 2005. Chemokines, chemokine receptors and pain. Trends Immunol. 26, 529–534. Alba, J. D., Clayton, N. M., Collins, S. D., Colthup, P., Chessell, I., and Knowles, R. G. 2006. GW274150, a novel and highly selective inhibitor of the inducible isoform of nitric oxide synthase (iNOS), shows analgesic effects in rat models of inflammatory and neuropathic pain. Pain 120, 170–181. Ali, Z., Raja, S. N., Wesselmann, U., Fuchs, P. N., Meyer, R. A., and Campbell, J. N. 2000. Intradermal injection of norepinephrine evokes pain in patients with sympathetically maintained pain. Pain 88, 161–168.

812 Pharmacological Modulation of Pain Aloe, L., Tuveri, M. A., Carcassi, U., and Levi-Montalcini, R. 1992. Nerve growth factor in the synovial fluid of patients with chronic arthritis. Arthritis Rheum. 35, 3351–3355. Altier, C. and Zamponi, G. W. 2004. Targeting Ca channels to treat pain: T type versus N-type. Trends Pharmacol. Sci. 26, 465–470. Altier, C., Khosravani, H., Evans, R. M. Hameed, S., Peloquin, J. B., Vartian, B. A., Chen, L., Beedle, A. M., Ferguson, S. S., Mezghrani, A., Dubel, S. J., Bourinet, E., McRory, J. E., and Zamponi, G. W. 2005. ORL-1 receptor mediated internalization of N-type calcium channels. Nature Neurosci. 9, 31–40. Amadesi, S., Nie, J., Vergnolle, N., Cottrell, G. S., Grady, E. F., Trevisani, M., Manni, C., Geppetti, P., McRoberts, J. A., Ennes, H., Davis, J. B., Mayer, E. A., and Bunnett, N. W. 2004. Protease-activated receptor 2 sensitizes the capsaicin receptor transient receptor potential vanilloid receptor 1 to induce hyperalgesia. J. Neurosci. 24, 4300–4312. Andreev, N., Dimitrieva, N., Kolzenburg, M., and McMahon, S. B. 1995. peripheral administration of nerve growth factor in the adult rat produces a thermal hyperalgesia that requires the presence of sympathetic postganglionic neurones. Pain 63, 109–115. Apfel, S. C. 2002. Nerve growth factor for the treatment of diabetic neuropathy: what went wrong, what went right, and what does the future hold? Int. Rev. Neurobiol. 50, 393–413. Apostolidis, A., Popat, R., Yiangou, Y., Cockyne, D., Ford, A. B. D. W., Davis, J. B., Dasgupta, P., Fowler, C. J., and Anand, P. 2005. Decreased sensory receptors P2X (3) and TRPV1 in suburothelial nerve fibers following intradetrusor injection of botulinum toxin for human detrusor overactivity. J. Urol. 174, 977–982. Araujo, M. C., Sinnott, C. J., and Strichartz, G. R. 2003. Multiple phases of relief from experimental mechanical allodynia by systemic lidocaine: responses to early and late infusions. Pain 103, 21–29. Baccei, M. L. and Kocsis, J. D. 2000. Voltage gated calcium currents in axotomized rat cutaneous afferent neurons. spinal dorsal horn of rats. Eur. J. Neurosci. 419, 1336–1342. Bandell, M., Story, G. M., Hwang, S. W., Viswanath, V., Eid, S. R., Petrus, M. J., Earley, T. J., and Pataapouian, A. 2004. Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron 41, 849–853. Bao, L., Jin, S. X., Zhang, C., Wang, L. H., Xu, Z. Z., Zhang, F. X., Wang, L. C., Ning, F. S., Cai, H. J., Guan, J. S., Xiao, H. S., Xu, Z. Q., He, C., Hokfelt, T., Zhou, Z., and Zhang, X. 2003. Activation of delta opioid receptors induces receptor induces receptor insertion and neuropeptide secretion. Neuron 37, 121–133. Bar, K. J., Natura, G., Telleria-Diaz, A., Tascher, P., Vogel, R., Vasques, E., Schaible, H. G., and Ebersberger, A. 2004. Changes in the effect of spinal prostaglandin E2 during inflammation: prostaglandin E9EP1-EP4) receptors in spinal nociceptive processing of input from the normal and inflamed knee joint. J. Neurosci. 24, 642–651. Bhave, G. and Gereau, R. W. 2004. Posttranslational mechanisms of peripheral sensitization. J. Neurobiol. 6188–6106. Bhave, G., Karim, F., Carlton, S. M., and Gereau, R. W. 2001. Peripheral group I metabotropic glutamate receptors modulate nociception in mice. Nat. Neurosci. 4, 417–423. Blackburn-Munro, G., Bomholt, S. F., and Erichsen, H. K. 2004. Behavioural effects of the novel AMPA/GluR5 selective receptor antagonist NS1209 after systemic administration in animal models of experimental pain. Neuropharmacology 47, 351–362. Boucher, T. J., Okuse, K., Bennett, D. L., Munson, J. B., Wood, J. N., and McMahon, S. B. 2000. Potent analgesic effects of GDNF in neuropathic pain states. Science 290, 124–127.

Boxall, S. J., Berthele, A., Laurie, D. J., Sommer, B., Zieglgansberger, W., Urban, L., and Tolle, T. R. 1998. Enhanced expression of metabotropic glutamate receptor 3 messenger RNA in the rat spinal cord during ultraviolet irradiation induced peripheral inflammation. Neuroscience 82, 591–602. Burgess, G. M., Perkins, M. N., Rang, H. P., Campbell, E. A., Browen, M. C., McIntyre, P., Urban, L., Dziadulewicz, E. K., Ritchie, T. J., Hallet, A., Snell, C. R., Wrigglesworth, R., Lee, W., Davis, C., Phagoo, S. B., Davis, A. J., Phillips, E., Drake, G. S., Hughes, G. A., Dunstan, A., and Bloomfield, G. C. 2000. Bradyzide, a potent nonpeptide B2 bradykinin receptors antagonist with long lasting oral activity in animal models of inflammatory hyperalgesia. Br. J. Pharmacol. 129, 77–86. Burstein, S. H., Karst, M., Schneider, U., and Zurier, R. B. 2004. Ajulemic acid: a novel cannabinoid produces analgesia without a ‘‘high’’. Life Sci. 75, 1513–1522. Byas-Smith, M. G., Max, M. B., Muir, J., and Kingman, A. 1995. Transdermal clonidine compared to placebo in painful diabetic neuropathy using a two-stage ‘enriched enrollment’ design. Pain 60, 267–274. Cahill, C. M., Morinville, A., Lee, M. C., Vincent, J. P., Collier, B., and Beaudet, A. 2001. Prolonged morphine treatment targets delta opioid receptors to neuronal plasma membranes and enhances delta-mediated antinociception. J. Neurosci. 21, 7598–7607. Campbell, F. A., Tramer, M. R., Carroll, D., Reynolds, D. J., Moore, R. A., and McQuay, H. J. 2001. Are cannabinoids an effective and safe treatment option in the management of pain? A quantitative systematic review. BMJ 323, 13–16. Campbell, J. N., Basbaum, A. I., Dray, A., Dubner, R., Dworkin, R. H., and Sang, C. N. (eds.) 2006. Emerging Strategies for the Treatment of Neuropathic Pain. IASP Press. Carlton, S. M., Hargett, G. L., and Coggeshall, R. E. 1995. Localization and activation of glutamate receptors in unmyelinated axons of rat glabrous skin. Neurosci. Lett. 197, 25–28. Caterina, M. J., Leffer, A., Malmberg, A. B., Martin, W. J., Trafton, J., Petersen-Zeitz, K. R., Koltzenburg, M., Basbaum, A. I., and Julius, D. 2000. Impaired nociception and pain sensation I mice lacking the capsaicin receptor. Science 288, 306–313. Cervero, F., Laird, J. M. A., and Garcia-Nicas, E. 2003. Secondary hyperalgesia and presynaptic inhibition: an update. Eur. J. Pharmacol. 7, 345–351. Chandrasekharan, N. V., Dai, H., Roos, K. L. T., Evanson, N. K., Tomsik, J., Elton, T. S., and Simmons, D. L. 2002. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc. Natl. Acad. Sci. U. S. A. 99, 13926–13931. Chang, L., Luo, L., Palmer, J. A., Sutton, S., Wilson, S. J., Barbier, A. J., Breitenbucher, J. G., Chaplan, S. R., and Webb, M. 2006. Inhibition of fatty acid amide hydrolase produces analgesia by multiple mechanisms. Br. J. Pharmacol. 148, 102–113. Chaplan, S. R., Guo, H. Q., Lee, D. H., Luo, L., Liu, C., Kuei, C., Velumian, A. A. L., Butler, M. P., Brown, S. M., and Dubin, A. E. 2003. Neuronal hyperpolarization-activated pacemaker channels drive neuropathic pain. J. Neurosci. 23, 1169–1178. Chessell, I. P., Hatcher, J. P., Bountra, C., Michel, A. D., Hughes, J. P., Green, P., Egerton, J., Murfin, M., Richardson, J., Peck, W. L., Grahames, C. B., Casula, M. A., Yiangou, Y., Birch, R., Anand, P., and Buell, G. N. 2005. Disruption of the P2x7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain. Pain 114, 386–396. Chiechio, S., Caricasole, A., Barletta, E., Storto, M., Catania, M. V., Copani, A., Vertechy, M., Nicolai, R., Calvani, M., Melchiorri, D., and Nicoletti, F. 2002. L-Acetylcarnitine induces analgesia by selectively

Pharmacological Modulation of Pain up-regulating mGlu2 metabotropic glutamate receptors. Mol. Pharmacol. 61, 989–996. Chizh, B., Napolitano, A., O’Donnell, M., Wang, J., Brooke, A., Lai, R., Aylott, M., Bullman, J., Gray, E., Williams, P., and Appleby, J. 2006. The TRPV1 antagonist SB705498 attenuates TRPV1 receptor-mediated activity and inhibits inflammatory hyperalgesia in humans: results from a Phase 1 study. Am. Pain Soc. 765. Cichewicz, D. L. and McCarthy, E. A. 2003. Antinociceptive synergy between delta9 tetrahydrocannabinol and opioids after oral administration J. Pharmacol. Exp. Ther. 304, 1010–1015. Claveau, D., Sirinyan, M., Guay, J., Gordon, R., Chan, C. C., Bureau, Y., Riendeau, D., and Mancini, J. A. 2003. Microsomal prostaglandin synthase-1 is a major terminal synthase that is selectively up-regulated during cyclooxygenase-2-dependent prostaglandin E2 production in the rat adjuvant-arthritis model. J. Immunol. 170, 4738–4744. Colquhoun, A., Lawrance, G. M., Shamovsky, I. L., Riopelle, R. J., and Ross, G. M. 2004. Differential activity of the nerve growth factor (NGF) antagonist PD90780 [7benzoylamino)-4,9-dihydro-4methyl-8-oxo-pyrazolo-[5,1b]-quinazoline-2-carboxylic acid] suggest altered NGFp75NTR interactions in the presence of TrkA. J. Pharmacol. Exp. Ther. 310, 505–511. Coull, J. A. M., Boudreau, R., Bachand, K., Prescott, S. A., Nault, F., Sik, A., de Konink, P., and de Konink, Y. 2003. Trans-synaptic shift in ionic gradient in spinal lamina 1 neurons as a mechanism of neuropathic pain. Nature 424, 938–942. Cravatt, B. F. and Lichtman, A. H. 2004. The endogenous cannabinoid system and its role in nociceptive behavior. J. Neurobiol. 61, 149–160. Cravatt, B. J., Demarest, K., Patricelli, M. P., Bracey, M. H., Giang, D. K., Martin, B. R., and Lichtman, A. H. 2001. Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolyse. Proc. Natl. Acad. Sci. U. S. A. 98, 9371–9376. Cummins, T. R. and Waxman, S. G. 1997. Downregulation of tetrodotoxin-resistant sodium currents and upregulation of a rapidly repriming tetrodotozin-sensitive sodium current in small spinal sensory neurons after nerve injury. J. Neurosci. 17, 3503–3514. Danysz, W. and Parsons, C. G. 1998. GlycineB recognition site of NMDA receptors and its antagonists. Amino Acids 14, 205–206. De Jongh, R. F., Vissers, K., Meert, T. F., Booij, L. H. D. J., de Deyne, C. S., and Heylen, R. J. 2003. The role of interleukin-6 in nociception and pain. Anaesth. Analg. 96, 1096–1103. Deng, Y. S., Zhong, J. H., and Zhou, X. F. 2000. Effects of endogenous neurotrophin on sympathetic sprouting in the dorsal root ganglia and allodynia following spinal nerve injury. Exp. Neurol. 164, 344–350. Devor, M. 2005. Sodium channels and mechanisms of neuropathic pain. J. Pain 7, S3–S12. Devor, M., Wall, P. D., and Catalan, N. 1992. Systemic lidocaine silences ectopic neuroma and DRG discharges without blocking nerve conduction. Pain 48, 261–268. Deuchars, S. A., Atkinson, L., Brooke, R. E., Musa, H., Milligan, C. J., Batten, T. F. C., Buckley, N. J., Parson, S. H., and Deuchars, J. 2001. Neuronal P2X7 receptors are targeted to presynaptic terminals in the central and peripheral nervous systems. J. Neurosci. 21, 7143–7152. Dogrul, A., Ossipov, M. H., Lai, J., Malan, T. P., and Porecca, F. 2000. Peripheral and spinal antihyperalgesic activity of SIB1757, a metabotropic glutamate receptor (mGluR5) antagonist, in experimental neuropathic pain in rats. Neurosci. Lett. 292, 115–118.

813

Dong, X., Han, S., Zylka, M. J., Simon, M. I., and Anderson, D. J. 2001. A diverse family of GPCRs expressed in specific subsets of nociceptive sensory neurons. Cell 106, 619–632. Dray, A. 1997. Kinins and their receptors in hyperalgesia. Can. J. Pharmacol. 75, 704–712. Dray, A. 1999. Alternatives to mu-Opioid Analgesics: deltaOpioid and Galanin-Receptor Selective Compounds. In: Progress in Pain research and Management (eds. E. Kalso, H. J. McQuay, and Z. Wiesenfeld-Hallin), pp. 269–280. IASP Press. Dray, A. and Perkins, M. N. 1993. Bradykinin and inflammatory pain. Trends Neurosci. 16, 99–104. Dube, G. R., Lehto, S. G., Breese, N. M., Baker, S. J., Wang, X., Matulenko, M. A., Honore, P., Stewart, A. O., Moreland, R. B., and Brioni, J. D. 2005. Electrophysiological and in vivo characterization of A-317567, a novel blocker of acid sensing ion channels. Pain 117, 88–96. Dyson, A., Peacock, M., Chen, A., Courade, J. P., Yaqoob, M., Groark, A., Brain, C., Loong, Y., and Fox, A. 2005. Antihyperalgesic properties of the cannabinoid CT-3 in chronic neuropathic and inflammatory pain states in the rat. Pain 116, 129–137. Eglen, R. M., Hunter, J. C., and Dray, A. 1999. Ions in the fire: recent ion-channel research and approaches to pain therapy. Trends Pharmacol. Sci. 8, 337–342. Eisenbarth, H., Rukwied, R., Petersen, M., and Schmelz, M. 2004. Sensitization to bradykinin B1 and B2 receptor activation in UV-B irradiated human skin. Pain 110, 197–204. Elmes, S. J. R., Winyard, L. A., Medhurst, L. A., Clayton, S. J., Wilson, N. M., Kendall, A. W., and Chapman, V. 2005. Activation of CB1 and CB2 receptors attenuates the induction and maintenance of inflammatory pain in the rat. Pain 118, 327–335. England, S., Bevan, S., and Dougherty, R. J. 1996. PGE2 modulate the tetrodotoxin-resistant sodium current in neonatal dorsal root ganglion neurons via the cyclic AMPprotein kinase A cascade. J. Physiol. 495, 429–440. Ferreira, J., Beirith, A., Mori, M. A. S., Araujo, R. C., Bader, M., Pesqero, J. B., and Calixto, J. B. 2005. Reduced nerve injury induced neuropathic pain in kinin B1 receptor knock-out mice. J. Neurosci. 25, 2405–2412. Fiorucci, S., Antonelli, E., Burgand, J. L., and Morelli, A. 2001. Nitric-oxide releasing NSAIDs: a review of their current status. Drug Saf. 24, 801–811. Finn, D. P., Jhaveri, M. D., Beckett, S. R., Kendall, D. A., Marsden, C. A., and Chapman, V. 2004. Cannabinoids modulate ultrasound-induced aversive responses in rats. Psychopharmacology 172, 41–51. Flatters, S. J. and Bennett, G. J. 2004. Ethosuximaide reverses paclitaxel and vincristine-induced painful peripheral neuropathy. Pain 109, 150–161. Flechtenmacher, J., Talke, M., Veith, D., Heil, K., Gebauer, A., and Schoenharting, M. 2004. Icatibant induces pain relief in patients with osteoarthritis of the knee. 9th World Cong. Osteoarthritis Res. Soc. Intl. 12, Abst. P332. Fjell, J., Cummings, T. R., Fried, K., Black, J. A., and Waxman, S. G. 1999. In vivo NGF deprivation reduces SNS expression and TTX-R sodium currents in IB4-negative DRG neurons. J Neurophysiol. 81, 803–810. Flower, R. J. 2003. The development of COX2 inhibitors. Nat. Rev. 2, 179–191. Fox, A. and Bevan, S. 2005. Therapeutic potential of cannabinoid receptor agonists as analgesic agents. Exp. Opin. Invest. Drugs 14, 695–703. Fox, A., Kaur, S., Li, B., Panasar, M., Saha, U., Davis, C., Dragoni, I., Colley, S., Ritchie, T., Bevan, S., Burgess, G., and McIntyre, P. 2005. Antihyperalgesic activity of a novel nonpeptide bradykinin B1 receptor antagonist in transgenic mice expressing the human B1 receptor. Br. J. Pharmacol. 144, 889–899.

814 Pharmacological Modulation of Pain Fox, A., Wotherspoon, G., McNair, K., Hudson, L., Patel, S., Gentry, C., and Winter, L. 2003. Regulation and function of spinal and peripheral neuronal B(1) bradykinin receptors in inflammatory mechanical hyperalgesia. Pain 104, 683–691. Fride, E., Suris, R., Weidenfeld, J., and Mechoulam, R. 2005. Differential response to acute and repeated stress in cannabinoid cB1 receptor knockout newborn and adult mice. Behav. Pharmacol. 16, 431–440. Fundytus, M. E., Osborne, M. G., Henry, J. L., Coderre, T. J., and Dray, A. 2002. Antisense oligonucleotide knockdown of mGluR(1) alleviates hyperalgesia and allodynia associated with chronic inflammation. Pharmacol. Biochem. Behav. 73, 401–410. Gabra, B. H. and Sirois, P. 2003. Beneficial effects of chronic treatment with the selective bradykinin B1 receptor antagonists, R-715 and R-953, in attenuating streptozotocin-diabetic thermal hyperalgesia. Peptides 24, 1131–1139. Gabra, B. H., Merino, V. F., Bader, M., Pasquero, J. B., and Sirois, P. 2005. Absence of diabetic hyperalgesa in bradykinin B1 receptor-knockout mice. Reg. Pept. 127, 245–248. Garcia-Martiez, C., Humet, M., Planells-Casas, R., Gomis, A., Capri, M., Viaa, F., de la Pena, E., Sachez-Baez, F., Carbonell, T., de Felipe, C., Perez-Paya, E., Belmote, C., Messeguer, A., and Ferrer-Motiel, A. 2002. Attenuation of thermal nociception and hyperalgesia by VR1 blockers. Proc. Natl. Acad. Sci. U. S. A. 99, 2374–2379. Gold, M. S., Levine, J. D., and Correa, M. 1998. Modulation of TTX-R INa by PKC and PKA and their role in PGE2-induced sensitization of rat sensory neurons in vitro. J. Neurosci. 18, 10345–10355. Gold, M. S., Weinreich, D., Kim, C. S., Wang, R., Treanor, J., Porecca, F., and Lai, J. 2003. Redistribution of Na(V) 1.8 in uninjured axons enables neuropathic pain. J. Neurosci. 23, 158–166. Gordh, T., Sharma, H. S., Alm, P., and Westman, J. 1998. Spinal nerve lesion induces upregulation of neuronal nitric oxide synthase in the spinal cord. An immunohistochemical investigation in the rat. Amino Acids 14, 105–112. Gougat, J., Ferrari, B., Sarran, L., Planchenault, C., Poncelet, M., Maruani, J., Alonso, R., Cudennec, A., Croci, T., Guagnini, F., Urban-Szabo, K., Martinolle, J. P., Soubrie´, P., Finance, O., and Le Fur, G. 2004. SSR240612 [(2R)-2-[((3R)-3-(1,3-benzodioxol-5-yl)-3-[[(6-methoxy-2naphthyl)sulfonyl]amino]propanoyl)amino]-3-(4-[[2R,6S)2,6-dimethylpiperidinyl]methyl]phenyl)-N-isopropyl-Nmethylpropanamide hydrochloride], a new nonpeptide antagonist of the bradykinin B1 receptor: biochemical and pharmacological characterization. J. Pharmacol. Exp. Ther. 309, 661–669. Gould, H. J., England, J. D., Soignier, R. D., Nolan, P., Minor, L. D., Liu, Z. P., Levinson, S. R., and Paul, D. 2004. Ibuprofen block changes in NaV1.7 and 1.8 sodium channels associated with complete Freund’s adjuvant-induced inflammation in rat. J. Pain 5, 270–280. Gracely, R., Lynch, S., and Bennett, G. 1992. Painful neuropathy: altered central processing, maintained dynamically by peripheral input. Pain 51, 175–194. Grazzini, E., Puma, C., Roy, M. O., Yu, X. H., O’Donnell, D., Schmidt, R., Dautry, S., Ducharme, J., Perkins, M., Panetta, R., Laird, J. M. A., Ahmad, S., and Lembo, P. M. 2004. Sensory neuron-specific receptor activation elicits central and peripheral nociceptive effects in rats. Proc. Nat. Acad. Sci. U. S. A. 101, 7171–7180. Grunke, M. and Schulze-Koops, H. 2006. Successful treatment of inflammatory knee osteoarthritis with tumour necrosis factor blockade. Annu. Rheum. Dis. 65, 555–556.

Gutierrez, T., Nackley, A. G., Neely, M. H., Freeman, K. G., Edwards, G. L., and Hohmann, A. G. 2003. Effects of neurotoxic destruction of descending noradrenergic pathways on cannabinoid antinociception in models of acute and tonic nociception. Brain Res. 987, 176–185. Hains, B. C., Saab, C. Y., Klein, J. P., Craner, M. J., and Waxman, S. G. 2004. Altered sodium channel expression in second-order spinal sensory neurons contributes to pain after peripheral nerve injury. J. Neurosci. 24, 4832–4839. Halliday, D. A., Zettler, C., Rush, R. A., Scicchitano, R., and McNeil, J. D. 1998. Elevated growth factor levels in the synovial fluid of patients with inflammatory joint disease. Neurochem. Res. 23, 919–922. Handy, R. L. and Moore, P. K. 1998. A comparison of the effects of L-NAME, 7NI and l-NIL on carrageenan induced hindpaw edema and NOS activity. Br. J. Pharmacol. 12, 1119–1126. Hao, J. X. and Xu, X. J. 1996. Treatment of a chronic allodynia-like response in spinally injured rats: effects of systemically administered nitric oxide synthase inhibitors. Pain 66, 313–319. Hao, S., Mata, M., Wolfe, D., Glorioso, J. C., and Fink, D. J. 2005. Gene transfer of glutamic acid decarboxylase reduces neuropathic pain. Ann. Neurol. 57, 914–918. Harvey, R. J., Depner, U. B., Wassle, H., Ahmadi, S., Heidl, C., Reinold, H., Smart, T. G., Harvey, K., Schultz, B., AboSalem, O. M., Zimmer, A., Poisbeau, P., Welzl, H., Wolfer, D. P., Betz, H., Zeilhofer, H. U., and Muller, U. 2004. GlyR3: an essential target for spinal PGE2-mediated inflammatory pain sensitization. Science 304, 884–887. Hefti, F. F., Rosenthal, A., Walicka, P. A., Wyatt, S., Vergara, G., Shelton, D. L., and Davis, A. M. 2005. Novel class of pain drug based on antagonism of NGF. Trends Pharmacol. Sci. 27, 85–91. Hogestatt, E. D., Jonsson, B. A. G., Ermund, A., Andersson, D. A., Bjork, H., Alexander, J. P., Cravatt, B. J., Basbaum, A. I., and Zygmunt, P. M. 2005. Conversion of acetaminophen to bioactive N-acylphenolamine AM4040 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. J. Biol. Chem. 280, 31405–31412. Hohmann, A. G. and Herkenham, M. 1999. Cannabinoid receptors undergo axonal flow in sensory nerves. Neuroscience 92, 1171–1175. Hohmann, A. G., Suplita, R. L., Bolton, N. M., Neely, M. H., Fegley, D., Mangieri, R., Krey, J. F., Walker, J. M., Holmes, P. V., Crystal, J. D., Duranti, A., Tonini, A., Mor, M., Tarzia, G., and Piomelli, D. 2005. An endocannabinoid mechanism for stress-induced analgesia. Nature 435, 1108–1112. Holthusen, H. and Arndt, J. O. 1994. Nitric oxide evokes pain in humans on intracutaneous injection. Neurosci. Letts. 165, 71–74. Honore, P., Kage, K., Mikusa, J., Watt, A. T., Johnston, J. F., Wyatt, J. R., Faltynek, C. R., Jarvis, M. F., and Lynch, K. 2002. Analgesic profile of intrathecal P2X(3) antisense oligonucleotide treatment in chronic inflammatory and neuropathic pain states in rats. Pain 99, 11–19. Honore, P., Rogers, S. D., Schwei, M. J., Salak-Johnson, J. L., Luger, N. M., Sabino, M. C., Clohisy, D. R., and Mantyh, P. W. 2000. Murine models of inflammatory, neuropathic and cancer pan each generate a unique set of neurochemical changes in the spinal cord and sensory neurons. J. Neurosci. 98, 585–598. Hudson, L. J., Bevan, S., McNair, K., Gentry, C., Fox, A., Kuhn, R., and Winter, J. 2002. Metabotropic glutamate receptor 5 upregulation in A-fibers after spinal nerve injury: 2-Methyl-6-(phenylethynyl)-pyridine (MPEP) reverses the induced thermal hyperalgesia. J. Neurosci. 22, 2660–2668. Hunt, S. P. and Mantyh, P. 2001. The molecular dynamics of pain control. Nat. Rev. 2, 83–91.

Pharmacological Modulation of Pain Hurley, R. W. and Hammond, D. L. 2000. The analgesic effects of supraspinal mu and delta opioid receptor agonists are potentiated during persistent inflammation J. Neurosci. 20, 1249–1259. Ibrahim, M. M., Porreca, F., Lai, J., Albrecht, P. J., Rise, F. L., Khodorova, A., Davar, G., Makriyannis, A., Vanderah, T. W., Mata, H. P., and Malan, T. P. 2005. CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc. Natl. Acad. Sci. U. S. A. 102, 3093–3098. Ibuki, T., Hama, A. T., Wang, X. T., Pappas, G. D., and Sagen, J. 1997. Loss of GABA-immunoreactivity in the spinal dorsal horn of rats with peripheral nerve injury and promotion of recovery by adrenal medullary grafts. Neuroscience 76, 845–858. Ikeda, H., Heinke, B., Ruscheweyh, R., and Sandkuhler, J. 2003. Synaptic plasticity in spinal lamina 1 projection neurons that mediate hyperalgesia. Science 299, 1237–1240. Jakobsson, P. J., Thoen, S., Morgenstern, R., and Samuelsson, B. 1999. Identification of human prostaglandin E synthase: a microsomal, glutathione-dependent, inducible enzyme, constituting a potential novel drug target. Proc. Natl. Acad. Sci. U. S. A. 96, 7220–7225. Jang, J. H., Kim, D. W., Sang Nam, T., Se Paik, K., and Leem, J. W. 2004. Peripheral glutamate receptors contribute to mechanical hyperalgesia in a neuropathic pain model of the rat. Neuroscience 128, 169–176. Jarvis, M. F., Burgard, E. C., McGaraughty, S., Honore, P., Lynch, K., Brennan, T. J., Subieta, A., van Biesen, T., Cartmell, J., Bianchi, B., Niforatos, W., Kage, K., Yu, H. X., Mikusa, J., Wismer, C. T., Zhu, C. Z., Chu, K., Lee, C. H., Stewart, A. O., Polakowski, J., Cox, B. F., Kowaluk, E., Williams, M., Sullivan, J., and Faltynek, C. 2002. A-3174919, a novel potent and selective non nucleotide antagonist of P2X(3) and P2X(2/3) receptors, reduces chronic inflammatory and neuropathic pain in the rat. Proc. Natl. Acad. Sci. U. S. A. 99, 17179–17184. Ji, R. R., Samad, T. A., Jin, S. X., Schmoll, R., and Woolf, C. J. 2002. P38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia. Neuron 36, 57–68. Karst, M., Salim, K., Burstein, S., Conrad, I., Hoy, L., and Schneider, U. 2003. Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain. JAMA 290, 1757–1762. Kastrup, J., Petersen, P., Dejgard, A., and Angelo, F. R. 1987. Intravenous lidocaine infusion – a new treatment of chronic painful diabetic neuropathy. Pain 28, 69–75. Kerr, B. J., Bradbury, E. J., Bennett, D. L., Trivedi, P. M., Dassan, P., French, J., Shelton, D. B., McMahon, S. B., and Thompson, S. W. 1999. Brain derived neurotrophic factor modulates nociceptive sensory neurone input and NMDAevoked responses in the rat spinal cord. J. Neurosci. 19, 5136–5149. Kim, C., Jun, K., Lee, T., Kim, S. S., et al., 2001. Altered nociceptive responses in mice deficient in the 1B subunit of the voltage dependent calcium channel. Mol. Cell Neurosci. 18, 235–245. Kim, C. H., Oh, Y., Chung, J. M., and Chung, K. 2002. Changes in three subtypes of tetrodotoxin sensitive sodium channel expression in the axotomized dorsal root ganglion in the rat. Neurosci. Letts. 323, 125–128. Krause, J. E., Chenard, B. L., and Cortright, D. N. 2005. Transient receptor potential ion channels for the discovery of pain therapeutics Curr. Opin. Inv. Drugs 6, 48–57. Kreitzer, A. C. and Regeher, W. G. 2002. Retrograde signaling by endocannabinoids. Curr. Opin. Neurobiol. 12, 324–330. Krishtal, O. 2003. The ASICs: signaling molecules? Modulators? TINS 26, 477–483.

815

LaBuda, C. J., Koblish, M., and Little, P. J. 2005. Cannabinoid CB2 receptor agonist activity in the hindpaw incision model of postoperative pain. Eur. J. Pharmacol. 527, 172–175. Lai, J., Hunter, J. C., and Porreca, F. 2003. The role of voltagegated sodium channels in neuropathic pain. Curr. Opin. Neurobiol. 13, 291–297. Laird, J. M. A., Garcı´a-Nicas, E., Delpire, E. J., and Cervero, F. 2004. Presynaptic inhibition and spinal pain processing in mice: a possible role of the NKCC1 cation-chloride cotransporter in hyperalgesia. Neurosci. Letts. 361, 200–203. Lane, N., Webster, L., Shiao-Ping, L., Gray, M., Hefti, F., and Walicke, P. 2005. RN624 (Anti-NGF) improves pain and function in subjects with moderate knee osteoarthritis: a phase I study. Arthritis Rheumat. 52, S461. Lee, D. H., Liu, X., Kim, H. T., Chung, K., and Chung, J. M. 1999. Receptor subtype mediating the adrenergic sensitivity of pain behavior and ectopic discharges in neuropathic Lewis rats. J. Neurophysiol. 81, 2226–2233. Lembo, P. M. C., Grazzini, E., Groblewski, T., O’Donnell, D., Roy, M. O., Zhang, J., Hoffert, C., Cao, J., Schmidt, R., Pelletier, M., Labarre, M., Gosselin, M., Fortin, Y., Banville, D., Shen, S. H., Strom, P., Payza, K., Dray, A., Walker, P., and Ahmad, S. 2002. Proenkephalin A gene products activate a new family of sensory neuron-specific GPCRs. Nat. Neurosci. 5, 201–209. Levy, D. and Zochodne, D. W. 2000. Increased mRNA expression of the B1 and B2 bradykinin receptors and antinociceptive effects of their antagonists in an animal model of neuropathic pain. Pain 86, 265–271. Levy, D., Kubes, P., and Zachodne, D. W. 2001. Delayed peripheral nerve degeneration, regeneration and pain in mice lacking inducible nitric oxide synthase. J. Neuropathol. Exp. Neurol. 60, 411–421. Liang, Y. F., Haake, B., and Reeh, P. W. 2001. Sustained sensitization and recruitment of rat cutaneous nociceptors by bradykinin and a novel theory of its excitatory action. J. Physiol. 532, 229–239. Lichtman, A. H., Leung, D., Shelton, C. C., Saghatelian, A., Hardouin, C., Boger, D. L., Cravatt, B. J. 2004. Reversible inhibitors of fatty acid amide hydrolase that promote analgesia: evidence for an unprecedented combination of potency and selectivity. J. Pharmacol. Exp. Ther. 311, 441–448. Lindenlaub, T. and Sommer, C. 2003. Cytokines in sural nerve biopsies from inflammatory and non-inflammatory neuropathies. Acta Neuropathol. 105, 593–602. Lindia, J. A., Kohler, M. G., Martin, W. J., and Abbadie, C. 2005. Relationship between sodium channel Nav1.3 expression and neuropathic pain behavior in rats. Pain 117, 145–153. Liu, J., Li, H., Bursten, S. H., Zurier, R. B., and Chen, J. D. 2003. Activation and binding of peroxisomal proliferator-activated receptor gamma by synthetic cannabinoid ajulemic acid. Mol. Pharmacol. 63, 983–992. Lu, B., Pang, P. T., and Woo, N. H. 2005. The Yin and Yang of neurotrophin action. Nat. Rev. Neurosci. 6, 603–614. Luo, Z. D., Calcutt, N. A., Higuera, E. S., Valder, C. R., Song, Y. H., Svensson, C. I., and Myers, R. R. 2002. Injury type-specific calcium channel alpha (2) delta-1 subunit upregulation in rat neuropathic pain models correlates with antiallodynic effects of gabapentin. J. Pharmacol. Exp. Ther. 303, 1199–1205. Ma, W., Zhang, Y., Bantel, C., and Eisenach, J. C. 2005. Medium and large injured dorsal root ganglion cells increase TRPV-1, accompanied by increased alpha2C-adrenoceptor co-expression and functional inhibition by clonidine. Pain 113, 386–394. Malan, T. P., Ibrahim, M. M., Lai, J., Vanderah, T. W., Makriyannis, A., and Porreca, F. 2003. CB2 cannabinoid

816 Pharmacological Modulation of Pain receptor agonists: pain relief without psychoactive effects?. Curr. Opin. Pharmacol. 3, 62–67. Malan, T. P., Mata, H. P., and Porreca, F. 2002. Spinal GABA(A) and GABA(B) receptor pharmacology in a rat model of neuropathic pain. Anesthesiology 96, 1161–1167. Mamet, J., Lazdunski, M., and Voilley, N. 2003. How nerve growth factor drives physiological and inflammatory expression of acid-sensing ion channels 3 in sensory neurons. J. Biol. Chem. 278, 48907–48913. Mantyh, P. W. and Yaksh, T. L. 2001. Sensory neurons are PARtial to pain. Nat. Med. 7, 772–773. Marceau, F., Hess, J. F., and Bachvarov, D. R. 1998. The B1 receptors for kinins. Pharmacol. Rev. 50, 357–386. Marsicano, G., Goodenough, S., Monory, K., Hermann, H., Eder, M., Cannich, A., Azad, S. C., Cascio, M., Ortega Gutierrez, S., Van der Stelt, M., Lopez-Rodriguez, M. L., Casanova, E., Schutz, G., Zieglgansberger, W., Di Marzo, V., Behl, C., and Lutz, B. 2003. CB1 cannabinoid receptors and on demand defense against excitotoxicity. Science 302, 84–88. Matthews, E. A. and Dickenson, A. H. 2001. Effects of spinally delivered N- and P-type voltage dependent calcium channel antagonists on dorsal horn neuronal responses in a rat model of neuropathy. Eur. J. Pharmacol. 415, 141–149. Matzner, O. and Devor, M. 1994. Hyperexcitability at sites of nerve injury depends on voltage sensitive – sodium channels. J. Neurophysiol. 72, 349–359. Meller, S. T., Pechman, P. S., Gebhart, G. F., and Maves, T. J. 1992. Nitric oxide mediates the thermal hyperalgesia produced in a model of neuropathic pain in the rat. Neuroscience 50, 7–10. Mense, S. 2004. Neurobiological basis for the use of botulinum toxin in pain therapy. J. Neurol. 251, S11–S17. Merskey, H., Loeser, J.D., and Dubner, R. (eds.) 2005. The Paths of Pain: 1975–2005. IASP Press. Millan, M. J. 1999. The induction of pain: an integrative review. Prog. Neurobiol. 57, 1–164. Miller, L. J., Fischer, K. A., Goralnick, S. J., Litt, M., Burleson, J. A., Albertsen, P., and Kreutzer, D. L. 2002. Nerve growth factor and chronic prostatis/chronic pelvic pain syndrome. Urology 59, 603–608. Milligan, E., Zapata, V., Schoeniger, D., Chacur, M., Green, P., Poole, S., Martin, D., Maier, S. F., and Watkins, L. R. 2005b. An initial investigation of spinal mechanisms underlying pain enhancement induced by fractalkine, a neuronally released chemokine. Eur. J. Neurosci. 22, 2775–2782. Milligan, E. D., Langer, S. J., Sloane, E. M., He, L., WieselerFrank, J., O’Connor, K., Martin, D., Forsayeth, J. R., Maier, S. F., Johnson, K., Chavez, R. A., Leinwand, L. A., and Watkins, L. R. 2005a. Controlling pathological pain by adenovirally driven spinal production of the anti-inflammatory cytokine, interleukin-10. Eur. J. Neurosci. 21, 2136–2148. Moore, A. K., Kohno, T., Karchewski, L. A., Scholz, J., Baba, H., and Woolf, C. J. 2002. Partial peripheral nerve injury promotes a selective loss of GABAergic inhibition in the superficial dorsal horn of the spinal cord. J. Neurosci. 22, 6724–6731. Nutt, J. G., Burchiel, K. J., Comella, C. L., Jankovic, J., Lang, A. E., Laws, E. R., Jr., Lozano, A. M., Penn, R. D., Simpson, R. K., Jr., Stacy, M., and Wooten, G. F. ICV GDNF Study Group. 2003. Implanted intracerebroventricular. Glial cell line-derived neurotrophic factor. Randomized, doubleblind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. Neurology 60, 69–73. Obata, K., Yamanaka, H., Kobayashi, K., Dai, Y., Mizushima, T., Katsura, H., Fukuoka, T., Tokunaga, A., and Noguchi, K. 2004. Role of mitogen-activated protein kinase activation in injured and intact primary afferent neurons for mechanical and heat hypersensitivity after spinal nerve ligation. J. Neurosci. 24, 10211–10222.

Oddiah, D., Anand, P., McMahon, S. B., and Rattray, M. 1998. Rapid increase of NGF, BDNF and NT3 mRNAs in inflamed bladder. Neuroreport 9, 603–608. Oh, S. B., Tran, P. B., Gillard, S. E., Hurley, R. W., Hammond, D. L., and Miller, R. J. 2001. Chemokines and glycoprotein 120 produce pain hypersensitivity by directly exciting primary nociceptive neurons. J. Neurosci. 21, 5027–5035. Ohtori, S., Takahashi, K., Moriya, H., and Myers, R. R. 2004. TNF-alpha and TNF-alpha receptor type 1 upregulation in glia and neurons after peripheral nerve injury: studies in murine DRG and spinal cord. Spine 29, 1082–1088. Okuse, K., Malik-Hall, M., Baker, M. D., Poon, W. Y., Kong, H., Chao, M. V., and Wood, J. N. 2002. Annexin II light chain regulates sensory neurone-specific sodium channel expression. Nature 417, 653–656. Olesen, J., Thomsen, L. L., and Iversen, H. 1994. Nitric oxide is a key molecule in migraine and other vascular headaches. Trend Pharmacol. Sci. 15, 149–153. Ottani, A., Leone, S., Sandrini, M., Ferrari, A., and Bertolinin, A. 2006. The analgesic activity of paracetamol is prevented by the blockade of cannabinoid CB1 receptors. Eur. J. Pharmacol. 531, 280–281. Owolabi, J. B., Rizkalla, G., Tehim, A., Ross, G. M., Riopelle, R. J., Kamboj, R., Ossipov, M., Bian, D., Wegert, S., Porreca, F., and Lee, DK. 1999. Characterization of antiallodynic actions ALE-0540, a novel nerve growth factor receptor antagonist, in the rat. J. Pharmacol. Exp. Ther. 289, 1271–1276. Pesquero, J. B., Araujo, R. C., Heppenstall, P. A., Stucjy, C. L., Silva, J. A., Walther, T., Oliveira, S. M., Pasquero, J. L., Paiva, A. C. M., Calixto, J. B., Lewin, G. R., and Bader, M. 2000. Hypoalgesia and altered inflammatory responses in mice lacking kinin B1 receptors. Proc. Natl. Acad. Sci. U. S. A. 97, 8140–8145. Petersen, M., Segond von Bachet, G., Heppelmann, B., and Kolzenburg, M. 1998. Nerve growth factor regulates the expression of bradykinin binding sites on adult sensory neurons via the neurotrophin p75. Neuroscience 83, 161–169. Pollock, J., McFarlane, S. M., Connell, M. C., Zehavi, U., Vandenabeele, P., MacEwan, D. J., and Scott, R. H. 2002. TNF-alpha receptors simultaneously activate Ca2þ mobilisation and stress kinases in cultured sensory neurons. Neuropharmacology 42, 93–106. Quartaroli, M., Fasdelli, N., Bettelini, L., Maraia, G., and Corsi, M. 2001. GV196771A, an NMDA receptor/glycine site antagonist, attenuates mechanical allodynia in neuropathic rats and reduces tolerance induced by morphine in mice. Eur. J. Pharmacol. 430, 219–227. Raghavendra, V., Tanga, F., Rutkowski, M. D., and DeLeo, J. A. 2003. Anti-hyperalgesic and morphine-sparing actions pf propentofylline following peripheral nerve injury in rats: mechanistic implications of spinal glia and proinflammatory cytokines. Pain 104, 655–664. Ramer, M. S., Bradbury, E. J., and McMahon, S. B. 2001. Nerve growth factor induces P2X(3) expression in sensory neurons. J. Neurochem. 77, 864–875. Rice, A. S. C., Farquhar-Smith, W. P., and Nagy, I. 2002. Endocannabinoids and pain: spinal and peripheral analgesia in inflammation and neuropathy. Prostaglandins Leukot. Essent. Fatty Acids 66, 243–256. Richardson, J. D., Kilo, S., and Hargreaves, K. M. 1998. Cannabinoids reduce hyperalgesia and inflammation via interactions with peripheral CB1 receptors. Pain 75, 111–119. Ro, L. S., Chen, S. T., Tang, L. M., and Jacobs, J. M. 1999. Effect of NGF and anti-NGF on neuropathic pain in rats following chronic constriction injury of the sciatic nerve. 79, 265–274.

Pharmacological Modulation of Pain Ross, R. A., Coutts, A. A., McFarlane, S. M., Anavi-Goffer, S., Irving, A. J., Pertwee, R. G., MacEwan, D. J., and Scott, R. H. 2001. Actions of cannabinoid receptor ligands on rat cultured sensory neurones: implications of antinociception. Neuropharmacology 40, 221–232. Rush, A. M., Craner, M. J., Kageyama, T., Dib-Haj, S. D., and Waxman, S. G. 2005. Contactin regulates the current density and axonal expression of tetrodotoxin-resistant but not tetrodotoxin- sensitive sodium channels in DRG neurons. Eur. J. Neurosci. 22, 39–49. Sachez-Baez, F., Carbonell, T., de Felipe, C., Perez-Paya, E., Belmote, C., Messeguer, A. and Ferrer-Motiel, A. 2002. Attenuation of thermal nociception and hyperalgesia by VR1 blockers. Proc. Natl. Acad. Sci. U. S. A. 99, 2374–2379. Saegusa, H., Kurihara, T., Zong, S., Kazuno, A., Matsuda, Y., Nonaka, T., Han, W., Toriyama, H., and Tanabe, T. 2001. Suppression of inflammation and neuropathic pain symptoms in mice lacking the N-type Ca2þ channel. EMBO J. 20, 2349–2356. Sagar, D. R., Kelly, S., Millns, P. J., O’Shaugnessey, C. T., Kendall, D. A., and Chapman, V. 2005. Inhibitory effects of CB1 and CB2 receptor agonist on responses of DRG neurons and dorsal horn neurons in neuropathic rats. Eur. J. Neurosci. 22, 371–379. Sah, D. W. H., Ossipov, M. H., and Porreca, F. 2003. Neurotrophic factors as novel therapeutics for neuropathic pain. Nat. Rev. Drug Disc. 2, 460–472. Sang, C. N., Hostetter, M. P., Gracely, R. H., Chappell, A. S., Schoepp, D. D., Lee, G., Whitcup, S., Caruso, R., and Max, M. B. 1998. AMPA/kainate antagonist LY293558 reduces capsaicin-evoked hyperalgesia but not pain in normal skin in humans. Anesthesiology 89, 1060–1067. Sarchielli, P., Alberti, A., Floridi, A., and Gallai, V. 2001. Levels of nerve growth factor in cerebrospinal fluid of chronic headache patients. Neurology 57, 132–134. Sato, J. and Perl, E. R. 1991. Adrenergic excitation of cutaneous pain receptors induced by peripheral nerve injury. Science 251, 1608–1610. Sawynok, J. 2003. Topical and peripherally acting analgesics. Pharmacol. Rev. 55, 1–20. Schafers, M., Marziniak, M., Sorkin, L. S., Yaksh, T. L., and Sommer, C. 2004. Cyclooxygenase inhibition in nerve-injury and TNF-induced hyperalgesia in the rat. Exp. Neurol. 185, 160–168. Schafers, M., Sorkin, L. S., Geis, C., and Shubayev, V. I. 2003a. Spinal ligation induces transient upregulation of tumor necrosis factor receptors 1 and 2 in injured and adjacent uninjured dorsal root ganglia of rat. Neurosci. Letts. 347, 179–182. Schafers, M., Svensson, C. I., Sommer, C., and Sorkin, L. S. 2003b. Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons. J. Neurosci. 23, 2517–2521. Scholz, J. and Woolf, C. J. 2002. Can we conquer pain? Nature Neurosci. 5, 1062–1065. Sevcik, M. A., Ghilardi, J. R., Peters, C. M., Lindsay, T. H., Halvorson, K. G., Jonas, BM, Kubota, K., Kuskowski, M. A., Boustany, L., Shelton, D. L., and Mantyh, P. W. 2005. AntiNGF therapy profoundly reduces bone cancer pain and the accompanying increase in markers for peripheral and central sensitisation. Pain 115, 128–141. Shelton, D. L., Zeller, J., Ho, W. H., Pons, J., and Rosenthal, A. 2005. Nerve growth factor mediates hyperalgesia and cachexia in auto-immune arthritis. Pain 116, 8–16. Shidoda, K., Hruby, V. J., and Porecca, F. 2006. Antihyperalgesic effects of loperamide in a model of rat neuropathic pain are mediated by peripheral -opioid receptors. Neurosci Letts. 411, 143–146.

817

Shinder, V., Govrin-Lippmann, R., Cohen, S., Belenky, M., Ilin, P., Fried, K., Wilkinson, H. A., and Devor, M. 1999. Structural basis of sympathetic-sensory coupling in rat and human dorsal root ganglia following peripheral nerve injury. J. Neurocytol. 28, 743–761. Shughrue, P. J., Ky, B., and Austin, C. P. 2003. Localization of B1 bradykinin receptors mRNA in the primate brain and spinal cord: an in situ hybridization study. J. Comp. Neurol. 46, 372–384. Sluka, K. A., Price, M. P., Breese, N. M., Stucky, C. L., Wemmie, J. A., and Welsh, M. J. 2003. Chronic hyperalgesia induced by repeated acid injections in muscle is abolished by loss of ASIC3, but not ASIC1. Pain 106, 229–239. Snutch, T. P. 2005. Targeting chronic and neuropathic pain: the N-type calcium channel comes of age. NeuroRx. 2, 662–670. Sokal, D. M., Elmes, S. J. R., Kendall, D. A., and Chapman, V. 2003. Intraplantar injection of anandamide inhibits mechanically-evoked responses of spinal neurons via activation of Cb2 receptors in anaesthetized rats. Neuropharmacology 45, 404–411. Sommer, C. and Kress, M. 2004. Recent findings on how proinflammatory cytokines cause pain: peripheral mechanisms in inflammatory and neuropathic hyperalgesia. Neurosci. Letts. 361, 184–187. Stein, C., Schafer, M., and Machelska, H. 2003. Attacking pain at its source: new perspectives on opioids. Nature Med. 9, 1003–1008. Stella, N. 2004. Cannabinoid signaling in glial cells. Glia 48, 267–277. Stewart, J. M. 2004. Bradykinin antagonists: discovery and development. Peptides 25, 527–732. Svenden, K. B., Jensen, T. S., and Bach, F. W. 2004. Does the cannabinoid dronabilon reduce central pain in multiple sclerosis? Randomized double blind placebo controlled crossover trial. BMJ 329, 253. Taniguchi, K., Shinjo, K., Mizutani, M., Shimada, K., Ishikawa, T., Menniti, F., and Nagahisa, A. 1997. Antinociceptive actions of CP-101,606, an NMDA receptor NR2B subunit antagonist. Br. J. Pharmacol. 12, 809–812. Theodosiou, M., Rush, R. A., Zhou, X. F., Hu, D., Walker, J. S., and Tracey, D. J. 1999. Hyperalgesia due to nerve damage: role of nerve growth factor. Pain 81, 245–255. Tracey, D. J., Cunningham, J. E., and Romm, M. A. 1995. Peripheral hyperalgesia in experimental neuropathy: mediation by alpha 2-adrenoreceptors on post-ganglionic sympathetic terminals. Pain 60, 317–327. Trebino, C. E., Stock, J. L., Gibbons, C. P., Naiman, B. M., Wachtmann, T. S., Umland, J. P., Pandher, K., Lapointe, J. M., Saha, S., Roach, M. L., Carter, D., Thomas, N. A., Durtschi, B. A., McNeish, J. D., Hambor, J. E. Jakobsson, P. J., Carty, T. J., Perez, J. R. and Audoly, L. P. 2003. Impaired inflammatory and pain responses in mice lacking an inducible prostaglandin E synthase. Proc. Natl. Acad. Sci. U. S. A. 100, 9044–9049. Tsuda, M., Shigemoto-Mogami, Y., Koizumi, S., Mizokoshi, A., Kohsaka, S., Salter, M. W., and Inoue, K. 2003. P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 424, 778–783. Urban, M. O., Hama, A. T., Bradbury, M., Anderson, J., Varney, M. A., and Bristow, L. 2003. Role of metabotropic glutamate receptor subtype 5 (mGluR5) in the maintenance of cold hypersensitivity following a peripheral mononeuropathy in the rat. Neuropharmacology 44, 983–993. Valenzano, K. J., Tafesse, L., Lee, G., Harrison, J. E., Bulet, J. M., Gottshall, S. L., Mark, L., Pearson, M. S., Miller, W., Shan, S., Rabadi, L., Rotshteyn, Y., Chaffer, S. M.,

818 Pharmacological Modulation of Pain Turchin, P. I., Elsmore, D. A., Toth, M., Koetzner, L., and Whiteside, G. T. 2005. Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy. Neuropharmacology 48, 658–672. Vellani, V., Mappleback, S., Moriondo, A., Davis, J. B., and McNaughton, P. A. 2001. Protein kinase C activation gating of the vanilloid receptor VR1 by capsaicin, protons, heat and anandamide. J. Physiol. 534, 813–825. Valleni, V., Zachrisson, O., and McNaughton, P. A. 2004. Functional bradykinin B1 receptors are expressed in nociceptive neurons and are upregulated by the neurotrophin GDNF. J. Physiol. 560, 391–401. Veneroni, O., Maj, R., Calbresi, M., Faravelli, L., Farielo, R. G., and Salvati, P. 2003. Anti-allodynic effect of NW-1029, a novel Na channel blocker, in experimental animal models of inflammatory and neuropathic pain. Pain 102, 17–25. Vergnolle, N., Ferazzini, M., D’Andrea, M. R., Buddenkotte, J., and Steinhoff, M. 2003. Proteinase-activated receptors: novel signals for peripheral nerves. Trends Neurosci. 26, 496–500. Wade, D. T., Robson, P., House, H., Makela, P., Aram, J. A. 2003. Preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clin. Rehabil. 17, 21–29. Walker, K., Bowes, M., Panesar, M., Davis, A., Gentry, C., Kesingland, A., Gasparini, F., Spooren, W., Stoehr, N., Pagano, A., Flor, P. J., Vranesic, I., Lingenhoehl, K., Johnson, E. C., Varney, M., Urban, L., and Kuhn, R. 2001. Metabotropic glutamate receptor subtype 5 (mGlu5) and nociceptive function. I. Selective blockade of mGlu5 receptors in models of acute, persistent and chronic pain. Neuropharmacology 40, 1–9. Wallace, M. S., Rowbotham, M. C., Katz, N. P., Dworkin, R. H., Dotson, R. M., Galer, B. S., Rauck, R. L., Backonja, M. M., Quessy, S. N., and Meisner, P. D. 2002. A randomized, double blind, placebo-controlled trial of a glycine antagonist in neuropathic pain. Neurology 59, 1694–1700. Water, L., Franklin, A., Witting, A., Wade, C., Xie, Y., Kunos, G., Mackie, K., and Stella, N. 2003. Nonpsychotropic cannabinoid receptors regulate microglial cell migration. J. Neurosci. 23, 1398–1405. Watkins, L. R. and Maier, S. 2002. Beyond neurons: evidence that immune and glial cells contribute to pathological pain states. Physiol. Rev. 82, 981–1011. Wei, P., Moskowitz, M. A., Boccalini, P., and Kontos, H. A. 1992. Calcitonin gene-related peptide mediates nitroglycerin and sodium nitroprusside-induced vasodilatation in feline cerebral arterioles. Circulation Res. 70, 1313–1319. Welch, M. J., Purkiss, J. R., and Foster, K. A. 2000. Sensitivity of embryonic rat dorsal root ganglia neurons to Clostridium botulinum neurotoxins. Toxicon 38, 245–258. Whiteside, G. T., Boulet, J. M., and Walker, K. 2005a. The role of central and peripheral mu opioid receptors in inflammatory pain and edema: a study using morphine and DiPOA ([8-(3,3diphenyl-propyl)-4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]dec3-yl]-acetic acid). J. Pharmacol. Exp. Ther. 314, 1234–1240. Whiteside, G. T., Gottshall, S., Boulet, J. M., Chaffer, S. M., Harrison, J. E., Pearson, J. E., Turchin, P. I., Mark, L., Garrison, A. E., and Valenzano, K. J. 2005b. A role for cannabinoid receptors, but not endogenous opioids in the antinociceptive activity of the CB(2) selective agonist GW405833. Eur. J. Pharmacol. 528, 65–72. Woodbury, J., Zwick, M., Wang, S., Lawson, J. J., Caterina, M. J., Koltzenbury, M., Albers, K. M., Koerber, H. R., and Davis, B. M. 2004. Nociceptors Lacking TRPV1 and TRPV2 Have Normal Heat Responses. J. Neurosci. 24, 6410–6415.

Woolf, C. J. and Salter, M. W. 2000. Neuronal plasticity: increasing the gain in pain. Science 288, 1765–1769. Wotherspoon, G. and Winter, J. 2000. Bradykinin B1 receptor is constitutively expressed in the rat sensory nervous system. Neurosci. Letts. 294, 175–178. Wu, Z. Z., Chen, S. R., and Pan, H. L. 2005. Transient receptor potential vanilloid type 1 activation down-regulates voltagegated calcium channels through calcium dependent calcineurin in sensory neurons. J. Biol. Chem. 280, 18142–18151. Yaksh, T. L. 1997. Pharmacology and mechanisms of opioid analgesic activity. Acta Anaesth. Scand. 41, 94–111. Yaksh, T. L. 2006. Calcium channels as therapeutic targets in neuropathic pain. J. Pain 7, S13–S30. Yaksh, T. L., Dirig, D. M., Conway, C. M., Svensson, C., Luo, Z. D., and Isakson, P. C. 2001. The acute hyperalgesic action of non-steroidal, anti-inflammatory drugs and release of spinal prostaglandin E2 is mediated by the inhibition of constitutive spinal cyclooxygenase-2 (COX-2) but not COX1. J. Neurosci. 21, 5847–5853. Yao, H., Donnelly, D. F., Ma, C., and LaMotte, R. H. 2003. Upregulation of the hyperpolarization-activation cation current after chronic compression of the dorsal root ganglion. J. Neurosci. 23, 2069–2074. Xiao, W. H. and Bennett, G. J. 1995. Synthetic omegaconopeptides applied to the site of nerve injury suppress neuropathic pains in rats. J. Pharmacol. Exp. Ther. 274, 666–672. Zhang, J. M., Li, H., and Munir, M. A. 2004. Decreasing sympathetic sprouting in pathological sympathetic ganglia: a new mechanism for treating neuropathic pain using lidocaine. Pain 109, 143–149. Zhang, J. M., Hoffert, C., Vu, K., Groblewski, T., Ahmad, S., and O’Donnell, D. 2003. Induction of CB2 receptor expression in the rat spinal cord of neuropathic but not inflammatory chronic pain models. Eur. J. Neurosci. 17, 2750–2754. Zhu, C. Z., Wilson, S. G., Mikusa, J. P., Wismer, C. T., Gauvin, D. M., Lynch, J. J., 3rd., Wade, C. L., Decker, M. W., and Honore, P. 2004. Assessing the role of metabotropic glutamate receptor 5 in multiple nociceptive modalities. Eur. J. Pharmacol. 506, 107–118. Zweifel, L. S., Kuruvilla, R., and Ginty, D. D. 2005. Functions and mechanisms of retrograde neurotrophin signaling. Nat. Rev. Neurosci. 6, 615–625. Zylka, M. J., Rise, F. L., and Anderson, D. J. 2005. Topographically distinct epidermal nociceptive circuits revealed by axonal tracers targeted to Mrgprd. Neuron 45, 17–25.

Further Reading Abdulla, F. A. and Smith, P. A. 2001. Axotomy- and autotomyinduced changes in the excitability of rat dorsal root ganglion neurons. Am. J. Physiol. 85, 630–643. Cahill, C. M., Morinville, A., Hoffert, C., O’Donnell, D., and Beaudet, A. 2003. Up-regulation and trafficking of delta opioid receptor in a model of chronic inflammation: implications for pain control. Pain 101, 199–208. Davis, K. D., Treede, R. D., Raja, S. N., Meyer, R. A., and Campbell, J. N. 1991. Topical application of clonidine relieves hyperalgesia in patients with sympathetically maintained pain. Pain 47, 309–317. Dray, A. 1994. Tasting the inflammatory soup: the role of peripheral neurones. Pain Rev. 1, 153–171.

Pharmacological Modulation of Pain Ferreira, J., Campos, M. M., Pesquero, J. B., Araujo, R. C., Bader, M., and Calixto, J. B. 2001. Evidence for the participation of kinins in Freund’s adjuvant induced inflammatory and nociceptive responses in kinin B1 and B2 knockout mice. Neuropharmacology 41, 1006–1012. Hao, S., Mta, M., and Goins, W. 2003. Transgene-mediated enkephaline release enhances the effect of morphine and evades tolerance to produce a sustained antiallodynic effect. Pain 102, 135–142.

819

Kim, S. F., Huri, D. A., and Snyder, S. H. 2005. Inducible nitric oxide synthase binds, N-nitrosylates and activates cyclooxygenase-2. Science 310, 1966–1970. Kress, M., Izydorcyk, I., and Kuhn, A. 2001. N- and L-but not P/ Q-type calcium channels contribute to neuropeptide release from rat skin in vitro. Neuroreport 12, 867–870. Ossovskaya, V. S. and Bunnett, N. W. 2003. Protease-activated receptors: contribution to physiology and disease. J. Physiol. 552, 589–601.

This page intentionally left blank

54 Forebrain Opiates J-K Zubieta, University of Michigan, Ann Arbor, MI, USA ª 2009 Elsevier Inc. All rights reserved.

54.1 54.2 54.2.1 54.2.2 54.2.3 54.2.4 References

Introduction Endogenous Opioid Mechanisms in the Regulation of Pain m-Opioid-Receptor-Mediated Pain Processing -Opioid-Receptor-Mediated Processing d-Opioid-Receptor-Mediated Processing Opioid Receptor-like (ORL-1, NOP Receptor)-Mediated Processing

54.1 Introduction The initial studies on the neurobiology of pain and the discovery and understanding of the endogenous opioid systems have been historically intrinsically linked. In the 1960s, early research by Liebeskind and coworkers (Mayer, D. J. et al., 1971) demonstrated that the electrical stimulation of the ventral periaqueductal and periventricular gray produced profound analgesia, an effect that was independently observed by Reynolds D. V. (1969). During the same time, Tsou K. and Jang C. S. (1964) observed similar analgesic effects when morphine was microinjected into these locations. As a consequence, and before opioid receptors or their ligands had been isolated, Mayer D. J. et al. (1971) proposed that electrical stimulation induced analgesia by activating neural substrates that are involved in the blockage of pain and that were related to the analgesic action of morphine. These observations were followed by the subsequent use of electrical stimulation of the posterior aspect of the paraventricular nucleus of the thalamus for the treatment of pain (Richardson, D. E. and Akil, H., 1977a; 1977b). In 1973, Snyder and Pert published the first manuscript demonstrating the existence of opioid receptors (Pert, C. B. and Snyder, S. H., 1973), a development that was paralleled by the work of Eric Simon (Simon, E. J. et al., 1973) and Lars Terenius (Terenius, L., 1973). These initial findings were followed by the identification of met- and leu-enkephalin (Hughes, J. et al., 1975), -endorphin (Li, C. H. et al., 1976; Loh, H. H. et al., 1976), and the dynorphin peptides (Goldstein, A. et al., 1979). The 1990s saw the cloning of the opioid receptors delta () (Evans, C. J. et al., 1992; Kieffer, B. L. et al., 1992), mu

821 821 821 824 825 826 827

() (Chen, Y. et al., 1993; Thompson, R. C. et al., 1993), and kappa ( ) (Li, S. et al., 1993; Meng, F. et al., 1993). These are seven transmembrane domain G-proteincoupled receptors inhibiting adenyl cyclase and modulating calcium and potassium conductance.

54.2 Endogenous Opioid Mechanisms in the Regulation of Pain 54.2.1 m-Opioid-Receptor-Mediated Pain Processing This chapter will cover the regulation of pain by supraspinal opioid systems. Investigation of these mechanisms has been most extensive for those pertaining to the -opioid receptor, as this is the site of action of opiate analgesics and the receptor most consistently associated with pain suppression. Knockout animals devoid of these receptors display shorter latencies in the tail flick and hot plate tests, thought to involve spinal and supraspinal mechanisms, respectively, as well as a lack of morphine effects (Sora, I. et al., 1997). Its endogenous ligands include -endorphin, derived from the peptide precursor proopiomelanocortin (POMC), the recently described endomorphins 1 and 2, and in some circuits, the enkephalins (cleaved from the larger preproenkephalin precursor). POMC-containing neurons are located in the arcuate nucleus of the hypothalamus and periarcuate regions of the medial-basal hypothalamus, with a smaller group localized in the nucleus of the tractus solitarius of the medulla. Projections are extensive to the periventricular thalamus, septum, and amygdala, dorsally descending to the periaqueductal gray (PAG), midline 821

822 Forebrain Opiates

raphe, and reticular formation, and laterally to the anterior and lateral hypothalamus. Lighter innervation is observed in the medial portion of the nucleus accumbens and olfactory cortex (Khachaturian, H. et al., 1985). Animals devoid of a functioning POMC gene show a lack of naloxone-reversible analgesia induced by mild swim stress, but greater nonopioid (naloxone nonreversible) analgesic effects and normal effects of morphine. These data demonstrated the involvement of -endorphin in stress-induced analgesic responses, while also highlighting the presence of alternate mechanisms not mediated by -endorphin and -opioid receptors (Rubinstein, M. et al., 1996). In contrast to the narrow localization of POMCcontaining cells, enkephalinergic cells and projections are widely distributed, forming both local circuits and long projections, with similar distributions for met- and leu-enkephalin, albeit with a higher level of met-enkephalin in all regions. The highest concentrations of terminals with these peptides are encountered in the globus pallidus and central and lateral amygdala nuclei. Globus pallidus and ventral pallidal projections form part of the enkephalinergic striatopallidal pathway, with cell bodies arising primarily in the nucleus accumbens and to a lesser extent in the ventromedial hypothalamus. Cell bodies containing preproenkephalin are also encountered in the olfactory bulb, septal nuclei, bed nucleus of the stria terminalis, throughout the basal ganglia and in the cortex. Terminal densities are moderate to dense in the cingulate, piriform, and entorhinal cortex, anterior and periventricular thalamus, and preoptic hypothalamus (the latter from both local projections and terminals arising from the amygdala and periamygdalar area). Both cell bodies and rich local projections are encountered in the PAG, raphe, locus coeruleus, nucleus ambiguus, and nucleus of the solitary tract (Petrusz, P. et al., 1985). Enkephalin-deficient mice display large increases in the concentration of -opioid receptors in the globus pallidus, central nucleus of the amygdala, bed nucleus of the stria terminalis and substantia innominata, preoptic, medial and lateral hypothalamus, medial thalamus, PAG, raphe, nucleus ambiguus, and nucleus of the tractus solitarius, suggesting substantial enkephalinergic activity on -opioid receptors in these regions, with compensatory upregulation in the knockouts (Brady, L. S. et al., 1999). Enkephalin-deficient mice display reductions in supraspinal analgesic responses as measured with the hot-plate test and rapid nocifensive responses in the formalin assay, but unaltered spinal analgesic responses (tail-flick test) and stress-induced analgesia (Konig, M. et al., 1996).

Last, the most recently identified family of opioid peptides, the endomorphins 1 and 2, and in a manner similar to that for -endorphin, is synthesized in the brain only in hypothalamic cells (periventricular, arcuate, and ventromedial and dorsomedial nuclei), and project to pain-processing regions of the brainstem and pons (trigeminal tract, parabrachial nucleus, nucleus of the tractus solitarious, PAG, and locus coeruleus) as well as to midline thalamic nuclei and the amygdala. Besides the hypothalamic cell bodies, the only other known areas containing endomorphinpositive cell bodies include the nucleus of the tractus solitarius and the dorsal root ganglia. Consistent with its actions at -opioid receptors, intracerebroventricular administration of endomorphins induces profound analgesia that may be dissociated from the rewarding properties associated with -opioid receptor agonists (Zadina, J. E., 2002). Initial studies on the role of supraspinal -opioidreceptor-mediated antinociception focused on the role of the PAG and its connections with the rostroventral medulla (RVM). These are regions that, together with the dorsolateral pontine tegmentum, control nociceptive transmission via projections through the spinal cord dorsolateral funiculus to the dorsal horn laminae (Fields, H. L. and Basbaum, A. I., 1978). Much of the focus during the following decades was then dedicated to the understanding of the mechanisms underlying this modulation. Both pain facilitatory and inhibitory cells have been described at the level of the RVM (Moreau, J. L. and Fields, H. L., 1986; Heinricher, M. M. et al., 1987; Urban, M. O. and Smith, D. J., 1994; Zhuo, M. and Gebhart, G. E., 1997). -Opioid receptors, through the activation of enkephalinergic neurotransmission and GABA interneurons in the PAG and RVM (al-Rodhan, N. et al., 1990), increase the activity of inhibitory (off) cells reducing pain transmission. The administration of opioid receptor agonists systemically, or directly into the PAG or RVM, increases the activity of these off cells, with blockade of the activation of these neurons preventing morphine’s antinociceptive effects (Heinricher, M. M. et al., 1999). Not surprisingly, in view of these results, the possible role of -opioid neurotransmission beyond the PAG, RVM, and descending pathways into the spinal cord (e.g., supraspinal mechanisms) was thought to be less critical and mostly regarded as secondary to the analgesia mediated primarily by brainstem and spinal cord regions. Nevertheless, examination of the distribution of -opioid receptors, mRNA in the rodent (Mansour,

Forebrain Opiates

A. et al., 1995) and in vivo -opioid receptor availability in the human brain (Frost, J. et al., 1985) demonstrate a broad distribution of these sites in telencephalic areas. Administration of -opioid receptor agonists increases the blood flow of brain regions rich in -opioid receptors (cingulate, prefrontal, temporal and insular cortices, thalamus, hypothalamus, basal ganglia, amygdala, and brainstem) (Adler, L. J. et al., 1997; Schlaepfer, T. et al., 1998; Casey, K. et al., 2000; Wagner, K. J. et al., 2001), and reduces pain-induced activation in the thalamus (Casey, K. et al., 2000). Some of these areas, such as thalamic and hypothalamic nuclei, the central nucleus of the amygdala, the agranular insular cortex and lateral orbitofrontal cortex, have been associated with the suppression of pain behavior in animal models (Mayer, D. J. and Liebeskind, J. C., 1974; Yaksh, T. L. and Rudy, T. A., 1978; Bodnar, R. J. et al., 1980; Coffield, J. A. et al., 1992; Burkey, A. R. et al., 1996; Manning, B., 1998; Manning, B. and Franklin, K., 1998; Harte, S. et al., 2000; Manning, B. H. et al., 2001). However, the inhibition of pain signaling elicited by the activation of -opioid receptors in these supraspinal regions is thought to take place through their connections with the PAG, since inactivation of the PAG or the administration of opioid antagonists in this area abolishes the analgesic response. In turn, PAG-induced analgesia is blocked by -opioid receptor antagonists microinjected in the RVM, then reducing nociceptive transmission from the spinal cord (Kiefel, J. M. et al., 1993; Roychowdhury, S. M. and Fields, H. L., 1996). In view of the critical role of the PAG and RVM on -opioid-receptor-mediated antinociception, perhaps the question to be answered regarding the involvement of opioid systems in supraspinal nuclei is their respective role in the experience of pain as a complex phenomenon. Opioid neurotransmission is activated in humans during clinical pain, or experimental pain of some duration, as evidenced by enhancements in pain ratings after the administration of naloxone, a nonselective opioid receptor antagonist (Levine, J. et al., 1978). Conversely, experimental pain of relatively short duration (e.g., 43  C) (Catarina, M. J. et al., 2000). Accordingly, TRPV1-deficient knockout (KO) mice have obvious deficits in chemical and thermal heat nociception but normal reactions to noxious mechanical and to noxious cold stimuli.

878 Neuropathic Pain: Clinical

After partial nerve injury and in streptozotocininduced diabetic rats the lesion triggers a TRPV1 downregulation on many damaged afferents but a novel expression of TRPV1 on uninjured C and A fibers (Figure 2(b)) (Hudson, L. J. et al., 2001; Hong, S. and Wiley, J. W., 2005) which is likely involved in the development C nociceptor sensitization and the associated symptom of heat hyperalgesia. Recent studies also provides evidence for a an upregulation of TRPV1 in medium and large injured dorsal root ganglion cells (Ma, W. et al., 2005). However, TRPV1 does not appear to be the only transduction mechanism for heat sensitization after nerve injury. After partial sciatic nerve ligation, wild-type and TRPV1-null mice exhibited comparable persistent enhancement of mechanical and thermal nociceptive responses (Catarina, M. J. et al., 2000). In this context, a recent study examined strain differences in the normal sensitivity to noxious heat in mice. These differences reflect differential responsiveness of primary afferent thermal nociceptors to heat stimuli due to a genetic variance in CGRP expression and sensitivity (Mogil, J. S. et al., 2005). In taxol-induced small-fiber painful polyneuropathy TRPV4 which is normally activated by heat of more than 30  C seems to play a crucial role in producing taxol-induced mechanical hyperalgesia (Alessandri-Haber, N. et al., 2004). Investigations into temperature-sensitive excitatory ion channels also identified several coldsensing ion channels in peripheral neurons. The cold- and menthol-sensitive TRP channel (TRPM8) is activated within the range of 8–28  C (Patapoutian, A. et al., 2003) and sensitized by menthol. This receptor is expressed in around 10% of all afferent ganglion neurons of rats, primarily within small-diameter cells (McKemy, D. D. et al., 2002). TRPA1 is activated at lower temperatures and its exogenous ligand is cinnamaldehyde, a constituent of cinnamon oil, mustard oil, and horseradish. Peripheral nerve lesions have been shown to upregulate the expression of the latter cold-sensing ion channels in DRG cells of rats that developed cold allodynia (Obata, K. et al., 2005). Therefore, upregulation or gating of these channels after injury may lead to the peripheral sensitization of cold-sensitive C nociceptors, resulting in the sensory phenomenon of cold hyperalgesia. Besides these temperature-sensitive receptors experimental nerve injury also triggers the expression of functional 1 or 2 adrenoceptors on cutaneous afferent fibers, these neurons develop

adrenergic sensitivity (Figure 2(b)). I.v. epinephrine or physiological noradrenaline release after stimulation of sympathetic efferents that have regenerated into the neuroma can excite afferent nociceptors. After section and reanastomosis of peripheral nerves, electrical stimulation of the sympathetic trunk at physiological stimulus frequencies activates regenerated C nociceptors through an 1 adrenoceptor mechanism (Habler, H. J. et al., 1987). Furthermore, sympathetic activity can sensitize identified intact nociceptors following damage to the nerve in which they run via an 2 adrenoceptor mechanism (Sato, J. and Perl, E. R., 1991). The concept of a pathological coupling between sympathetic postganglionic fibers and afferent neurons via noradrenaline forms the conceptual framework for the therapeutic application of sympathetic blocks in certain pain syndromes, e.g., CRPS (Price, D. D. et al., 1998; Baron, R. et al., 1999b). There is increasing evidence that also uninjured fibers running in a partially lesioned nerve may take part in pain signaling (Wasner, G. et al., 2005). Uninjured fibers comingle with degenerating fibers in the same nerves. Products associated with Wallerian degeneration released in the vicinity of spared fibers (e.g., nerve growth factor (NGF)) may be the trigger for channel and receptor expression and may alter the properties of uninjured afferents (Hudson, L. J. et al., 2001; Wu, G. et al., 2001). Expression of sodium channels, TRPV1 receptors, adrenoreceptors and an increase of TNF- sensitivity has been shown to play a role in uninjured fibers adjacent to lesioned axons.

57.5.2

Central Sensitization

As a consequence of periphereal nociceptor hyperactivity also dramatic secondary changes in the spinal cord dorsal horn occur. Peripheral nerve injury leads to an increase in the general excitability of nociceptive and multireceptive spinal cord neurons (multiple synaptic input from C as well as A fibers, wide dynamic range neurons). This phenomenon is called central sensitization and is defined as an increased responsiveness of nociceptive neurons in the CNS to their normal afferent input. Central sensitization is manifested by at least three different modes: 1. increase of neuronal activity to noxious stimuli, 2. expansion of size of neuronal receptive fields, and 3. spread of spinal hyperexcitability to other segments.

Neuropathic Pain: Clinical

Central sensitization is initiated and maintained by activity in pathologically sensitized C fibers, which sensitize second-order spinal cord dorsal horn neurons by releasing glutamate acting on N-methylD-aspartic acid (NMDA) receptors and the neuropeptide substance P. Furthermore, central neuronal voltage-gated N-calcium channels located at the presynaptic sites on terminals of primary afferent nociceptors are involved in central sensitization by facilitation of the release of glutamate and substance P. This channel is overexpressed after peripheral nerve lesion and in rats with streptozotocin-induced diabetes (Luo, Z. D. et al., 2001). As a consequence of peripheral nerve lesion the dorsal horn neurons abnormally express HNav1.3 (Hains, B. C. et al., 2004) also enhancing central sensitization. Several intracellular cascades contribute to central sensitization, in particular the mitogen-activated protein kinase (MAPK) system ( Ji, R. R. and Woolf, C. J., 2001). If central sensitization is established, normally innocuous tactile stimuli become capable of activating spinal cord pain signalling neurons via A and A low-threshold mechanoreceptors (Tal, M. and Bennett, G. J., 1994). By this mechanism, light innocuous mechanical stimuli to the skin induces pain, i.e., punctuate and dynamic mechanical allodynia. Besides these dramatic changes in the spinal cord, sensitized neurons were also found in the thalamus and primary somatosensory cortex after partial peripheral nerve injury (Guilbaud, G. et al., 1992). There is increasing evidence that neuropathic pain is in part mediated by an interaction of nonneural spinal cord glia and nociceptive neurons (Figure 2(d)). In experimental pain states in animals, astrocytes and microglia are activated by neuronal signals including substance P, glutamate, and fractalkine (Wieseler-Frank, J. et al., 2005). Activation of glia by these substances in turn leads to the release of mediators that then act on other glia and also on central nociceptive neurons. These include proinflammatory cytokines and most likely also other neuroexcitatory compounds like glutamate. By this interaction central sensitization is augmented. While traditional therapies for pathological pain have focused on neuronal targets, glia might be new therapeutic targets. Some patients with neuropathic pain, in particular patients with CRPS characteristically report ‘extraterritorial’ and/or ‘mirror-’ image pain. The pain is experienced not only in the area of trauma but also in neighboring healthy tissues. In cases of mirror-image pain, the pain is perceived from the healthy,

879

corresponding part on the opposite side of the body. New data suggest that communication of activated astrocytes via gap junctions may mediate such spread of pain. 57.5.3 Central Disinhibition and Fascilitation Physiologically dorsal horn neurons receive a strong intraspinal inhibitory control by gamma-aminobutyric acid (GABA)-ergic interneurons. Partial peripheral nerve injury may promote a selective apoptotic loss of these GABA-ergic inhibitory neurons in the superficial dorsal horn of the spinal cord (Moore, K. A. et al., 2002), a mechanism which would further increases central sensitization. Furthermore, there is a novel mechanism of disinhibition following peripheral nerve injury. This mechanism involves a trans-synaptic reduction in the expression of the potassium chloride exporter KCC2 in lamina I nociceptive neurons. This induces a consequent disruption of the anion homeostasis in these dorsal horn neurons. The resulting shift in the transmembrane anion gradient caused normally inhibitory anionic synaptic currents to be excitatory. Due to this mechanism the release of GABA from normally inhibitory interneurons now exerts an excitatory action on lamina I neurons via GABAA receptors (Coull, J. A. et al., 2003). The changes in lamina I neurons is induced by brainderived neurotrophic factor (BDNF) released from activated spinal cord glia (Coull, J. A. et al., 2005). Dorsal horn neurons receive a powerful descending modulating control from supraspinal brainstem centers (inhibitory as well as faciliatory) (Vanegas, H. and Schaible, H. G., 2004) (Figures 2(a) and 2(c)). It was hypothesized that a loss of function in descending inhibitory serotonergic and noradrenergic pathway contributes to central sensitization and pain chronicity. This idea nicely explained the efficacy of serotonin and noradrenaline reuptake blocking antidepressants in neuropathic pain. However, in animals, mechanical allodynia after peripheral nerve injury was dependent upon tonic activation of descending pathways that facilitate pain transmission indicating that structures in the mesencephalic reticular formation – possibly the nucleus cuneiformis (NCF) and the periaqueductal gray (PAG) – are involved in central sensitization in neuropathic pain (Ossipov, M. H. et al., 2000). Interestingly, exactly the same brainstem structures were shown to be active in humans with allodynia using advanced functional MRI (fMRI) techniques

880 Neuropathic Pain: Clinical

(Zambreanu, L. et al., 2005). Because in most animal pain models descending facilitation and inhibition are triggered simultaneously, it will be important to elucidate why inhibition predominates in some neuronal pools and facilitation in others. 57.5.4 Pain

be fostered in the future. The solution of the problem neuropathic pain can only be unraveled in the human experiment, that is, in patients that really feel all components of this complex sensation of neuropathic pain.

Inflammation and Neuropathic

The connective tissue sheath of peripheral nerves is innervated by sensory fibers, the nervi nervorum, which enter the sheath with the nutrient blood vessels. Some of these fine diameter primary afferents are nociceptors (Zochodne, D. W., 1993). Nervi nervorum are a potential source of pain in diseases of peripheral nerve especially in those conditions with an inflammatory component. A different mechanism involves the production of inflammatory mediators at the site of nerve injury (local inflammation) that might be a critical factor in the cascade of events leading to neuropathic pain. Activated macrophages infiltrating from endoneurial blood vessels have been demonstrated in experimentally injured nerves (Sommer, C. and Myers, R. R., 1996) and also the dorsal root ganglia after nerve transection (Lu, X. and Richardson, P. M., 1993). Proinflammatory cytokines and in particular TNF released by activated macrophages can induce ectopic activity in injured but also in adjacent uninjured primary afferent nociceptors at the lesion site (Sorkin, L. S. et al., 1997) and thus is a potential cause of pain and hyperalgesia (Sommer, C. et al., 1998; Wagner, R. et al., 1998; Sommer, C., 2003; Marchand, F. et al., 2005).

57.6 Pathophysiological Mechanisms in Patients in Relation to Their Somatosensory Profile Although we have achieved enormous progress in the understanding of pathophysiological mechanisms generating neuropathic pain the most important question is whether it is possible to translate these concepts into the clinical situation. In the following section the findings of the correlation of mechanisms and somatosensory abnormalities in animal experiments will be matched by observations in human experimental and clinical pain conditions. In order to get more insight into the puzzle of neuropathic pain and even solve the therapeutic dilemma this type of translational research should

57.6.1 Peripheral Sensitization of Primary Afferent Neurons in Patients Microneurographic single-fiber recordings support the idea of peripheral sensitzation of primary afferent neurons in patients with painful nerve lesions by demonstrating abnormal activity and reduced thresholds in cutaneous afferents. Abnormal ectopic activity of myelinated mechanosensitive fibers were found in traumatic nerve lesions, entrapment neuropathies, or radiculopathies (Figure 3). Because the ectopic nerve activity correlated in intensity and time course to the perceived paresthesias it is likely that pathological activity in A fibers is the underlying mechanism of positive nonpainful sensations. Recordings from transected nerves in awake human amputees with phantom limb pain have demonstrated spontaneous ectopic activity as well as barrages of action potential firing in afferent A and C fibers projecting into the neuroma (Nystrom, B. and Hagbarth, K. E., 1981). Ectopic excitation occurred at multiple sites in damaged sensory neurons. Ongoing activity and mechanical sensitivity were recorded proximal to the nerve neuroma. Following local anesthetic blockade of the nerve distal to the recording site, impulses evoked by mechanical stimulation of the neuroma were abolished, but ongoing activity at the recording site continued, suggesting that this residual activity arose from the DRGs. As these patients suffered from spontaneous burning pain and electric shocklike sensations it is very likely that these symptoms are associated with ectopic firing in primary afferent C fibers. In few patients with characteristic burning pain and heat hyperalgesia microneurographic recordings have provided evidence for sensitized C nociceptors. In patients with erythromelalgia nociceptors displayed ongoing activity, which is normally not observed in nociceptors, and there was a sensitization of mechanically insensitive afferents to nonpainful tactile stimuli. These abnormalities were only present in nociceptive fibers, but not of the sympathetic unmyelinated fibers, as an indicator of a neuropathic process (Figure 4) (Orstavik, K. et al., 2003). In the

Neuropathic Pain: Clinical

881

(a)

Stimulation

Recording

1s

(b)

Intensity of paraesthesiae

5s

Straining during chin–chest manoeuvre Figure 3 Microneurographic multiunit recording from the sural nerve in a patient with a compression of the S1 spinal root by a herniated disc. (a) Excitation of mechanosensitive units in the receptive field by tactile stimulation (bars). (b) Straining and chin–chest maneuver-provoked paresthesiae and an ectopic discharge of afferent fibers originating from the compressed root. Adapted from Nordin, M., Nystro¨m, B., Wallin, U., and Hagbarth, K. E. 1984. Ectopic sensory discharges and paresthesiae in patients with disorders of peripheral nerve, dorsal roots and dorsal columns. Pain 20, 231–245. Elsevier Ltd.

autosomal dominantly inherited form of erythromelalgia a mutation in SCN9A was found, a gene that encodes the Nav1.7 sodium channel, leading to an altered firing pattern in afferent neurons (Dib-Hajj, S. D. et al., 2005). Hence, erythromelalgia is the first channelopathy associated with chronic pain. Several clinical observations also support the concept of sensitized nociceptors in PHN patients. About 30% of patients with PHN do not show any loss of sensory function in the affected extremity indicating that in these particular group of patients loss of neurons is minimal or absent. Accordingly, thermal sensory thresholds in their region of greatest pain are either normal or even decreased (heat hyperalgesia) by up to 2–4  C (Rowbotham, M. C. and Fields H. L., 1996; Pappagallo, M. et al., 2000). The decrease of heat pain perception thresholds is a well-known phenomenon of peripheral nociceptor sensitization. Using skin punch biopsy, it was shown that thermal sensitivity is directly correlated with density of cutaneous innervation in the area of most severe pain (Rowbotham, M. C. et al., 1996). Moreover, in PHN patients with heat hyperalgesia acute topical application of the vanilloid compound capsaicin (TRPV1 agonist), enhances pain, a sign that is indicative of an increased capsaicin sensitivity of nociceptors in the affected skin area and has been attributed to a sensitization of nociceptors as the driving element in some patients (Petersen, K. L. et al., 2000). Furthermore, in a similar group of

PHN patients cutaneous iontophoresis of histamine evoked a burning pain sensation whereas only itch was elicited in normal skin. Again, this phenomenon indicates that nociceptive neurons in the affected skin are abnormally sensitive to histamine (Baron, R. et al., 2001) probably due to expression of a novel receptor pattern. These observations suggest that spontaneous burning pain and heat hyperalgesia at least in part are associated with sensitization of primary afferent C fibers to TRPV1 agonists and histamine or with an altered firing pattern in these fibers due to abnormal sodium channels. Cutaneous hypersensitivity to cold, i.e., cold hyperalgesia, is particularly prominent in patients with posttraumatic neuralgias, some small-fiber polyneuropathies and chronic CRPS. Another condition of acute cold intolerance occurs after systemic injection of the cancer chemotherapeutic agent oxaliplatin, which is associated with paresthesiae and painful hypersensitivity aggravated by cold. Psychophysical studies of human volunteers using the topical menthol model suggest that sensitization of cold-sensitive nociceptors can produce cold hyperalgesia in normal volunteers (Wasner, G. et al., 2004). Peripheral sensitization also appears to occur in acute oxaliplatin-induced peripheral neuropathy (Lehky, T. J. et al., 2004). Therefore, it is likely that cold hyperalgesia in some patients is induced by sensitization of primary afferent coldsensitive nociceptors.

882 Neuropathic Pain: Clinical

57.6.2 Sensitization to Catecholamines in Patients

Control subject

1/8

0.125 Hz

1/4

Electrical stimulation

Patient with erthermalgia

0.25 Hz

1/2

0.5 Hz 0.25 Hz

1/4

530

560 590 500 530 Response latency (ms)

560

Figure 4 Microneurographic C fiber recordings from the peroneal nerve of a normal volunteer (left) and a patient suffering from erythromelalgia (right). The first trace shows the original nerve signal. The subsequent recordings are a falling leaf display in which each action potential is symbolized by a series of dots. Each row of dots represents the latency, at different electrical stimulation frequencies of the fiber, of its receptive field in the skin. Simultaneous recording of three afferent C fibers in a control subject shows two units with activitydependent latency increases at low-frequency stimulation, and one unit that displays latency increases when excitation frequency increases to 1 impulse per 2 s. These biophysical features are characteristic for mechanically insensitive and mechanically sensitive nociceptive C fibers, respectively. Stimulation of the receptive field with a 750-mN von Frey hair (arrow) excited only the mechanosensitive C nociceptor, as evidenced by a strong latency shift to electrical stimulation. Mechanically insensitive afferents are not activated by this stimulus. The right panel shows a C fiber recording from a patient with erythromelalgia. The unit had the biophysical properties of a mechanically insensitive C fiber but responded reproducibly to mechanical stimulation (arrows). This is consistent with the hypothesis that mechanically insensitive afferents become sensitized in erythromelalgia. An alternative explanation would be that mechanically sensitive nociceptors start to display a different pattern of activitydependent latency slowing in this disease. Adapted from Orstavik, K., Weidner, C., Schmidt, R., Schmelz, M., Hilliges, M., Jorum, E., Handwerker, H. and Torebjork, E. 2003. Pathological C-fibres in patients with a chronic painful condition. Brain 126, 567–578. Copyright 2003 Oxford University Press.

Several clinical observations support the idea that nociceptors acquire a sensitivity to catecholamines that permits an abnormal excitation by either noradrenaline or by circulating catecholamines. This chemical sensitization makes the nociceptors susceptible for noradrenaline released from efferent sympathetic fibers in the periphery. The consecutive pathological sympathetic–afferent coupling forms the conceptual framework for sympathetically maintained pain states. Noradrenergic sensitivity has been described in several human neuropathies and suggests that the ongoing pain can be caused or maintained by the sympathetic nervous system in selected patients: In amputees, perineuromal administration of physiological doses of norepinephrine induces intense pain as compared with saline injections (Raja, S. N. et al., 1998). Intraoperative stimulation of the sympathetic chain induces an increase of spontaneous pain in patients with causalgia (CRPS II) but not in patients with hyperhidrosis. In PHN, application of norepinephrine into a symptomatic skin area increased spontaneous pain and dynamic mechanical hyperalgesia (Choi, B. and Rowbotham, M. C., 1997). In CRPS II and posttraumatic neuralgias, intracutaneous norepinephrine rekindles pain and hyperalgesia that had been relieved by sympathetic blockade. Also intradermal norepenephrine, in physiologically relevant doses, was demonstrated to evoke greater pain in the affected regions of patients with sympathetically maintained pain (SMP) than in the contralateral unaffected limb, and in control subjects (Ali, Z. et al., 2000). Because noradrenaline-induced pain occurs during a differential blockade of myelinated fibers, unmyelinated fibers appear to signal sympathetically maintained pain (Torebjork, E. et al., 1995). We performed a study in patients with CRPS I using physiological stimuli of the sympathetic nervous system (Baron, R. et al., 2002). Cutaneous sympathetic vasoconstrictor outflow to the painful extremity was experimentally activated to the highest possible physiological degree by whole body cooling. During the thermal challenge the affected extremity was clamped to 35  C in order to avoid thermal effects at the nociceptor level. The intensity as well as area of spontaneous pain and mechanical allodynia (dynamic and punctate) increased significantly in patients that had been classified as having SMP by positive sympathetic blocks but not in SIP

Neuropathic Pain: Clinical

patients (Figure 5). The experimental setup used in the latter study selectively alters sympathetic cutaneous vasoconstrictor activity without influencing other sympathetic systems innervating the

extremities, i.e., piloarrector, sudomotor, and muscle vasoconstrictor neurons. Therefore, the interaction of sympathetic and afferent neurons measured here is likely to be located within the skin as

(a)

Skin blood flow (PU)

883

Affected limb

300

200

100 Unaffected limb

Skin temperature (°C)

(b)

Affected limb 34

29

24

Unaffected limb 0

(c)

40

80

High sympathetic activity

0

40

80

Low sympathetic activity

Dynamic mechanical hyperalgesia

Figure 5 Experimental modulation of cutaneous sympathetic vasoconstrictor neurons by physiological thermoregulatory reflex stimuli in 13 complex regional pain syndrome (CRPS) patients. With the help of a thermal suit, whole-body cooling and warming was performed to alter sympathetic skin nerve activity. The subjects were lying in a suit supplied by tubes, in which running water of 12  C and 50  C, respectively (inflow temperature) was used to cool or warm the whole body. By these means sympathetic activity can be switched on and off. (a) High sympathetic vasoconstrictor activity during cooling induces considerable drop in skin blood flow on the affected and unaffected extremity (laser Doppler flowmetry). Measurements were taken at 5-min intervals (mean SD). (b) On the unaffected side, a secondary decrease of skin temperature was documented. On the affected side, the forearm temperature was clamped at 35  C by a feedback-controlled heat lamp to exclude temperature effects on the sensory receptor level. Measurements were taken at 5-min intervals (mean SD). (c) Effect of cutaneous sympathetic vasoconstrictor activity on dynamic mechanical hyperalgesia in one CRPS patient with sympathetically maintained pain (SMP). Activation of sympathetic neurons (during cooling) leads to a considerable increase of the area of dynamic mechanical hyperalgesia. From Baron, R., Schattschneider, J., Binder, A., Siebrecht, D. and Wasner, G. 2002. Relation between sympathetic vasoconstrictor activity and pain and hyperalgesia in complex regional pain syndromes: a case–control study. Lancet 359, 1655–1660, with permission.

884 Neuropathic Pain: Clinical

predicted by the pain-enhancing effect of intracutaneous norepinephrine injections (Ali, Z. et al., 2000). Interestingly, the relief of spontaneous pain after sympathetic blockade was more pronounced than changes in spontaneous pain that could be induced experimentally by sympathetic activation. One explanation for this discrepancy might be that a complete sympathetic block affects all sympathetic outflow channels projecting to the affected extremity. It is very likely that in addition to a coupling in the skin, a sympathetic–afferent interaction may also occur in other tissues, in particular in the deep somatic domain such as bone, muscle, or joints. Supporting this view, especially these structures are extremely painful in some cases with CRPS (Baron, R. and Wasner, G., 2001). Furthermore, there may be patients who are characterized by a selective or predominant sympathetic–afferent interaction in deep somatic tissues sparing the skin (Wasner, G. et al., 1999). In summary, it is likely that sympathetically maintained pain is a consequence of an adrenergic sensitization of C nociceptors.

57.6.3

Central Sensitization in Patients

One hallmark of central sensitization of spinal cord neurons in animals is that activity in A fiber mechanoreceptors is allowed to gain access to the nociceptive system and induces pain. These phenomena are called mechanical allodynia or hyperalgesia. Mechanical hypersensitivity is a common phenomenon in neuropathic pain states in patients. There are several lines of evidence that also in patients central mechanisms contribute to these sensory phenomena. Two distinct types have been described in patients, dynamic mechanical and pinprick mechanical hypersensitivity. There is consensus that dynamic mechanical allodynia is signaled out of the skin by afferent mechanoreceptors with large myelinated axons that normally encode nonpainful tactile stimuli: 1. Reaction time measurements show dynamic mechanical allodynia in patients to be signaled by afferents with conduction velocities appropriate for large myelinated axons (Lindblom, U. and Verrillo, R. T., 1979; Campbell, J. N. et al., 1988), 2. transcutaneous or intraneural stimulation of nerves innervating the allodynic skin can evoke pain at stimulus intensities which only produce

tactile sensations in healthy skin (Gracely, R. H. et al., 1992; Price, D. D. et al., 1992), and 3. using differential nerve blocks dynamic allodynia is abolished at time points when tactile sensations is lost, but other modalities remain unaffected (Campbell, J. N. et al., 1988; Ochoa, J. L. and Yarnitsky, D., 1993). Therefore, patients with dynamic mechanical allodynia would be expected to have central sensitization as their underlying mechanism. Hyperalgesia to pinprick stimuli, typically elicited by probing of the skin with a stiff von Frey hair is distinct from dynamic mechanical allodynia because of its different spatial and temporal profile and the fact that it is signaled by nonsensitized, heat-insensitive, A nociceptors. Notably, in many neuropathic pain patients the mechanically sensitive skin area expands widely into the secondary zone, i.e., the area not affected by the primary nerve lesion, which is also indicative for CNS mechanisms involved. Furthermore, the area of secondary mechanical hypersensitivity is a dynamic phenomenon. In PHN patients with signs of peripheral nociceptor sensitization (heat hyperalgesia, see above) cutaneous capsaicin application into the primary skin area leads to an increase of the allodynic zone into previously nonallodynic and nonpainful skin that had normal sensory function and cutaneous innervation. These observations support the hypothesis that allodynia in a subgroup of PHN patients is a form of chronic secondary hyperalgesia dynamically maintained by input from intact and possibly sensitized (‘irritable’) primary afferent nociceptors to a sensitized CNS (Fields, H. L. et al., 1998; Petersen, K. L. et al., 2000). Because central sensitization involves the NMDA receptor, the fact that the NMDA receptor antagonist ketamine relieves some neuropathic pain disorders further supports the concept of central sensitization. Besides these dramatic changes in the spinal cord, there is now evidence that higher centers of the neuraxis demonstrate an increased excitability as well as fundamental changes in the somatosensory representation. Magnetic encephalography (MEG), positron emission tomography (PET), and fMRI studies revealed cortical changes in patients with phantom limb pain, CRPS, and central pain syndromes (Flor, H. et al., 1995; Willoch, F. et al., 2000; Pleger, B. et al., 2004; Willoch, F. et al., 2004; Maihofner, C. et al., 2005a) as well as experimental pain models (Baron, R. et al., 1999a; Baron, R. et al.,

Neuropathic Pain: Clinical

2000). Interestingly, these changes correlated with the intensity of the perceived pain and disappeared after successful treatment of the pain (Maihofner, C. et al., 2004; Pleger, B. et al., 2005).

57.6.4 Central Disinhibition Leading to Cold Hyperalgesia Cutaneous hypersensitivity to cold, i.e., cold hyperalgesia is particularly prominent in patients with posttraumatic neuralgias, some polyneuropathies, and chronic CRPS. Some observations in neuropathic pain patients point to central disinhibition as the underlying mechanism in a subgroup of patients. Cold stimuli are usually transmitted centrally by cold-sensitive A fibers, whereas cold pain is conveyed via nociceptive cold-sensitive C fibers. In patients with polyneuropathies a disproportionate loss of A axons and relative sparing of C fibers have been described (Ochoa, J. L. and Yarnitsky, D., 1994). These patients suffer from the so-called triple cold syndrome (CCC syndrome): cold hypoesthesia in combination with cold hyperalgesia and a cold skin. A selective damage of cold-sensitive A fibers leads to a lack of inhibition (disinhibition) on C nociceptors transmission normally exerted by concomitant activation of myelinated cold A fibers. This mechanism of a central interaction between cold specific afferents and nociceptors would nicely explain the combination of cold hyperalgesia and cold hypoesthesia in the above patients. Furthermore, it is suggested to play a crucial role in central pain syndromes after infarction of the dorsolateral thalamus with cold hyperalgesia and paradoxical heat sensation. In these patients the lesion in the lateral thalamus might disinhibit the nociceptive system projecting through the medial thalamus. Recently, direct evidence was provided for the central disinhibhition theory of cold hyperalgesia in an experimental pain model in humans. Selective A fiber block induces the symptom combination of cold hyperalgesia and cold hypoesthesia and therefore mimics the situation in polyneuropathy patients with A fiber degeneration. With fMRI the disinhibition of the medial nociceptive system (medial thalamus, anterior cingulate cortex (ACC), and frontal cortices) could be demonstrated. Thus, a loss of peripheral A fiber function disinhibits the nociceptive system centrally leading to cold hyperalgesia.

885

This is an entirely different mechanism as compared with the peripheral sensitization process of cold-sensitive C nociceptors described above leading to the same somatosensory phenomenon, cold hyperalgesia.

57.6.5 Deafferentation: Hyperactivity of Central Pain Transmission Neurons The above data convincingly support a role for sensitization mechanisms in the peripheral as well as the CNS in the generation of neuropathic pain. However, in some patients there is a profound cutaneous deafferentation of the painful area. Up to 60% of PHN patients show considerable signs of neuronal degeneration and loss of sensory function within the affected tissues. Interestingly, some of these patients still suffer from severe dynamic mechanical allodynia although the function of nociceptors is diminished or absent in the same skin area (Wasner, G. et al., 2005). Punch skin biopsies and the anti-PGP 9.5 antibody, a panaxonal marker, were used in PHN patients and zoster patients without pain to quantify sensory nerve endings in the affected skin and compared the numbers with the homologous contralateral site (Rowbotham, M. C. et al., 1996; Oaklander, A.L., 1998; Oaklander, A.L., 2001). A severe loss could be demonstated on the affected side (20% as compared with the controls). Neurite loss was more prominent in the epidermis than in the dermis. Furthermore, the PHN group also had lost half of the neurites in the contralateral epidermis whereas distant areas where unaffected. However, these contralateral changes could not be observed with QST or axon reflex measurements (Baron, R. and Saguer, M., 1994). Functional studies support the concept of degeneration of cutaneous C nociceptors. By using these C fiber axon reflex reactions it is possible to objectively assess cutaneous C fiber function in the human skin. In some patients the histamine evoked axon reflex vasodilatation and flare size were impaired or abolished in skin regions with intense dynamic allodynia (Baron, R. and Saguer, M., 1993). Similarly, during capsaicin stimulation, a subgroup did not experience worsening of pain (Petersen, K. L. et al., 2000). Using quantitative sensory testing (QST) some chronic PHN patients have extremely high thermal thresholds in areas with marked dynamic allodynia (Nurmikko, T. and Bowsher, D., 1990; Nurmikko, T. et al., 1994; Choi, B. and Rowbotham, M. C.,

886 Neuropathic Pain: Clinical

1997). Thus, there is a subset of PHN patients with pain and loss of cutaneous C nociceptor function. Assuming that the DRG cells and the central afferent connections are lost in such patients, their pain must be the result of intrinsic CNS changes. In animal studies, following complete primary afferent loss of a spinal segment, many dorsal horn cells begin to fire spontaneously at high frequencies (Lombard, M. C. and Larabi, Y., 1983; Fields, H. L. et al., 1998). There is some evidence that a similar process may underlie the pain that follows extensive denervating injuries in human. Recordings of spinal neuron activity in a pain patient whose dorsal roots were injured by trauma to the cauda equina revealed high-frequency regular and paroxysmal bursting discharges (Loeser, J. D. et al., 1967). That patient complained of spontaneous burning pain in a skin region that was anesthetic by the lesion (anesthesia dolorosa). Thus, extensive degeneration of primary afferents associated with severe somatosensory deficits points to an increased excitability of deafferented central neurons as underlying mechanism. 57.6.6

Inflammation in Patients

In patients with inflammatory demyelinating neuropathies such as acute Guillain–Barre´ syndrome or vasculitic neuropathies deep proximal aching pain in addition to paroxysmal types of pains is a characteristic phenomenon. Accordingly, COX2 was found to be upregulated in nerve biopsy specimens from patients with chronic inflammatory demyelinating neuropathy and an increased expression of proinflammatory cytokines have been demonstrated in peripheral nerves of most vasculitic neuropathies (Lindenlaub, T. and Sommer, C., 2003). About 15– 50% of AIDS patients suffer from distal predominantly sensory neuropathy, which very often is painful. In sarcoidosis, painful small-fiber neuropathy may be present in a subgroup of patients. In the fluid of artificially produced skin blisters significantly higher levels of IL-6 and TNF- were observed in CRPS-affected extremities as compared with the uninvolved extremity. In CRPS patients with hyperalgesia higher levels of the soluble TNF- receptor type I were found (Maihofner, C., et al., 2005b). Accordingly, a significant increases in IL-1 and IL-6, but not TNF- was demonstrated in the CSF of individuals afflicted with CRPS as compared with controls (Alexander, G. M. et al., 2005). Acute zoster is accompanied by intense inflammation along the affected peripheral nerve that typically

resolves in several weeks. However, a small subgroup of patients with PHN has inflammatory infiltrates throughout the affected peripheral nerve, DRG, and dorsal root (Watson, C. P. et al., 1991). Moreover, Gilden D. H. et al. (1991) have described a subpopulation of PHN patients with evidence of continuing low-level viral expression whose pain responds to antiviral agents. Thus continuing VZV expression could produce sensitization and activity in primary afferents secondary to inflammation.

57.7 Diagnostic Tools for Neuropathic Pain Modern research into the mechanisms of neuropathic pain clearly revealed that the nerve lesion leads to dramatic changes in the PNS and CNS that makes it distinct from other chronic pain types in which the nociceptive system is intact (chronic nociceptive pain, e.g., osteoarthritis). Furthermore, neuropathic pain states require different therapeutic approaches, e.g., anticonvulsants, that are not effective in nociceptive pain. To make the situation even more complex, many chronic pain states are characterized by a combination of both the pain types. Best examples for the so-called mixed pain syndromes are chronic radicular back pain, tumor pain, or CRPS. For the clinician, it is, therefore, of utmost importance to have valid diagnostic tools that differentiate neuropathic from nociceptive pain or estimate the neuropathic pain component in mixed pain syndromes. The easiest approach to this would be to use somatosensory symptoms assessed by questionnaires or history questions or simple signs testable at the bedside that are characteristic for neuropathic pain. However, a recent study on this issue raised several caveats (Rasmussen, P. V. et al., 2004): This study prospectively looked at symptoms and signs in 214 patients with suspected chronic neuropathic pain that were a priori classified by pain experts as having the so-called definite, possible or unlikely neuropathic pain. Pain symptoms including pain descriptors were recorded and sensory tests including repetitive pinprick stimulation, examination for cold-evoked pain by an acetone drop and brush-evoked pain were carried out in the maximal pain area and in a control area in order to determine if symptoms and signs cluster differentially in groups of patients with increasing evidence of neuropathic pain. Several symptoms (touch- or cold-provoked pain) and signs

Neuropathic Pain: Clinical

(brush-evoked allodynia) were more prominent in patients with definite or possible neuropathic pain; however, there was considerable overlap with the clinical presentation of patients with unlikely neuropathic pain. Even worse, the used pain descriptors could not at all distinguish between the three clinical categories. 57.7.1

887

diagnosed according to the results of two independent pain specialists who determined the predominant pain type (neuropathic versus nociceptive) by means of clinical experience as well as neurological examination, electrophysiologic, or imaging techniques. This questionnaire showed a correct classification rate of 82.5% with a sensitivity of 80.8% and a specificity 84.7%.

Questionnaires

Other approaches to find easy screening tools for neuropathic pain gave more promising results: a clinician-administered 10-item questionnaire (DN4) consists of sensory descriptors (seven items) as well as signs related to bedside sensory examination (three items) (Bouhassira, D. et al., 2004). The interview questions address the quality of the pain (burning, painful cold, and electric shocks) and associated symptoms (tingling, pins and needles, numbness, and itching). The examination consists of the assessment of hypoesthesia to touch, prick and allodynia to brush. This questionnaire was validated in a prospective study of 160 patients presenting with pain of nociceptive and neuropathic origin and showed 86.0% of correctly identified patients (sensitivity 82.9%, specificity 89.9%). A different approach to distinguish neuropathic from nonneuropathic pain uses a patient-based questionnaire with nine questions without the need of examinations by the physician (PainDetect) (Freynhagen, R. et al., 2006). The questionnaire consists of slightly different sensory descriptors (seven items, burning pain, tingling or prickling (electricity), sensitivity to touch (clothes, blanket), pain caused by light pressure (e.g., with finger), shooting pain or electric shock-like pain, occasional painful cold or heat (e.g., bath tub), and numbness), the question whether the pain is spatially radiating and a questions addressing the individual pain pattern. In the latter, the patients have to choose one of four graphically illustrated pain patters (permanent pain with a light variability, stable permanent pain with paroxysmal pain attacks, paroxysmal pain attacks with no permanent pain, and pain attacks with fluctuating permanent pain in between). This questionnaire was validated in 392 patients recruited at 10 highly specialized pain centers with either pain of pure predominant neuropathic origin (n ¼ 167, e.g., PHN, painful polyneuropathies, and nerve trauma) or pure or predominant nociceptive origin (n ¼ 225, e.g., ostheoathritis, mechanical low back pain, and inflammatory arthropathies). Patients were

57.7.2 Pain

Bedside Assessment of Neuropathic

Patients with neuropathic pain demonstrate a variety of distinct sensory symptoms and signs that can coexist in combinations (see above). Therefore, the sensory bedside examination should include the following qualities: touch, pinprick, pressure, cold, heat, vibration, temporal summation, and after sensations (Bouhassira, D. et al., 2004; Cruccu, G. et al., 2004, definition in Table 6). To assess either a loss (negative) or a gain of somatosensory function (positive sensory signs) the responses can be graded as normal, decreased or increased. The stimulus-evoked (positive) pain types are classified as hyperalgesic or allodynic, and according to the dynamic or static character of the stimulus (Rasmussen, P. V. et al., 2004). Touch can be assessed by gently applying cotton wool to the skin, pinprick sensation by the response to sharp pinprick stimuli, deep pain by gentle pressure on muscle and joints, and cold and heat sensation by measuring the response to a thermal stimulus, for example, thermorollers kept at 20 or 45  C. Cold sensation can also be assessed by the response to acetone spray. Vibration can be assessed by a tuning fork placed at strategic points (interphalangeal joints, etc.). Abnormal temporal summation is the clinical equivalent to increasing neuronal activity following repetitive C fiber stimulation >0.3 Hz. This winduplike pain can be produced by mechanical and thermal stimuli. After-sensations – the persistence of pain long after termination of a painful stimulus – is another characteristic feature of neuropathic pain, which is closely related to a coexistent dynamic or static hyperalgesia. When present, allodynia or hyperalgesia can be quantified by measuring intensity and area. At present, it is generally agreed that assessment should be carried out in the area of maximal pain using the contralateral area as control. However, contralateral segmental changes following a unilateral nerve or root lesion cannot be excluded, so an examination at mirror sites may not necessarily represent a true control site.

888 Neuropathic Pain: Clinical Table 6

Definition and assessment of negative and positive sensory symptoms or signs in neuropathic pain Assessment Bedside exam

Expected pathological response

Touch skin with painters brush, cotton swab, or gauze Apply tuning fork on bone or joint Prick skin with single pin stimulus Contact skin with objects of 10  C (metal roller, glass with water, coolants like acetone) Contact skin with objects of 45  C (metal roller, glass with water)

Reduced perception, numbness

Grade intensity (0–10) Area in cm2 Number per time Grade intensity (0–10) Threshold for evocation Grade intensity (0–10) Area in cm2

–

Normally nonpainful light moving stimuli on skin evoke pain

Stroking skin with painters brush, cotton swab, or gauze

Mechanical static allodynia

Normally nonpainful gentle static pressure stimuli at skin evoke pain

Manual gentle mechanical pressure at the skin

Mechanical punctuate, pinprick hyperalgesia

Normally not painful/slightly stinging stimuli evoke pain

Manual pricking the skin with a safety pin, sharp stick, or stiff von Frey hair

Temporal summation

Repetitive application of identical single noxious stimuli is perceived as increasing pain sensation (windup like pain) Normally nonpainful/slightly painful cold stimuli evoke pain

Pricking skin with safety pin at interval >6 5 4 3

Heat hyperalgesia

Static hyperalgesia to blunt pressure

Pinprick hyperalgesia

2 Z-score

1 0 –1 Loss of function

–2 –3 –4 –5

Cold and warm hypoesthesia

Tactile hypoesthesia

Pinprick hypoalgesia

Static hypoalgesia to blunt pressure