The Pharmacology of Pain

493 Pages·1997·11.24 MB·English

by  A. Tjølsen

Handbook of
Experimental Pharmacology
Volume 130
Editorial Board
G.V.R.Born,London
P. Cuatrecasas, Ann Arbor, MI
D. Ganten, Berlin
H. Herken, Berlin
K.L. Melmon, Stanford, CA
K. Starke, Freiburg i. Br.
Springer
Berlin
Heidelberg
New York
Barcelona
Budapest
Hong Kong
London
Milan
Paris
Santa Clara
Singapore
Tokyo
The Pharll1acology of Pain
Contributors
1. Appleton, D.L.H. Bennett, J.-M. Besson, P.J. Birch,
V. Chapman, M. Devor, A. Dickenson, A. Dray,
H.L. Fields, M. Fitzgerald, D.L. Hammond, K. Hole,
B.L. Kieffer, M. Koltzenburg, J. Lai, T.O. Malan,
S.B. McMahon, H.J. McQuay, M.J. Millan, R.A. Moore,
M.H. Ossipov, F. Porreca, M.e. Rowbotham, A. Tj0lsen,
S. Wiesenfeld-Hallin, X.-J. Xu
Editors
A. Dickenson and J.-M. Besson
Springer
Professor A. Dickenson
University College London
Department of Pharmacology
Gower Street
London WC1E 6BT
UNITED KINGDOM
Dr. 1.-M. Besson
INSERM, U.161
Physiopharmacologie du Systeme Nerveux
et Laboratoire de Physiopharmacologie
de la Douleur (EPHE)
2, rue d'Alesia
F-7S014 Paris
FRANCE
With 41 Figures and 21 Tables
Library of Congress Cataloging-in-Publication Data
The pharmacology of pain 1 editors, A. Dickenson and l.-M. Besson: contributors. I. Appieton ... [et al.].
p. em. - (Handbook of experimental pharmacology; v. 130)
Includes bibliographical references and index.
ISBN-13: 978-3-642-64550-1 e-ISBN-13: 978-3-642-60777-6
DOl: 10.1007/978-3-642-60777-6
1. Pain. 2. Analgesia. I. Dickenson, A.H. II. Besson, lean-Marie R. III. Appleton, I. (Ian)
IV. Series.
[DNLM: l. Pain-drug therapy. 2. Nociceptors-drug effects. 3. Receptors, Neurotransmitter
drug effects. 4. Analgesics-pharmacology. 5. Anesthetics-pharmacology.
WI HAS I L v. 130 1997 1 WL 704 P536 1997]
QP905.H3 vol. 130
[RBI27] 615'. Is-dc21 [615'.783]
DNLMIDLC
for Library of Congress 97-23531
CIP
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Preface
Pain is a symptom of many clinical disorders, afflicts a large proportion of
the population and is largely treated by pharmacological means. However, the
two main classes of drugs used are the opioids and the non-steroidal anti
inflammatory drugs, drugs that have a long history. The last decade has seen
remarkable advances in our understanding of some of the pharmacological
bases of pain and analgesia and this book aims to reflect these rapid changes
in our understanding of pain mechanisms. One impetus to these scientific
advances has been dialogue and interactions between scientists and clinicians;
as a result we now has a number of animal models of clinical pain states, to
mimic certain aspects of clinical pathophysiological pain states. Molecular
aspects of receptors and the synthesis of tools for probing receptor function
have also been rapid growth areas. A number of controlled clinical studies
using novel licensed drugs have also resulted from recent research, offering
hope to certain patients with severe intractable pain. However, we desperately
need the pharmaceutical industry to develop new drugs based on these novel
targets for analgesic therapy. This book attempts to provide an overview of the
important areas of the pharmacology of pain.
This book, although providing an account of the pharmacology of pain
transmission and its control based on the underlying anatomical organization
and physiological responses, does not attempt to cover these latter two areas.
Neither does it provide details of all aspects of opioid function since the
Handbook of Experimental Pharmacology, volume 104, covered this area in
great detail in 1993. Those readers who wish to have a better understanding of
the anatomy and physiology of pain and analgesia are referred to several
recent reviews, listed at the end of this preface, which amplify some of the
details given in this book.
The study of the receptor systems involved in the transmission of pain and
its modulation involves the investigation of processes occurring at the periph
eral endings of sensory neurones as well as central events. Whereas acute pain
rarely presents as a clinical problem, pain caused by inflammation and tissue
damage can be produced by operative procedures, trauma, childbirth, cancer
etc. In addition, pain from nerve damage, neuropathic pain, can be produced
by trauma and tumours invading nervous tissue. The mechanisms of inflamma
tory and neuropathic pain are very different from acute pain, and there is
considerable plasticity in both the transmission and modulating systems in
VI Preface
these prolonged pain states. Due to state- and time-dependent plasticity a full
range of models spanning the short and longer term inflammatory and
neuropathic states is a prerequisite for characterization of all potential recep
tor systems involved in pain and analgesia.
Models for studying pain have to take into account these different mecha
nisms and the plasticity inherent in the pharmacology. Simple models of acute
pain will not reveal many of the receptors and channels important in the more
persistent pain states. Some of the animal models of pain are discussed by
KJELL HOLE and colleagues in Chap. 1.
Peripheral Events
The transmission of acute pain involves activation of sensory receptors on
peripheral C-fibres, the nociceptors. However, once tissue damage and in
flammation occurs, the actions of prostanoids, bradykinin, 5HT etc. on their
excitatory receptors plays a major role in sensitization and activation of C
fibres. ANDY DRAY discusses new aspects of excitatory events in the periphery
(Chap. 2), PHIL BIRCH covers the roles of the tachykinins at both the peripheral
and central levels (Chap. 6) and IAN ApPLETON provides a basis for the pro
duction of new and more benign NSAIDs based on different forms of
the cycloxygenase enzyme (Chap. 3). Other factors such as NGF and cytokines
are also important at the peripheral level, and resultant changes in the
phenotype of the sensory neurones are considered by McMAHON and BENNETT
(Chap. 7).
Neuropathic pain states are generated in the peripheral sensory neurones
by events that are independent of nociceptors. Clustering of sodium channels
around areas of nerve damage set up ectopic activity that can spread to the
ganglion cells. Sympathetic activity can facilitate these events. Thus mem
brane stabilizers and agents acting on the sympathetic nervous system have a
place in the control of neuropathic pain, and this is covered by HOWARD
FIELDS, MARSHALL DEVOR and MICHAEL ROWBOTHAM (Chap. 5).
MARTIN KOLTZENBURG reviews the evidence for an involvement of the
sympathetic nervous system in nerve damage related pains (Chap. 4).
Central Excitatory Systems
The arrival of sensory information from nociceptors in the dorsal horn of the
spinal cord adds considerable complexity to study of pain and analgesia due to
the fact that most of the receptors found in the CNS are also present in the
areas where the C-fibres terminate. The density of neurones in these areas is
equal to or exceeds that seen elsewhere in the CNS.
Interactions between peptides and excitatory amino acids (EAA) are
critical for setting the level of pain transmission from the spinal cord to the
brain and motoneurones.
Preface VII
The AMPA receptor for the EAA, the release of substance P and its
actions on the neurokinin-l receptor removes the Mg2+ block of the NMDA
receptor. Other peptides may also contribute. Activation of the NMDA recep
tor underlies wind-up, and this increased responsivity of dorsal horn neurones
is probably the basis for central hypersensitivity. The NMDA receptor does not
participate in responses to acute stimuli but is involved in persistent inflamma
tory and neuropathic pains. Adenosine appears to be released in response to
NMDA receptor activation and then, by actions on the Al receptor, acts as a
negative feedback system. TONY DICKENSON reviews the roles of these systems
(Chap. 8).
Nitric oxide is generated in the spinal cord and periphery and this gas,
together with other chemical transmitters such as the peptide cholecystokinin,
are discussed by X.-J. Xu and ZSUSANNA WIESENFELD-HALLIN (Chap. 9).
Induction of the immediate early gene, c-fos, in spinal neurones is rapid
and, since it relates to the intensity of stimulus, can be used as a marker of
activity and a powerful tool for the study of modulatory effects. VICTORIA
CHAPMAN and JEAN-MARIE BESSON review this area (Chap. 10).
Central Inhibitory Systems
Excitatory transmission can be controlled by simply blocking the effects of
excitatory transmitters but can also be controlled by the augmentation of
inhibitory controls. The roles of the mu, delta and kappa opioid receptors have
been established, and despite the long history of the use of opium there are
still opportunities for the development of better opioid analgesics. Most clini
cally used drugs act on the mu receptor, and the delta receptor may provide a
target for opioids with fewer side-effects than with morphine. The endogenous
opioid peptides have controlling influences on the spinal transmission of pain
whereas the dynorphins have complex actions.
BRIGITTE KIEFFER covers the cloning of the opioid receptors and molecular
aspects of the receptors (Chap. 11), whereas FRANK PORRECA et al. reviews the
functional aspects of the multiple opioid receptors in different pain models
(Chap. 12). HENRY MCQUAY and ANDREW MOORE point out the key influence
of metabolism and tolerance to opioids with the presently available drugs
(Chap. 13). Tonic GABA and GABA receptor controls are important in
A B
controlling acute, inflammatory and neuropathic pain states. The former re
ceptor appears to prevent low-threshold inputs from triggering nociception,
and DONNA HAMMOND provides a review of the roles of this inhibitory amino
acid (Chap. 14).
Monoamine systems originating in the midbrain and brainstem act on the
spinal transmission of pain. Alpha2 adrenoceptors appear to be important in
the roles of noradrenaline. There is still great confusion regarding the relative
roles of the multiple 5HT receptors. MARK MILLAN reviews this field (Chap. 15).
A decade ago it was held that infants did not feel pain - this view has
radically changed but there is little basis for a rational approach to analgesia in
VIII Preface
young children. There are dramatic alterations in receptor ontogeny, location
and function during development. The pharmacology of pain in immature is
very different form the adult, and MARIA FITZGERALD discusses this area
(Chap. 16).
We would like to thank all our contributors to this book for their enthusi
asm and, in many cases, for their promptness in providing their chapters. We
are also grateful to our colleagues in London and Paris for their assistance and
wish to thank DORIS WALKER at Springer-Verlag for her guidance in the
project.
Additional Reading
Besson 1M, Chaouch A (1987) Peripheral and spinal mechanisms of pain. Physiol Rev
67:67-186
Belmonte C, Cervero F (1996) Neurobiology of nociceptors. Oxford University Press,
Oxford, p 531
Pain 1996 - an overview. IASP, Seattle
Postgraduate Educational Issue (1995) Inflammatory and neurogenic pain; new mol
ecules, new mechanisms. Br J Anaesthesia 75:123-227
Willis WD, Coggeshall RE (1991) Sensory mechanisms of the spinal cord. Plenum,
New York
List of Contributors
ApPLETON, 1., School of Biological Sciences, The Stopford Building,
The University of Manchester, Oxford Road, Manchester,
M13 9PT, United Kingdom
BENNETT, D.L.H., Department of Physiology,
St. Thomas Hospital Medical School, Lambeth Palace Road,
London SEI 7EH, United Kingdom
BESSON, J.-M., Physiopharmacologie du Systeme Nerveux, INSERM U.161
and Laboratoire de Physiopharmacologie de la Douleur (EPHE),
2 rue d'Alesia, F-75014 Paris, France
BIRCH, P.J., Astra Research Centre Montreal, 7171 Frederick Banting,
St. Laurent, Quebec, Canada H4S lZ9
CHAPMAN, Y., Physiopharmacologie du Systeme Nerveux, INSERM U.161
and Laboratoire de Physiopharmacologie de la Douleur (EPHE),
2 rue d'Alesia, F-75014 Paris, France
DEVOR, M., Department of Cell and Animal Biology, Life Sciences Institute,
Hebrew University of Jerusalem, Jerusalem 91904, Israel
DICKENSON, A., Department of Pharmacology, University College London,
Gower Street, London WCIE 6BT, United Kingdom
DRAY, A., Astra Research Centre Montreal 7171 Frederick-Banting,
St-Laurent, Quebec, Canada H4S lZ9
FIELDS, H.L., Department of Neurology,
University of California San Francisco, 505 Parnassus Avenue, M-794,
San Francisco, CA 94143-0114, USA
FITZGERALD, M., Department of Anatomy and Developmental Biology,
University College London, Gower Street, London WCl 6BT,
United Kingdom
HAMMOND, D.L., Department of Anesthesia and Critical Care,
University of Chicago, 5841 South Maryland Ave., M/C 4028, Chicago,
IL 60637, USA
x
List of Contributors
HOLE, K., Department of Physiology, University of Bergen, Arstadveien 19,
N-5009 Bergen, Norway
KIEFFER, B.L., CNRS UPR 9050 ESBS, Pare d'Innovation,
Boulevard S. Brandt, F-67400 Illkirch, France
KOLTZENBURG, M., Department of Neurology, University of Wtirzburg,
Josef-Schneider-Str. 11, D-97080 Wtirzburg, Germany
LAI, J., Department of Pharmacology,
The University of Arizona Pain Institute, Health Sciences Center,
Tucson, AZ 85724, USA
MALAN, T.O., Department of Anesthesiology, University of Arizona,
Health Sciences Center, Tucson, AZ 85724, USA
McMAHON, S.B., Department of Physiology,
St. Thomas Hospital Medical School, Lambeth Palace Road,
London SE1 7EH, United Kingdom
MCQUAY, H.J., Pain Research and Nuffield Department of Anesthetics,
University of Oxford, Oxford OX3 7LJ, United Kingdom
MILLAN, M.J., Institut de Recherches Servier,
Centre de Recherches de Croissy, Psychopharmacology Department,
125, Chemin de Ronde, F-78290 Croissy-sur-Seine (Paris), France
MOORE, R.A., Pain Research and Nuffield Department of Anesthetics,
University of Oxford, Oxford OX3 7LJ, United Kingdom
OSSIPOV, M.H., Department of Pharmacology,
The University of Arizona Pain Institute, Health Sciences Center,
Tucson, AZ 85724, USA
PORRECA, F., Department of Pharmacology,
The University of Arizona Pain Institute, Health Sciences Center,
Tucson, AZ 85724, USA
ROWBOTHAM, M.e., Department of Neurology,
University of California San Francisco, 505 Parnassus Avenue, M-794,
San Francisco, CA 94143-0114, USA
TJ0LSEN, A., Department of Physiology, University of Bergen,
Arstadveien 19, N-5009 Bergen, Norway
WIESENFELD-HALLIN, S., Karolinska Institute,
Department of Medical Laboratory Sciences and Technology,
Section of Clinical Neurophysiology, Huddinge University Hospital,
S-141 86 Huddinge, Sweden
Xu, X.-J., Karolinska Institute, Department of Medical Laboratory Sciences
and Technology, Section of Clinical Neurophysiology,
Huddinge University Hospital, S. 141 86 Huddinge, Sweden