Progress in Inflammation Research

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Progress in Inflammation Research

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Birkhäuser Verlag Basel · Boston · Berlin

Sodium Channels, Pain, and Analgesia

Kevin Coward Mark D. Baker Editors

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The publisher and editor can give no guarantee for the information on drug dosage and administration contained in this publication. The respective user must check its accuracy by consulting other sources of reference in each individual case.

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ISBN-10: 3-7643-7062-9 Birkhäuser Verlag, Basel – Boston – Berlin ISBN-13: 978-3-7643-7062-6 Birkhäuser Verlag, Basel – Boston – Berlin

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Library of Congress Cataloging-in-Publication Data

Sodium channels, pain, and analgesia / Kevin Coward, Mark D. Baker, editors.

p. ; cm. -- (Progress in inflammation research) Includes bibliographical references and index.

ISBN 3-7643-7062-9 (alk. paper)

1. Pain. 2. Sodium channels. 3. Analgesics. I. Coward, Kevin, 1969– II. Baker, Mark D., 1960- III. PIR (Series)

RB127.S64 2005 616’.0472--dc22

2005048132 Editors

Kevin Coward

Department of Pharmacology University of Oxford Mansfield Road Oxford OX1 3QT UK

Mark D. Baker

Molecular Nociception Group Department of Biology Medawar Building University College London Gower Street

London WC1E 6BT UK

Bibliographic information published by Die Deutsche Bibliothek

Die Deutsche Bibliothek lists this publication in the Deutsche Nationalbibliografie;

detailed bibliographic data is available in the internet at http://dnb.ddb.de

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List of contributors . . . vii Preface . . . ix Joel A. Black, Bryan C. Hains, Sulayman D. Dib-Hajj and

Stephen G. Waxman

Voltage-gated sodium channels and pain associated with nerve injury

and neuropathies. . . 1 Jeffrey J. Clare

Current approaches for the discovery of novel Na_Vchannel inhibitors

for the treatment of brain disorders. . . 23 Jennifer M.A. Laird and Fernando Cervero

Voltage-gated sodium channels and visceral pain. . . 63 Kenji Okuse and Mark D. Baker

The functional interaction of accessory proteins and voltage-gated

sodium channels. . . 71 James A. Brock

Sodium channels and nociceptive nerve endings. . . 85 Grant D. Nicol

Signalling cascades that modulate the activity of sodium channels

in sensory neurons . . . 107 Lodewijk V. Dekker and David Cronk

Na_V1.8 as a drug target for pain. . . 123 Michael S. Gold

Role of voltage-gated sodium channels in oral and craniofacial pain. . . 145

List of contributors

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viii

Michael S. Gold, Department of Biomedical Sciences, University of Maryland Den- tal School, 666 W. Baltimore St., Room 5-A-12 HHH, Baltimore, MD 21201, USA;

e-mail: msg001@dental.umaryland.edu

Bryan C. Hains Department of Neurology and Center for Neuroscience and Regen- eration Research, Yale University School of Medicine, New Haven, CT 06510, and Rehabilitation Research Center, VA Connecticut Healthcare System,West Haven, CT 06516, USA

Jennifer M.A. Laird, Bioscience Department, AstraZeneca R & D Montréal, 7171 Frédérick-Banting, Ville Saint-Laurent, Quebec H4S 1Z9, Canada;

e-mail: jennifer.laird@astrazeneca@com

Grant D. Nicol, Department of Pharmacology and Toxicology, 635 Barnhill Drive, Indiana University School of Medicine, Indianapolis, IN 46202, USA;

e-mail: gnicol@iupui.edu

Kenji Okuse, Wolfson Institute for Biomedical Research, University College Lon- don, Gower Street, London WC1E 6BT, UK; present address: London Pain Con- sortium, Department of Biological Sciences, South Kensington Campus, Imperial College of Science, Technology and Medicine, London SW7 2AZ, UK;

e-mail: k.okuse@imperial.ac.uk

Andreas Scholz, Physiologisches Institut, Universität Giessen, Aulweg 129, 35392 Giessen, Germany; e-mail: andreas.scholz@physiologie.med.uni-giessen.de

Stephen G. Waxman Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT 06510, and Rehabilitation Research Center, VA Connecticut Healthcare System,West Haven, CT 06516, USA

John N. Wood, Molecular Nociception Group, Biology Department, UCL, Gower Street, London WC1E 6BT, UK; e-mail: j.wood@ucl.ac.uk

List of contributors

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The treatment of chronic pain, for example that resulting from damage or dysfunc- tion of the nervous system, or that associated with cancer, is at present inadequate and pain still represents a serious unmet clinical need. The costs of pain, in terms of personal anguish, finance and in national healthcare costs are enormous. Because sodium channels confer excitability on neurones in nociceptive pathways and exhib- it neuronal tissue-specific and injury-regulated expression, their study has become an important branch of pain research, and they form the focus of this book. As well as reviewing why sodium channel subtypes are potentially important drug targets in the treatment of pain, this volume also brings together recent insights into the control of expression, functioning and membrane trafficking of nervous system sodium channels.

A recent previous review of sodium channel function, with particular emphasis on the ways in which aberrant sodium channel behaviour can contribute to nervous system pathophysiology, was based on a Novartis Foundation symposium held in London in 2000, chaired by Stephen Waxman. At that time it had become clear that sodium channels were a group of proteins exhibiting both molecular and functional diversity, and that neuronal hyperexcitability, contributing to such phenomena as chronic pain following nerve injury, might be explained by changes in sodium channel function. This included the selective upregulation and downregulation of expression of different sodium channel genes. The control of sodium channel gene expression in the nervous system following injury has remained very much a hot topic in the intervening years and is an important theme in this book. Evidence has also accrued on the importance of G-protein pathway control of sodium channel function, and the post-translational modification of channel function based on phos- phorylation is also discussed in this volume.

The ability to discriminate pharmacologically between sodium channel subtypes, which show substantial sequence homology, is another important theme and one where key developments are expected. The technologies used for screening com- pounds on sodium channel function are reviewed in this book. Sodium channel subtypes appear to be distributed to specific regions of the axon, and may therefore

ix

Preface

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make highly individual contributions to normal acute noxious sensation. These must include tetrodotoxin-resistant channels, known to be functional in at least some of the smallest peripheral endings. Furthermore, sodium channels are chaper- oned to the neuronal membrane and are tethered there by a complex of proteins, contacting both the extracellular matrix and the intracellular cytoskeleton. Many protein–protein interactions must ensure correct channel function and turnover.

These interactions can be sodium channel sub-type specific, for example that between p11 and Na_v1.8. Thus, certain channel associated molecules might provide additional drug targets in the treatment of pain.

Our understanding of pain transmission and transduction in mammals has been greatly facilitated by the development of sodium channel gene knockout mice. This has allowed us to assign roles to certain sodium channel subtypes that could not be selectively targeted by pharmacological methods, and the endeavour has allowed sodium channel subtypes to be validated as potential future drug targets. The further sophistication of gene knockout technology, developed at least in part to over- come lethality, has been the use of tissue-specific nulls where the activation of a tissue-specific gene promoter can be used to express the bacteriophage cre-recombi- nase. Finally, the use of tissue-specific inducible nulls is expected to contribute to the future study of sodium channel function. This technology holds out the promise of gene deletion without developmental compensation resulting in a diluted pheno- type, and thus may provide the clearest insight possible into the function of genes in subsets of neurones.

This book aims to summarise the current understanding of voltage-gated sodium channels, their association with pain and their potential as targets for the development of novel analgesics. Individual chapters address the potential therapeutic role of voltage-gated sodium channels and their respective roles in neuropathy and nerve injury, brain disorders, visceral pain and dental pain. Further chapters address the role of these molecules in nociceptive endings, the regulation and modulation of sodium channels, channel gating and drug blockade. A specific chapter is devoted to the Na_v1.8 channel, viewed by many as an important therapeutic target, and the final chapter discusses current opinion and future direction in sodium channel research.

We wish to thank all the authors who participated in writing this book.

Oxford/London, February 2005 Kevin Coward

Mark D. Baker

Progress in Inflammation Research

Sodium Channels, Pain, and Analgesia

Contents

List of contributors

Preface