Progress in Inflammation Research

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Progress in Inflammation Research

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NPY Family of Peptides in Immune Disorders, Inflammation, Angiogenesis and Cancer, G.Z. Feuerstein, Z. Zukowska (Editors), 2005

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Chemokine Biology: Basic Research and Clinical Application, Volume I: Immunobiology of Chemokines, K. Neote, L. G. Letts, B. Moser (Editors), 2005

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Advisory Board

G. Z. Feuerstein (Wyeth Research, Collegeville, PA, USA)

M. Pairet (Boehringer Ingelheim Pharma KG, Biberach a. d. Riss, Germany) W. van Eden (Universiteit Utrecht, Utrecht, The Netherlands)

Birkhäuser Verlag Basel · Boston · Berlin

Turning up the Heat on Pain: TRPV1 Receptors in Pain and Inflammation

Annika B. Malmberg Keith R. Bley

Editors

ISBN-10: 3-7643-7080-7 Birkhäuser Verlag, Basel – Boston – Berlin ISBN-13: 978-3-7643-7080-0 Birkhäuser Verlag, Basel – Boston – Berlin

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.

The use of registered names, trademarks etc. in this publication, even if not identified as such, does not imply that they are exempt from the relevant protective laws and regulations or free for general use.

This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, re-use of illustrations, recitation, broadcasting, reproduction on micro- films or in other ways, and storage in data banks. For any kind of use, permission of the copyright owner must be obtained.

© 2005 Birkhäuser Verlag, P.O. Box 133, CH-4010 Basel, Switzerland Part of Springer Science+Business Media

Printed on acid-free paper produced from chlorine-free pulp. TCF ∞ Cover design: Markus Etterich, Basel

Cover illustration: Schematic diagram of TRPV1 activation and ionic permeation Printed in Germany

ISBN-10: 3-7643-7080-7 e-ISBN: 3-7643-7379-2

ISBN-13: 978-3-7643-7080-0

9 8 7 6 5 4 3 2 1 www.birkhauser.ch

Editors

Annika B. Malmberg Elan Pharmaceuticals 800 Gateway Boulevard South San Francisco, CA 94080 USA

Keith R. Bley NeurogesX, Inc.

981F Industrial Road San Carlos, CA 94070 USA

Library of Congress Cataloging-in-Publication Data

Turning up the heat on pain : TRPV1 receptors in pain and inflammation / Annika B. Malmberg, Keith R. Bley, editors.

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

ISBN-13: 978-3-7643-7080-0 (alk. paper) ISBN-10: 3-7643-7080-7 (alk. paper)

1. Nociceptors. 2. Pain. 3. Inflammation. 4. Inflammation--Mediators. I. Malmberg, Annika B., 1966–

II. Bley, Keith R. III. PIR (Series) QP451.4.T87 2005

612.8’8--dc22

2005048122

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

List of contributors

vii Preface

xi Part I: Historical perspective on capsaicin and its receptor

János Szolcsányi

Hot peppers, pain and analgesics

3 Part II: Molecular and cellular properties of vanilloid receptors

Makoto Tominaga

Structural determinants of TRPV1 functionality

25

Janet Winter

TRPV1 distribution and regulation

39 Part III: Pharmacology and physiology of vanilloid receptors

Peter M. Blumberg, Derek C. Braun, Noemi Kedei, Jozsef Lazar, Vladimir Pavlyukovets and Larry V. Pearce

Insights into TRPV1 pharmacology provided by non-capsaicin ligands

55

Ruth A. Ross

Endocannabinoids and vanilloid TRPV1 receptors

71

Zoltán Sándor and Arpad Szallasi

Vanilloid receptor-mediated hyperalgesia and desensitization

95

Lars Arendt-Nielsen and Ole K. Andersen

Capsaicin in human experimental pain models of skin, muscle and

visceral sensitization

117

Contents

Part IV: Vanilloid receptor involvement in disease states

Peter Holzer

TRPV1 in gut function, abdominal pain and functional bowel disorders

147

Maria G. Belvisi and Peter J. Barnes

TRPV1 in the airways

167 Part V: Therapeutic potential of vanilloid agonists and antagonists

Keith R. Bley and Annika B. Malmberg

TRPV1 agonist-based therapies: mechanism of action and clinical prospects

191

Francisco Cruz, Carlos Silva and Paulo Dinis

TRPV1 agonist therapies in bladder diseases

211

Kenneth J. Valenzano, James D. Pomonis and Katharine Walker

TRPV1 antagonists and chronic pain

227

Index

245

vii

Ole K. Andersen, Center for Sensory-Motor Interaction, Laboratory for Experi- mental Pain Research, Aalborg University, Fredrik Bajers Vej 7, D3, DK-9220 Aalborg, Denmark

Lars Arendt-Nielsen, Center for Sensory-Motor Interaction, Laboratory for Exper- imental Pain Research, Aalborg University, Fredrik Bajers Vej 7, D3, DK-9220 Aalborg, Denmark; E-Mail: LAN@smi.auc.dk

Peter J. Barnes, Respiratory Pharmacology Group and Airway Disease Section, National Heart & Lung Institute, Imperial College, Dovehouse Street, London SW3 6LY, UK; E-Mail: p.j.barnes@imperial.ac.uk

Maria G. Belvisi, Respiratory Pharmacology Group, Airway Disease Section, National Heart & Lung Institute, Faculty of Medicine, Imperial College, Dovehouse Street, London SW3 6LY, UK; E-Mail: m.belvisi@imperial.ac.uk

Keith R. Bley, NeurogesX, Inc., 981F Industrial Road, San Carlos, CA 94070, USA;

E-Mail: kbley@neurogesx.com

Peter M. Blumberg, Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, Building 37, Room 4048, 37 Convent Drive MSC 4255, Bethesda, MD 20892-4255, USA; E-Mail: blumberp@dc37a.nci.nih.gov

Derek C. Braun, Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, Bethesda, MD 20892, USA;

E-Mail: braund@mail.nih.gov

Francisco Cruz, Department of Urology, Hospital S. João and Faculty of Medicine of Porto, Alameda Prof Hernâni Monteiro, 4200–076 Porto, Portugal;

E-Mail: cruzfjmr@med.up.pt

List of contributors

viii

Paulo Dinis, Department of Urology, Hospital S. João and Faculty of Medicine of Porto, Alameda Prof Hernâni Monteiro, 4200–076 Porto, Portugal;

E-Mail: padioli@mail.telepac.pt

Peter Holzer, Department of Experimental and Clinical Pharmacology, Medical Uni- versity of Graz, Universitätsplatz 4, A–8010 Graz, Austria;

E-Mail: peter.holzer@meduni-graz.at

Noemi Kedei, Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, Bethesda, MD 20892, USA;

E-Mail: kedein@mail.nih.gov

Jozsef Lazar, Laboratory of Cellular Carcinogenesis and Tumor Promotion, Nation- al Cancer Institute, Bethesda, MD 20892, USA;

E-Mail: lazarjo@mail.nih.gov

Annika B. Malmberg, Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA 94080, USA; E-Mail: Annika.Malmberg@elan.com

Vladimir Pavlyukovets, Laboratory of Cellular Carcinogenesis and Tumor Promo- tion, National Cancer Institute, Bethesda, MD 20892, USA;

E-Mail: pavlyukv@mail.nih.gov

Larry V. Pearce, Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, Bethesda, MD 20892, USA;

E-Mail: pearcel@mail.nih.gov

James D. Pomonis, Algos Therapeutics, 1246 University Ave W, Suite 205, St. Paul, MN 55104, USA; E-Mail: jpomonis@algosinc.com

Ruth A. Ross, School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, Scotland, United Kingdom;

E-mail: r.ross@abdn.ac.uk

Zoltán Sándor, Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, H–7624 Pécs, Hungary

Carlos Silva, Department of Urology, Hospital S. João and Faculty of Medicine of Porto, Alameda Prof Hernâni Monteiro, 4200–076 Porto, Portugal;

E-Mail: carsil@mail.telepac.pt

List of contributors

Arpad Szallasi, Department of Pathology, Monmouth Medical Center, 300 Second Avenue, Long Branch, NJ 07740, USA; E-Mail: aszallasi@sbhcs.com

János Szolcsányi, Department of Pharmacology and Pharmacotherapy, University Medical School of Pécs, Neuropharmacological Research Group of the Hungarian Academy of Sciences, Szigeti u. 12, H–7624 Pécs, Hungary;

E-Mail: janos.szolcsanyi@aok.pte.hu

Makoto Tominaga, Section of Cell Signaling, Okazaki Institute for Integrative Bio- science, National Institutes of Natural Sciences, Okazaki 444–8787, Japan;

E-Mail: tominaga@nips.ac.jp

Kenneth J. Valenzano, Amicus Therapeutics, 6 Cedarbrook Drive, Cranbury, NJ 08512, USA; E-Mail: valenzano@amicustherapeutics.com

Katharine Walker, Beatson Institute for Cancer Research, Garscube Estate, Switch- back Road, Glasgow G61 1BD, Scotland, UK; E-Mail: k.walker@beatson.gla.ac.uk

Janet Winter, Novartis Institute for Medical Sciences, 5 Gower Place, London WC1E 6BN, United Kingdom;

E-Mail: Janet.Winter@Novartis.com, WinterJa@tiscali.co.uk

ix

List of contributors

Despite tremendous advances in the understanding of the sensory nervous system which have accompanied the recent explosive growth of the neurosciences, remark- ably few innovative medicines directed towards pain and inflammation are avail- able. Indeed, many patients are still prescribed analgesic and anti-inflammatory medications that were identified long ago as components of herbal remedies. Simi- larly, potential new medicines in clinical evaluation based on capsaicin and the cap- saicin receptor are both grounded firmly on folk traditions and yet rely upon the most contemporary techniques of drug discovery and delivery.

The first formal report of the pain-relieving properties of capsaicin appeared in 1850 [1]. However, for centuries before this, capsaicin-containing extracts had been used as folk medicines in cultures with access to pepper plants, much in the same way as poppy or willow-bark extracts were. Despite widespread use, it was not until 1878 that the selective action of capsaicin on the sensory nervous system was rec- ognized [2]. In Chapter 1 of this volume, Janos Szolcsányi reviews this early research, which culminated with the seminal studies of Nicholas Jansco and his col- leagues in Hungary in the 1940s. Since then, capsaicin and related vanilloid com- pounds have played a prominent role in analgesia and inflammation investigations because of their ability to selectively activate a subpopulation of sensory neurons and produce sensations of pain and localized erythema. The widespread production of pungent molecules such as capsaicin by plants has recently been explained in terms of advantages with respect to seed dispersal and deterrence of ambulatory seed eaters [3].

Since 1997 there has been profound interest in capsaicin and pungent vanilloids because of the cloning of a specific ion channel that mediates the effect of this class of compounds [4]. Specifically, it has been found that pungent vanilloids mediate their effects by selective agonism of an ion channel, the transient receptor potential vanil- loid receptor 1 (TRPV1; or, according to older nomenclature, VR1). TRPV1 is a lig- and-gated, non-selective cation channel expressed preferentially in small-diameter, primary afferent neurons, including nociceptive sensory nerves. In addition to being activated by capsaicin and related vanilloids, TRPV1 responds to heat and extracel- lular acidification, and will integrate simultaneous exposures to these stimuli.

xi

Preface

The aim of this volume is to summarize recent insights into the role of TRPV1 in pain and inflammation, and how discuss how modulation of this receptor may lead to important advances in analgesic and anti-inflammatory drug development.

The book contains chapters relating to five themes: (1) historical perspectives on capsaicin and its receptor; (2) the molecular and cellular properties of TRPV1; (3) the pharmacology and physiology of TRPV1; (4) evidence for the involvement of TRPV1 in diseases and syndromes; and (5) the therapeutic potential of TRPV1 ago- nists and antagonists. It is our hope that this book will provide an integrated overview of the actions of classes of compounds that have been used extensively – for a wide range of reasons – by cultures around the world. Possibly more impor- tantly, we hope that this book will also provide insights into the prospects for the therapeutic potential of TRPV1 activation or inhibition, particularly in various painful or inflammatory conditions.

References

1 Turnbull A (1850) Tincture of capsaicin as a remedy for chilblains and toothache.

Dublin Free Press 1: 95–96

2 Hőgyes A (1878) Beiträge zur physiologischen Wirkung der Bestandteile des Capsicum annuum. Arch Exp Pathol Pharmakol 9: 117–130

3 Tewksbury JJ, Nabhan GP (2001) Seed dispersal. Directed deterrence by capsaicin in chilies. Nature 412: 403–404

4 Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389:

816–824

xii

Preface

Part I

Historical perspective on capsaicin and its receptor