Progress in Drug Research 68 Series Editor: K. D. Rainsford Omar M. E. Abdel-Salam E ditor Capsaicin as a Therapeutic Molecule Progress in Drug Research Volume 68 Series editor K. D. Rainsford, Sheffield Hallam University, Biomedical Research Centre, Sheffield, UK For further volumes: http://www.springer.com/series/4857 Omar M. E. Abdel-Salam Editor Capsaicin as a Therapeutic Molecule 1 3 Editor Omar M. E. Abdel-Salam Department of Toxicology and Narcotics National Research Center Cairo Egypt ISBN 978-3-0348-0827-9 ISBN 978-3-0348-0828-6 (eBook) DOI 10.1007/978-3-0348-0828-6 Springer Basel Heidelberg New York Dordrecht London Library of Congress Control Number: 2014934672 © Springer Basel 2014 This work is subject to copyright. 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Printed on acid-free paper Springer Basel AG is part of Springer Science Business Media (www.springer.com) + Preface Capsaicin, a homovanillic acid derivative (8-methyl-N-vanillyl-6-nonenamide), is the pungent ingredient in red peppers of the plant genus Capsicum, including chillies and jalapenos. Capsaicin has long been used as a probe for sensory neu- ronal mechanisms. This is because capsaicin selectively stimulates, and at large doses, defunctionalizes a subset of primary afferent neurons with unmyelinated C fiber or thinly myelinated Aδ fibers. Most capsaicin-sensitive fibers are polymodal nociceptors (which respond to a range of sensory stimuli including noxious heat, pressure, and chemical irritation) as well as heat nociceptors, mechano-heat insensitive chemonociceptors, and warm receptors. The molecular site of action of capsaicin and other structurally related substances have been identified and cloned. This receptor, the transient receptor potential vanilloid 1 (TRPV1), formerly vanil- loid receptor subtype 1 (VR1), forms a nonselective cation channel in the plasma membrane that is highly expressed in peripheral and central terminals of these primary sensory neurons. Capsaicin application at submicromolar concentrations activates the subset of polymodal nociceptor fibers that express its receptor; this leads to release of neuropeptides, such as substance P and calcitonin gene-related peptide, from nerve terminals and burning pain. Higher concentrations or the repeated application of low concentrations of capsaicin leads to desensitization, i.e., decline in response to capsaicin and also to other stimuli of polymodal nocic- eptors. This desensitizing action has made capsaicin attractive for use as a periph- erally acting analgesic for chronic painful syndromes. Capsaicin has moved toward clinical applications and is used currently in topi- cal creams and gels to relieve intractable neuropathic pain, uremic pruritus, and rheumatoid arthritis. Capsaicin also proved of value in nonallergic (vasomotor) rhinitis, migraine, cluster headache, herpes zoster, and bladder overactivity and interstitial cystitis. Resiniferatoxin is an ultrapotent capsaicin analog isolated from the dried latex of the cactus-like plant Euphorbia resinifera. In patients with overactive bladder, intravesical resiniferatoxin improves bladder function without having significant irritancy and/or toxicity. Intrathecal resiniferatoxin is currently undergoing clinical trials in patients with intractable cancer pain. Capsaicin and capsaicin-like molecules have thus remarkable potential as pharmaceutical agents for treating various human aliments. The intended purpose of this volume is to compile the available knowledge and the most recent achievements pertaining to the application of capsaicin and v vi Preface capsaicin-like molecules in the management of various human aliments. It also seems timely to cover basic issues on the capsaicin receptor, the mechanisms of its action, and its role in physiological and pathological processes and provide the latest perspectives on these issues. The book aimed to combine both basic science on the pathophysiological role of sensory nerves and TRPV1 in the disease process itself, in addition to covering current knowledge and h ighlighting the most recent progress in the use of capsaicin as a therapeutic agent. Each chapter is written by noted experts in their field of endeavor. In this way, it is hoped that the book will be useful for both clinicians and researchers and that it will stimulate their future research. I would like to thank all the authors of this volume who worked diligently to produce such outstanding chapters that not only covered current knowledge but also discussed important potential pharmaceutical implications for further research in this field. This book has been only possible because of their efforts. I am most indebted to the Series Editor, Prof. Dr. Kim Rainsford, and the Senior Editor Dr. Hans Detlef Klüber for their idea that has led to this book, for kindly invit- ing me to produce this volume and for the invaluable support. I would also like to gratefully acknowledge the Springer’s edition Staff and in particular the Project Coordinator Dr. Andrea Schlitzberger for her continued help and advice through- out the preparation and production of this book. Omar M. E. Abdel-Salam Contents 1 Capsaicin and Sensory Neurones: A Historical Perspective ......... 1 János Szolcsányi 2 Pharmacology of the Capsaicin Receptor, Transient Receptor Potential Vanilloid Type-1 Ion Channel ......................... 39 Istvan Nagy, Dominic Friston, João Sousa Valente, Jose Vicente Torres Perez and Anna P. Andreou 3 TRPV1 in the Central Nervous System: Synaptic Plasticity, Function, and Pharmacological Implications ..................... 77 Jeffrey G. Edwards 4 Topical Capsaicin Formulations in the Management of Neuropathic Pain ......................................... 105 Mark Schumacher and George Pasvankas 5 Capsaicin-Based Therapies for Pain Control ..................... 129 Howard Smith and John R. Brooks 6 Intranasal Capsaicin in Management of Nonallergic (Vasomotor) Rhinitis ......................................... 147 Umesh Singh and Jonathan A. Bernstein 7 Capsaicin as an Anti-Obesity Drug ............................. 171 Felix W. Leung 8 The Potential Antitumor Effects of Capsaicin .................... 181 Inés Díaz-Laviada and Nieves Rodríguez-Henche 9 Capsaicin as New Orally Applicable Gastroprotective and Therapeutic Drug Alone or in Combination with Nonsteroidal Anti-Inflammatory Drugs in Healthy Human Subjects and in Patients ............................... 209 Gyula Mózsik vii viii Contents 10 Capsaicin Receptor as Target of Calcitonin Gene-Related Peptide in the Gut.......................................... 259 Stefano Evangelista 11 Capsaicin for Osteoarthritis Pain............................. 277 Laura L. Laslett and Graeme Jones 12 The Role of Capsaicin in Dermatology......................... 293 Katherine Boyd, Sofia M. Shea and James W. Patterson 13 Use of Vanilloids in Urologic Disorders ........................ 307 Harris E. Foster Jr. and AeuMuro G. Lake Index ......................................................... 319 Chapter 1 Capsaicin and Sensory Neurones: A Historical Perspective János Szolcsányi Abstract Capsaicin, the pungent ingredient of red pepper has become not only a “hot” topic in neuroscience but its new target-related unique actions have opened the door for the drug industry to introduce a new chapter of analgesics. After several lines of translational efforts with over 1,000 patents and clinical tri- als, the 8 % capsaicin dermal patch reached the market and its long-lasting local analgesic effect in some severe neuropathic pain states is now well established. This introductory chapter outlines on one hand the historical background based on the author’s 50 years of experience in this field and on the other hand empha- sizes new scopes, fascinating perspectives in pharmaco-physiology, and molecular pharmacology of nociceptive sensory neurons. Evidence for the effect of capsaicin on C-polymodal nociceptors (CMH), C-mechanoinsensitive (CHMi), and silent C-nociceptors are listed and the features of the capsaicin-induced blocking effects of nociceptors are demonstrated. Common and different characteristics of noci- ceptor-blocking actions after systemic, perineural, local, intrathecal, and in vitro treatments are summarized. Evidence for the misleading conclusions drawn from neonatal capsaicin pretreatment is presented. Perspectives opened from cloning the capsaicin receptor “Transient Receptor Potential Vanilloid 1’’ (TRPV1) are outlined and potential molecular mechanisms behind the long-lasting functional, ultrastructural, and nerve terminal-damaging effects of capsaicin and other TRPV1 agonists are summarized. Neurogenic inflammation and the long-list of “capsaicin- sensitive” tissue responses are mediated by an unorthodox dual sensory-efferent function of peptidergic TRPV1-expressing nerve terminals which differ from the classical efferent and sensory nerve endings that have a unidirectional role in neuroregulation. Thermoregulatory effects of capsaicin are discussed in detail. It is suggested that since hyperthermia and burn risk due to enhanced noxious heat J. Szolcsányi (*) Department of Pharmacology and Pharmacotherapy, University of Pécs Medical School, Szigeti u. 12, Pécs H-7624, Hungary e-mail: [email protected] O. M. E. Abdel-Salam (ed.), Capsaicin as a Therapeutic Molecule, Progress in Drug 1 Research 68, DOI: 10.1007/978-3-0348-0828-6_1, © Springer Basel 2014 2 J. Szolcsányi threshold are the major obstacles of some TRPV1 antagonists, they could be over- come. The special “multisteric” gating function of the TRPV1 cation channel pro- vides the structural ground for blocking chemical activation of TRPV1 without affecting its responsiveness to physical stimuli. A new chapter of potential anal- gesics targeting nociceptors is now already supported for pain relief in persistent pathological pain states. 1.1 Introduction Capsaicin is the main pungent hot principle of the fruit capsicum species (Capsicum annuum, Capsicum frutescent, Capsicum longum etc.) of the genus Solanaceae. This plant originated from the Americas and has become a popular culinary spice of food throughout the world. Thus capsicum is known under vari- ous names such as chilli pepper, red pepper, paprika, cayane pepper, tabasco, jala- peno, or under its ancient name aji. Archeological evidence from Mesoamerica documented that inhabitants of the Tehuacan valley consumed red pepper back to about 7000 BC. From burials from this age, pepper fruits and seeds were found in early settlements of Mexico. Ancient native people domesticated chilli around 5200–3400 BC, (Mac Neish 1964; Mózsik et al. 2009) and potteries from the Nazca Culture in Peru were deco- rated with figures of chilli fruits (Lembeck 1987). For further interesting readings see (Mózsik et al. 2009; Szállási and Blumberg 1999). The written history of red pepper started with Christopher Columbus, who described in his log in 1493 that inhabitants of the New World commonly eat foods with chilli (Szolcsányi 1993). He named it red pepper because of its spicy taste resembling the black and white peppers of the Piper genus used in Europe as favorite and rather expensive spices. Red pepper was also popular in the Old World. Beyond its culinary usage capsicum has been used also since centuries as folk medicine. Since the nineteenth century, extracts prepared from pungent pods were listed in Pharmacopoeia of the United States as Oleoresin capsicin since 1860 (Du Mez 1917), and an alcoholic extract, Tinctura capsici was used in Europe as topical counterirritant analgesic remedies (Nothnagel 1870; Geissler and Moeller 1887). Since these preparations with the burning sensation induced also cutane- ous vasodilatation and reddening of the skin they were also called rubefacients. In tropical countries, chilli intake was used as folk medicine to cope with the hot cli- mate by enhancing heat loss regulation with capsicum-induced skin vasodilatation and “gustatory sweating” (Lee 1954). Isolation of the pungent principle and studies on the pharmacological effects of capsicum started in the early decades of the nineteenth century. Impure extract made by Christian Friedrich Bucholz was first named as capsicin and the oily impure ingredient isolated by Rudolf Buchheim was named capsicol since it was thought to be a nitrogen-free nonalkaloid compound. Thresh crystallized for the first time the active principle in 1876 and renamed it capsaicin (Geissler and