Handbook of Experimental Pharmacology
Volume 231
Editor-in-Chief
W. Rosenthal, Jena
Editorial Board
J.E. Barrett, Philadelphia
V. Flockerzi, Homburg
M.A. Frohman, Stony Brook, NY P. Geppetti, Florence
F.B. Hofmann, Mu ̈nchen
M.C. Michel, Ingelheim
C.P. Page, London
A.M. Thorburn, Aurora, CO
K. Wang, Beijing
More information about this series at http://www.springer.com/series/164
Roger G. Pertwee Editor
Endocannabinoids
Springer
Editor
Roger G. Pertwee
Professor of Neuropharmacology
University of Aberdeen Institute of Medical Sciences Aberdeen
United Kingdom
Roger G. Pertwee
Professor of Neuropharmacology
University of Aberdeen Institute of Medical Sciences Aberdeen
United Kingdom
ISSN 0171-2004 ISSN 1865-0325 (electronic) Handbook of Experimental Pharmacology
ISBN 978-3-319-20824-4 ISBN 978-3-319-20825-1 (eBook) DOI 10.1007/978-3-319-20825-1
Library of Congress Control Number: 2015951984
ISBN 978-3-319-20824-4 ISBN 978-3-319-20825-1 (eBook) DOI 10.1007/978-3-319-20825-1
Library of Congress Control Number: 2015951984
Springer Cham Heidelberg New York Dordrecht London
# Springer International Publishing Switzerland 2015
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Printed on acid-free paper
Springer International Publishing AG Switzerland is part of Springer Science+Business Media (www.springer.com)
# Springer International Publishing Switzerland 2015
This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use.
The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made.
Printed on acid-free paper
Springer International Publishing AG Switzerland is part of Springer Science+Business Media (www.springer.com)
For Teresa
Preface
The Endocannabinoid System: A Look Back and Ahead
The major neurotransmitter systems were discovered many decades ago. It is strange that the endocannabinoid system—certainly one of major physiological importance remained unknown until the early 1990s. This was due, in part at least, to the lack of research on the plant cannabinoids, made difficult by legal constraints. Indeed, many of the major plant cannabinoids were not isolated, and their structures were not elucidated until the 1960s. Later, their chemistry, metabolism, biochemistry, and pharmacology were extensively investigated. However, the mechanism of action of Δ9-tetrahydrocannabinol (THC), the major psychoactive constituent, remained elusive for nearly 20 years. It was originally believed that it acts nonspecifically on neural membranes. Gradually, pharmacological and chemi- cal data surfaced, which were inconsistent with the nonspecificity of THC action. Indeed, in the late 1980s and early 1990s, two specific cannabinoid receptors, CB1 and CB2, were identified. Stimulation of CB1 leads to the well-known marijuana effects; CB2 is apparently part of a major, new protective system. Two endogenous cannabinoids (endocannabinoids), anandamide and 2-AG, were isolated in the 1990s. Anandamide is arachidonoyl ethanolamide and 2-AG is the arachidonoyl ester of glycerol. Thereafter, enzymes involved in their biosynthesis and metabolism were found. Many thousands of papers on this novel system have been published [see Di Marzo et al. (2015), Maccarrone et al. (2014), and Mechoulam et al. (2014), for recent reviews on the endocannabinoid system]. However, we are still far away from fully understanding this system, or, indeed, plant cannabinoids. Thus, although there are thousands of publications on THC and many hundreds on cannabidiol (CBD), the rest of the plant cannabinoids have barely been investigated. And neither anandamide nor 2-AG has ever been administered to humans. By comparison, insulin was administered to humans almost immediately after its discovery in the 1920s and became a medicine within months. Are we missing something?
Several additional endogenous fatty acid ethanol amides, in which the fatty acid moiety is not derived from arachidonic acid as in anandamide, but from other fatty acids, have been found to bind to the endocannabinoid receptors. Are they relevant to endocannabinoid activity? There are also some chemically related endogenous fatty acid–amino acid amides, which lower brain trauma damage, but do not bind to cannabinoid receptors. However, their activity can be blocked by CB1 or CB2 antagonists and they do not act on CB2 knockout mice. Is the endocannabinoid system actually much more complex than was first thought?
Recently, two synthetic cannabinoid enantiomers were both reported to be CB2 agonists; however, an inverse relationship was found between binding affinity and biological potency, which was cannabinoid-based (Smoum et al. 2015). A molecular modeling analysis suggested that these enantiomers have two different binding conformations within the CB2 receptor, with one of them possibly responsible for the affinity difference. Hence, different cannabinoid ligands may have different orientations relative to the same binding site. Thus, cannabinoid orientation targeted ligands, at least for the CB2 receptor, may have promising potential for the pharmacological activation of distinct processes. Is this a general phenomenon?
Many patients claim that plant extracts work better than pure THC in many disease states. It is widely believed that Cannabis sativa extracts differ in their activity from Cannabis indica extracts, regardless of the level of THC. And, in spite of the wide use of various medicinal cannabis products, which are mixtures of cannabinoids and other plant constituents, pure THC has remained a minor drug. Is this due to modification of THC actions via “entourage effects”? CBD is well known to modify THC activity in human users. Do additional plant cannabinoids and terpene constituents also affect THC activity?
Over the last few years, several research groups have noted that both THC and CBD, as well as anandamide, cause epigenetic modifications by methylation, leading to distinct therapeutic effects. Does epigenetics play a major role in the functioning of the endocannabinoid system? If it does, then cannabinoids may affect the bases of at least some diseases rather than their symptoms a major difference from the activity of many drugs used today.
There have been very few clinical trials with THC or with CBD or with cannabis extracts containing fixed ratios of the major constituents. Such trials on small numbers of patients have shown very positive results in epilepsy, post-trauma, Parkinson’s disease, Crohn’s disease, and a few other disorders. Somewhat larger clinical trials on schizophrenia and graft-versus-host-disease (GVHD) have led to statistically significant therapeutic effects. But, where are the clinical trials in various cancer diseases where anecdotal evidence points to possible therapeutic effects?
We have made major advances in understanding the chemistry, biochemistry, and pharmacological effects of the plant cannabinoids and the endocannabinoids. The present book provides an outstanding summary of a wide variety of important endocannabinoid findings that will help generate novel ideas for future research.
Thus, I have no doubt that further research with endocannabinoids will throw additional light on the actions of these compounds. However, I believe that the most important future steps in the endocannabinoid area are to advance cannabinoid-based clinical trials in many disease states where strong anecdotal evidence already exists.
Jerusalem, Israel – Raphael Mechoulam
References
Di Marzo V, Stella N, Zimmer A (2015) Endocannabinoid signalling and the deteriorating brain. Nat Rev Neurosci 16:30–42
Maccarrone M, Guzma ́n M, Mackie K, Doherty P, Harkany T (2014) Programming of neural cells by (endo)cannabinoids: from physiological rules to emerging therapies. Nat Rev Neurosci 15:786–801
Mechoulam R, Hanusˇ LO, Pertwee R, Howlett AC (2014) Early phytocannabinoid chemistry to endocannabinoids and beyond. Nat Rev Neurosci 15:757–764
Smoum R, Baraghithy S, Chourasia M, Breuer A, Mussai N, Attar-Namdar M, Kogan N, Raphael B, Bolognini D, Cascio MG, Marini P, Pertwee RG, Shurki A, Mechoulam R, Bab I (2015) CB2 cannabinoid receptor agonist enantiomers HU-433 and HU-308: an inverse relationship between binding affinity and biological potency. Proc Natl Acad Sci USA 112(28):8774–8779
Di Marzo V, Stella N, Zimmer A (2015) Endocannabinoid signalling and the deteriorating brain. Nat Rev Neurosci 16:30–42
Maccarrone M, Guzma ́n M, Mackie K, Doherty P, Harkany T (2014) Programming of neural cells by (endo)cannabinoids: from physiological rules to emerging therapies. Nat Rev Neurosci 15:786–801
Mechoulam R, Hanusˇ LO, Pertwee R, Howlett AC (2014) Early phytocannabinoid chemistry to endocannabinoids and beyond. Nat Rev Neurosci 15:757–764
Smoum R, Baraghithy S, Chourasia M, Breuer A, Mussai N, Attar-Namdar M, Kogan N, Raphael B, Bolognini D, Cascio MG, Marini P, Pertwee RG, Shurki A, Mechoulam R, Bab I (2015) CB2 cannabinoid receptor agonist enantiomers HU-433 and HU-308: an inverse relationship between binding affinity and biological potency. Proc Natl Acad Sci USA 112(28):8774–8779
Contents
Endocannabinoids and Their Pharmacological Actions . . . . . . . . . . . . . . 1 Roger G. Pertwee
BiosynthesisandFateofEndocannabinoids…………………. 39 Maria Grazia Cascio and Pietro Marini
Distribution of the Endocannabinoid System in the Central NervousSystem…………………………………….. 59 Sherry Shu-Jung Hu and Ken Mackie
The Potential of Inhibitors of Endocannabinoid Metabolism forDrugDevelopment:ACriticalReview…………………… 95 Christopher J. Fowler
Genetic Manipulation of the Endocannabinoid System . . . . . . . . . . . . . . 129 Andreas Zimmer
Endocannabinoids and the Immune System in Health and Disease . . . . . 185 Guy A. Cabral, Gabriela A. Ferreira, and Melissa J. Jamerson
Endocannabinoids in Multiple Sclerosis and Amyotrophic Lateral Sclerosis…………………………………………. 213 Gareth Pryce and David Baker
Endocannabinoids and Neurodegenerative Disorders: Parkinson’s
Disease, Huntington’s Chorea, Alzheimer’s Disease, and Others . . . . . . . 233 Javier Ferna ́ndez-Ruiz, Julia ́n Romero, and Jose ́ A. Ramos
EndocannabinoidsandMentalDisorders…………………… 261 TIziana Rubino, Erica Zamberletti, and Daniela Parolaro
Cannabis and Endocannabinoid Signaling in Epilepsy . . . . . . . . . . . . . . 285 Istva ́n Katona
Endocannabinoids and the Endocrine System in Health and Disease . . . 317 Cecilia J. Hillard
Endocannabinoids and Reproductive Events in Health and Disease . . . . 341 Natalia Battista, Monica Bari, and Mauro Maccarrone
BiosynthesisandFateofEndocannabinoids…………………. 39 Maria Grazia Cascio and Pietro Marini
Distribution of the Endocannabinoid System in the Central NervousSystem…………………………………….. 59 Sherry Shu-Jung Hu and Ken Mackie
The Potential of Inhibitors of Endocannabinoid Metabolism forDrugDevelopment:ACriticalReview…………………… 95 Christopher J. Fowler
Genetic Manipulation of the Endocannabinoid System . . . . . . . . . . . . . . 129 Andreas Zimmer
Endocannabinoids and the Immune System in Health and Disease . . . . . 185 Guy A. Cabral, Gabriela A. Ferreira, and Melissa J. Jamerson
Endocannabinoids in Multiple Sclerosis and Amyotrophic Lateral Sclerosis…………………………………………. 213 Gareth Pryce and David Baker
Endocannabinoids and Neurodegenerative Disorders: Parkinson’s
Disease, Huntington’s Chorea, Alzheimer’s Disease, and Others . . . . . . . 233 Javier Ferna ́ndez-Ruiz, Julia ́n Romero, and Jose ́ A. Ramos
EndocannabinoidsandMentalDisorders…………………… 261 TIziana Rubino, Erica Zamberletti, and Daniela Parolaro
Cannabis and Endocannabinoid Signaling in Epilepsy . . . . . . . . . . . . . . 285 Istva ́n Katona
Endocannabinoids and the Endocrine System in Health and Disease . . . 317 Cecilia J. Hillard
Endocannabinoids and Reproductive Events in Health and Disease . . . . 341 Natalia Battista, Monica Bari, and Mauro Maccarrone
EndocannabinoidsandMetabolicDisorders…………………. 367 Blandine Gatta-Cherifi and Daniela Cota
Endocannabinoids and the Cardiovascular System in Health andDisease……………………………………….. 393 Saoirse Elizabeth O’Sullivan
Endocannabinoids and the Digestive Tract and Bladder in Health andDisease……………………………………….. 423 Angelo A. Izzo, Giulio G. Muccioli, Michael R. Ruggieri,
and Rudolf Schicho
EndocannabinoidsandCancer………………………….. 449 Guillermo Velasco, Cristina Sa ́nchez, and Manuel Guzma ́n
Index……………………………………………. 473
Endocannabinoids and the Cardiovascular System in Health andDisease……………………………………….. 393 Saoirse Elizabeth O’Sullivan
Endocannabinoids and the Digestive Tract and Bladder in Health andDisease……………………………………….. 423 Angelo A. Izzo, Giulio G. Muccioli, Michael R. Ruggieri,
and Rudolf Schicho
EndocannabinoidsandCancer………………………….. 449 Guillermo Velasco, Cristina Sa ́nchez, and Manuel Guzma ́n
Index……………………………………………. 473
