Cannabinoids E-Book

Vincenzo Di Marzo

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 632

Veröffentlichungsjahr: 2014

Beschreibung

Cannabinoids

‘Cannabinoids’ is a broad term covering a group of natural products from Cannabis sativa, one of which locks on to specific receptors – protein molecules on the surface of cells – known as cannabinoid receptors. Over the past decades scientists have found that cannabinoid receptors and their endogenous ligands, the endocannabinoids, are involved in a vast array of physiological functions, including helping to control brain activity, energy metabolism, heart function, the immune system and even reproduction.

In Cannabinoids, Vincenzo Di Marzo has assembled contributions from international experts to provide the definitive guide to what continues to be a rapidly developing research field. After an introductory historical chapter, the book continues by looking at the biochemical, genetic and molecular elements of cannabinoids, followed by chapters covering their role in health and disease. The final chapter outlines the need for a new nomenclature to reflect the complex and multi-disciplinary nature of this area.

• An authoritative guide to the history, development and possible future of cannabinoid research.
• Includes contributions from leading international experts in the field.
• Clearly written, well organised and logically presented.

Cannabinoids will prove invaluable to researchers, practitioners and students across a wide range of disciplines, needing an up-to-date guide to this significant area of research.

Leseprobe

Table of Contents

Cover

Title Page

Copyright

Dedication

In memoriam

List of Contributors

Preface

References

Chapter 1: Looking ahead after 50 years of research on cannabinoids

1.1 Summary

1.2 Introduction

1.3 Cannabidiol (CBD)

1.4 Fatty acid amides of amino acids and related compounds

1.5 Conclusions

1.6 References

Chapter 2: Cannabinoid receptor intracellular signalling: The long journey from binding sites to biological effects

2.1 Historical progression: Serendipity to opportunity

2.2 Significance of being a G protein coupled receptor (GPCR)

2.3 CB

1

cannabinoid receptor interactions with other cellular signals

2.4 Functional role of CB

1

receptor accessory proteins

2.5 Opportunities: Pharmacotherapeutic insights based on cell signalling

2.6 Concluding remarks

2.7 References

Chapter 3: Endocannabinoid biochemistry: What do we know after 50 years?

3.1 Introduction

3.2 Endocannabinoids and related molecules

3.3 Biosynthesis of endocannabinoids and related molecules

3.4 Degradation of endocannabinoids

3.5 Oxidative metabolism of endocannabinoids

3.6 Conclusions and future perspectives

Acknowledgements

3.7 References

Chapter 4: Genetic dissection of the endocannabinoid system and how it changed our knowledge of cannabinoid pharmacology and mammalian physiology

4.1 Introduction: To set the stage

4.2 Tool box for genetic dissection

4.3 Understanding cannabinoid pharmacology

4.4 Unravelling endocannabinoid system functions

4.5 Caveats in genetics

4.6 What have we learnt about cannabinoid pharmacology and mammalian physiology?

4.7 Perspectives

4.8 References

Chapter 5: Cannabinoids, endocannabinoids and stress

5.1 Introduction

5.2 Regulation of endocannabinoid signalling by stress

5.3 ECS regulation of the HPA axis response to stress

5.4 ECS role in SNS responses to stress

5.5 Stress and ECS in the periphery

5.6 Summary

Acknowledgements

5.7 References

Chapter 6: Cannabinoids and the brain: New hopes for new therapies

6.1 Cannabinoids and the brain: A long journey together

6.2 Brain processes and brain disorders investigated in relation to the endocannabinoid system

6.3 Concluding remarks and future perspectives

6.4 References

Chapter 7: Potential therapeutic applications of cannabinoids in gastrointestinal and liver diseases: Focus on Δ9-tetrahydrocannabinol pharmacology

7.1 Introduction

7.2 The endocannabinoid system in the gut and in the liver

7.3 Potential therapeutic applications of cannabinoids in the gastrointestinal tract

7.4 Potential therapeutic applications of cannabinoids in the liver

7.5 Conclusions

Abbreviations

7.6 References

Chapter 8: Fifty years of ‘cannabinoid research’ and the need for a new nomenclature

8.1 An introduction to cannabinoid research and the ‘old’ nomenclature in this field (before the year 2000)

8.2 ‘New’ nomenclature (after the year 2000)

8.3 ‘Multi-target’ compounds

8.4 Conclusions

8.5 References

Index

End User License Agreement

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Guide

Cover

Table of Contents

Preface

Chapter 1: Looking ahead after 50 years of research on cannabinoids

List of Illustrations

Figure 1.1

Figure 1.2

Figure 1.3

Figure 3.1

Figure 3.2

Figure 3.3

Figure 3.4

Figure 3.5

Figure 3.6

Figure 3.7

Figure 5.1

Figure 5.2

Figure 6.1

Figure 8.1

Figure 8.2

List of Tables

Table 3.1

Table 3.2

Table 3.3

Table 4.1

Table 4.2

Table 6.1

Table 8.1

Cannabinoids

Edited by

Vincenzo Di Marzo

Institute of Biomolecular Chemistry

Consiglio Nazionale delle Ricerche

Pozzuoli, Italy

This edition first published 2014 © 2014 by John Wiley & Sons, Ltd

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Library of Congress Cataloging-in-Publication Data

Cannabinoids (2014)

Cannabinoids / [edited by] Vincenzo Di Marzo.

p. ; cm.

Includes bibliographical references and index.

ISBN 978-1-118-45129-8 (cloth)

I. Di Marzo, Vincenzo, editor of compilation. II. Title.

[DNLM: 1. Cannabinoids– history. 2. Cannabinoids– pharmacology. 3. Cannabinoids– therapeutic use. 4. History, 20th Century. 5. Receptors, Cannabinoid– physiology. QV 77.7]

QP801.C27

615.7′827— dc23

2014005428

A catalogue record for this book is available from the British Library.

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books.

Cover image: Courtesy of Vincenzo Di Marzo

To Raphael ‘Raphi’ Mechoulam, the ‘father of cannabinoid research’, and a dear friend, who never stops amazing me and is still short of just one important prize, at least thus far.

To Geoffrey W. Guy who realised the dream of many scientists in this field by making the development of a cannabinoid-based medicine possible.

To William A. ‘Bill’ Devane, the inventor of the name ‘anandamide’, and an important player in its discovery as well as in that of cannabinoid receptors, whom I have not forgotten.

To Adriana and Marta, for having had to indirectly endure 7-days-a-week cannabinoid research for 21 and 17 years of their lives, respectively, and yet always being several orders of magnitude more important for me.

In memoriam

I would like to remember Ester Fride, Billy R. Martin and J. Michael Walker who have made fundamental contributions to cannabinoid research and, very sadly, are no longer among us.

List of Contributors

Lawrence C. Blume

Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, USA

Francesca Borrelli

Department of Pharmacy, University of Naples Federico II and Endocannabinoid Research Group, Naples, Italy

Paolo Caraceni

Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy

Luciano De Petrocellis

Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy

Vincenzo Di Marzo

Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy

Khalil M. Eldeeb

Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, USA; and Pharmacology Department, Faculty of Medicine, Al Azhar University, New Damietta, Egypt

Javier Fernández-Ruiz

Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain; and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain

Filomena Fezza

Department of Experimental Medicine & Surgery, Tor Vergata University of Rome, Rome, Italy; and European Center for Brain Research/IRCCS Santa Lucia Foundation, Rome, Italy

Yolanda García-Movellán

Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain; and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain

Ferdinando A. Giannone

Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy

Mariluz Hernández

Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain; and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain

Cecilia J. Hillard

Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, USA

Allyn C. Howlett

Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, USA

Angelo A. Izzo

Department of Pharmacy, University of Naples Federico II and Endocannabinoid Research Group, Naples, Italy

Qing-song Liu

Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, USA

XiaoQian Liu

Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, USA

Beat Lutz

Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany

Mauro Maccarrone

European Center for Brain Research/IRCCS Santa Lucia Foundation, Rome, Italy; and Center of Integrated Research, Campus Bio-Medico University of Rome, Rome, Italy

Raphael Mechoulam

Institute for Drug Research, Hebrew University Medical Faculty, Jerusalem, Israel

Christopher J. Roberts

Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, USA

Bin Pan

Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, USA

Leyu Shi

Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, USA

Preface

Vincenzo Di Marzo

Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy

When hearing the word ‘cannabinoid’, even the layman immediately knows that this must have to do with the Cannabis plant and its various psychotropic preparations, such as marijuana and hashish, which undoubtedly still represent the most widely used drug in the Western world after nicotine and alcohol. Yet, the recreational use of cannabis is only one of several that mankind has found for this plant over many centuries. Unlike other plants used as sources of substances of abuse, hemp has in fact accompanied human progress in many of its aspects, and different varieties of Cannabis have been used, among other things, as a source of ‘inspiration’ in religious rites, a strong fibre for ropes and fabric, and as medicinal preparations, thus helping in at least four fundamental aspects of human life since its early origins: religion, health, manufacture and recreation.

The medicinal use of cannabis probably originates in ancient China, nearly 4000 years ago. Although the earliest written reference to the use of hemp against pain and inflammation is the Chinese Rh-Ya (1500 BC), the ‘red emperor’ Shen Nung (2838–2698 BC), who is considered the father of all herbalists, is alleged to have documented its use in his book The Herbal. More recent evidence for the use of cannabis, for example against various inflammatory and painful conditions, can be found in the ancient Egyptian, Indian, Greek and Roman pharmacopeias, but also in medieval Islamic medicine; whereas the Irish physician William O'Shaughnessy is credited with introducing the therapeutic use of cannabis to Western medicine in the 1830s (O'Shaughnessy, 1838–1840). Despite this centuries old, mostly anecdotal, history of medicinal use, it was only during the 1960s, with the explosion of marijuana abuse in Western countries, that major efforts were made to identify the chemical components of this preparation that could be responsible for its psychotropic activity. Thus, the first studies on the mechanism of action of cannabis were initiated to explain its psychotropic effects and, in some cases, to substantiate its purported dangerousness, rather than its medicinal actions. This potential bias has somewhat influenced research on cannabinoids for many decades, but nevertheless led first to the discovery of the psychotropic component of cannabis, Δ9-tetrahydrocannabinol (THC), and later to the identification of specific plasma membrane, G protein-coupled receptors for this compound, named ‘cannabinoid receptors’. Then followed their endogenous ligands, the endocannabinoids and their metabolic enzymes—that is the whole ‘endocannabinoid system’. This signalling system is currently regarded by many as a fundamental pro-homeostatic regulatory system involved in all physiological and pathological conditions in mammals (Pacher and Kunos, 2013).

A major player in the discovery of the endocannabinoid system—through having led studies towards first the chemical identification of THC and later its pharmacological characterisation, the development of tools that allowed the discovery of its receptors, and finally to the isolation of the first endogenous ligands of such receptors, anandamide (Devane et al., 1992)—Raphael Mechoulam had to be the author of the first chapter of this celebrative book. Universally recognised as the ‘father of cannabinoid research’, Prof. Mechoulam reviews the milestones in this field, and then describes two topics that represent new trends of high potential therapeutic importance: the physiological role of some anandamide-related mediators, that is the fatty acid amides of amino acids, and the pharmacology of the most abundant non-psychotropic cannabinoid, cannabidiol (CBD). Indeed, the discovery of anandamide triggered interest in other endogenous lipids that do not necessarily act via cannabinoid receptors and are just emerging as important actors in mammalian physiology. On the other hand, non-psychotropic cannabinoids, such as CBD, have been neglected in the past due to the socio-political urgency to focus research on Δ9-THC, and only now are coming out as potential contributors to the medicinal properties of cannabis. This is also witnessed by the recent approval of Sativex®, a combination of botanical extracts enriched in THC and CBD in a 1 : 1 ratio, used to effectively relieve pain and spasticity in multiple sclerosis (Podda and Constantinescu, 2012).

The second chapter of this book is by Allyn Howlett and her colleagues, Lawrence Blume and Khalil Eldeeb. Prof. Howlett is another ‘pivot’ in cannabinoid research as, among other things, she coordinated the first studies leading to the identification of specific binding sites for THC in the brain (Devane et al., 1988). She and her co-authors review here the crucial experimental steps that led to this discovery, and the latest developments on how such receptors work in terms of their intracellular signalling and regulation and inactivation by other proteins, which are all aspects of the endocannabinoid system to which Prof. Howlett has provided fundamental contributions during the last 20 years. It goes without saying that a full understanding of cannabinoid receptor function is of paramount importance for the future development of new therapies obtained by targeting these proteins.

The third chapter of the book still covers biochemical aspects of the endocannabinoid system, although focusing on the enzymes that regulate the tissue levels of the endogenous cannabinoid receptor ligands, or ‘endocannabinoids’, and related lipid mediators. Such enzymes are currently the focus of attention from many pharmaceutical companies, based on the assumption that the pharmacological manipulation of endocannabinoid levels should produce safer therapeutic actions than the direct targeting of receptors. The chapter is authored by Prof. Mauro Maccarrone, one of the major contributors to our current understanding of endocannabinoid biochemistry, and his collaborator, Filomena Fezza. The authors cover important aspects of the enzymes that biosynthesise and degrade the two major endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG), such as the diacylglycerol lipases, on the one hand, or the fatty acid amide hydrolase and monoacylglycerol lipase, on the other hand. They also discuss other important enzymes involved in the metabolism of endocannabinoid-related mediators, as well as emerging catabolic pathways for endocannabinoids.

A crucial step in the dissection of the role played by the various ‘endocannabinoid proteins’, be they receptors or enzymes, in basically all aspects of mammalian physiology and pathology (Pacher and Kunos, 2013) has been the development of both ‘global’ and ‘conditional’ genetically modified mice in which such proteins have been inactivated or overexpressed. Beat Lutz and his group have played a fundamental role in these studies over the last 13 years. In his chapter, he reviews how the genetic dissection of the endocannabinoid system has not only illuminated, to the careful eye, the function played by this pleiotropic regulatory system under both physiological and pathological conditions, but also shown how THC exerts its pharmacological effects in mammals. Prof. Lutz also wisely calls for caution against the use of the genetic approach without combining it with other experimental strategies.

One of the earliest functions to be postulated (Di Marzo et al., 1998), the physiological role as an endogenous pro-homeostatic regulator that helps re-establishing the ‘steady state’ after its perturbation by acute or chronic pathological challenges, such as after cellular or psychological stress, is currently the most widely recognised ‘systemic’ function of the endocannabinoid system. Cecelia Hillard has authored seminal studies on how stress and endocannabinoids are intimately linked. Together with her colleagues, Qing-song Liu, XiaoQian Liu, Bin Pan, Christopher J. Roberts and Leyu Shi, she reviews here the effect of chronic unpredictable stress exposure on several components of the endocannabinoid signalling system in various brain regions, as well as on cannabinoid CB1 receptor-mediated regulation of GABA release in the prelimbic region of the medial prefrontal cortex. These data show how the endocannabinoid system plays a vital role in the regulation of the impact of stress on the brain and body, and identify this system as a potential target for the treatment of many stress-related dysfunctions, such as depression and post-traumatic stress disorders.

Indeed, by being the most abundant G protein-coupled receptor in the mammalian brain, and coupled to inhibition of neurotransmitter release from presynaptic terminals, cannabinoid CB1 receptors are ideally located to play their pro-homeostatic role also in many neurological disorders characterised by neurotransmitter unbalance. On the other hand, by being upregulated in glial cells during inflammatory conditions, and coupled to inhibition of inflammatory cytokine release, cannabinoid CB2 receptors are ideal candidates to tone down neuroinflammation during such disorders (Velayudhan et al., 2013). This evidence is elegantly reviewed here by Javier Fernandez-Ruiz, perhaps the researcher that has most contributed to our current knowledge of the role of the endocannabinoid system in neuroinflammatory disorders, together with Mariluz Hernández and Yolanda García-Movellán. Importantly, Prof. Fernandez-Ruiz and his colleagues also discuss the role of this signalling system in other disorders that, at least in part, originate from, or are amplified by, brain dysfunctions, including: neuropathic pain, psychiatric disorders, addictive disorders, nausea and vomiting, sleep disorders, brain tumours and feeding disorders, thus making Chapter 6 of this book probably one of the most comprehensive reviews on endocannabinoids and CNS function and dysfunction that has appeared thus far in the literature on this topic.

Brain and gut, it is a fact, share many signals, and endocannabinoids make no exception. In fact, the beneficial effects of cannabis on diarrhea have been known for centuries (O'Shaughnessy, 1838–1840). Paolo Caraceni, Francesca Borrelli, Ferdinando Giannone and, particularly, Angelo Izzo have played a seminal role in our understanding of endocannabinoid function in the gut and review here state-of-the-art data on the adaptive changes that the endocannabinoid system undergoes in response to gastrointestinal and liver disturbances. They also describe potential areas of therapeutic interest in which cannabinoids and endocannabinoid-based drugs might be used in the near future, such as gastrointestinal reflux disease, irritable bowel syndrome, inflammatory bowel disease, colon cancer and chronic liver diseases, thus providing, again, one of the most comprehensive review articles on this subject to date.

This celebrative book could not be concluded without some reflections on how the use of the correct nomenclature can contribute to tone down the potential general feeling of confusion that might be engendered by the quick succession of discoveries in the rapidly expanding field of cannabinoid research. Having suggested in the past some names that have then met with general approval in the field, I thought I could be entitled to write a chapter on ‘cannabinoid nomenclature’. Together with Luciano De Petrocellis, we have tried to describe the history of cannabinoid research and its most important milestones in parallel with the sequential appearance of various names and definitions which have been, and still are, used. This is not a trivial issue for many reasons, including the fact that, as mentioned above, there is an ever increasing interest towards: (i) abundant non-THC cannabinoids from various cannabis varieties, and (ii) endocannabinoid-related endogenous mediators. These chemical entities, unlike THC and 2-AG, respectively, do not have as their main molecular mechanism of action the ability to interact with cannabinoid CB1 and CB2 receptors, and for this reason too the nomenclature developed so far in the cannabinoid field (Pertwee et al., 2010) cannot be easily applied to these compounds.

In conclusion, the present book celebrates a very intense half-century of cannabinoid research since THC's discovery in 1964, as well as its impact not only on our understanding of basic physiology, but also on therapeutic drug development. First, with the use of THC to combat cachexia and emesis in cancer and AIDS patients (Martin and Wiley, 2004), then with the development of the first endocannabinoid system-based drug for obesity—the CB1 inverse agonist rimonabant, subsequently withdrawn from the market due to psychiatric side-effects that might have been avoided with a more careful choice of the target patient and indication (Di Marzo and Després, 2009); and, lastly, with the development and marketing of Sativex® (Podda and Constantinescu, 2012) (yes indeed, back to the plant!), for which an approval to also treat cancer pain is currently being sought. The contributors, to whom I am extremely grateful for having provided eight top-class chapters, have also opened a window on what could be the potential future outcomes of the next half-century of experimental efforts, in terms of both basic and medical research. We must now only wait and see if all the expectations will be met in the end.

References

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Chapter 1Looking ahead after 50 years of research on cannabinoids

Raphael Mechoulam

Institute for Drug Research, Hebrew University Medical Faculty, Jerusalem, Israel

1.1 Summary

My lab has been involved in research on cannabis and endogenous cannabinoids for 50 years. In this overview I first summarise some of our work over these decades. Then, on the basis of previous research, I speculate on a few of the pathways cannabinoid investigations may follow in the future. Two possible research trends are discussed:

Cannabidiol—effects and mechanisms.

Fatty acid amides of amino acids and related endogenous molecules—biological roles.

1.2 Introduction

Cannabis research has a long and convoluted history. The first chemical endeavours were published in the 1840s. Around the end of the nineteenth century, crystalline cannabinol acetate was obtained after acetylation of an extract of hashish. Its structure was elucidated in the 1930s, when cannabidiol (CBD) was also isolated, but only a partial structure for it was put forward. Roger Adams and Alexander Todd published numerous, mostly synthetic, papers on cannabis and found that some synthetic tricyclic compounds had cannabis-like activity in dogs. Loewe (1950) summarised the pharmacological work on cannabis extracts and synthetic compounds carried out over a century. For early reviews, with an emphasis on the chemical aspects, see Mechoulam and Gaoni (1967a) and Mechoulam (1973).