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...