Actions and Regulation of Ionotropic Cannabinoid Receptors

Preparations of the Cannabis plant have been used by man for multiple purposes for millennia; however, a pharmacological understanding of the plant’s unique metabolites has only come about in the last 60–70 years. A key landmark in cannabinoid science was the work of Raphael Mechoulam identifying the nature of many of these unique metabolites, notably Δ9-tetrahydrocannabinol (THC) in the early 1960s. In the late 1980s, William Devane and Allyn Howlett provided evidence for the existence of a cannabinoid receptor in the brain, where THC predominantly acts. Molecular identification of this CB1 cannabinoid receptor and a “peripheral” CB2 cannabinoid receptor was reported in the early 1990s by Tom Bonner and Sean Munro, respectively. At about that time, Raphael Mechoulam and Roger Pertwee expanded the field further with identification of the two major endogenous agonists at the cannabinoid receptors, paving the way for characterization of the multiple constituents of the endocannabinoid system. Today, a simple interrogation of PubMed reveals tens of thousands of published articles relating to Cannabis and the cannabinoids. The breadth of involvement of cannabinoids and their receptors in basic physiology and pathophysiology is immense ranging from roles in the most basic aspects of gene expression to suspected mediation of complex disease processes including chronic pain, cancer, schizophrenia, and neurodegeneration. Getting to grips with such a massive and diverse subject requires some signposting and the Pharmacology of Cannabinoids aims to do just that. The chapters are authored by combinations of experienced and well-published experts in the field who have not, in the main, worked together previously, a strategy which we think facilitates fresh approaches to the topics covered. The scene is set with reviews of the pharmacology of the plant-derived cannabinoids and the diverse range of endogenous lipids that underpin cannabinoid signaling in the body. How these endocannabinoids are practically analyzed and quantified is also explained, as well as descriptions of the mechanisms of their turnover. The multiple targets for the endogenous and exogenous cannabinoids are discussed in chapters covering the G proteincoupled CB1 and CB2 receptors, cannabinoid-receptor-like orphan GPCR, ion channels (particularly the transient receptor potential channels), and nuclear receptors; postreceptor signaling mechanisms are described within these chapters. It is now clear that agonist signaling in general is more dynamic than previously thought and a chapter on cannabinoid agonist bias is included. Understanding the roles of cannabinoids in the pathophysiology of important disease states and the potential for developing new therapies based on an expanded knowledge base is crucial and chapters are devoted to in-depth accounts of cannabinoid involvement in pain, cancer, and cardiovascular and neuroinflammatory diseases. We are sincerely grateful to our friends and colleagues who have contributed to this volume which we trust will be a useful reference source and, hopefully, an inspiration to scientists, be they novices in the field or cannabinoid aficionados.