An introduction to the endocannabinoid system: from the early to the latest concepts

A rather complex and pleiotropic endogenous signalling system was discovered in the late 1990s, starting from studies on the mechanism of action of Δ9-tetrahydrocannabinol, the major psychoactive principle of the hemp plant Cannabis sativa. This system includes: (1) at least two G-protein-coupled receptors, known as the cannabinoid CB1 and CB2 receptors; (2) the endogenous agonists at these receptors, known as endocannabinoids, of which anandamide and 2-arachidonoylglycerol are the best known; and (3) proteins and enzymes for the regulation of endocannabinoid levels and action at receptors. The number of the members of this endocannabinoid signalling system seems to be ever increasing as new non-CB1 non-CB2 receptors for endocannabinoids, endocannabinoid-related molecules with little activity at CB1 and CB2 receptors, and new enzymes for endocannabinoid biosynthesis and degradation are being identified every year. The complexity of the endocannabinoid system and of its physiological and pathological function is outlined in this introductory chapter, for a better understanding of the subsequent chapters in this special issue.