The endocannabinoid system: a general view and latest additions

Abstract

After the discovery, in the early 1990s, of specific G-protein-coupled receptors for marijuana's psychoactive principle Delta(9)-tetrahydrocannabinol, the cannabinoid receptors, and of their endogenous agonists, the endocannabinoids, a decade of investigations has greatly enlarged our understanding of this altogether new signalling system. Yet, while the finding of the endocannabinoids resulted in a new effort to reveal the mechanisms regulating their levels in the brain and peripheral organs under physiological and pathological conditions, more endogenous substances with a similar action, and more molecular targets for the previously discovered endogenous ligands, anandamide and 2-arachidonoylglycerol, or for some of their metabolites, were being proposed. As the scenario becomes subsequently more complicated, and the experimental tasks to be accomplished correspondingly more numerous, we briefly review in this article the latest 'additions' to the endocannabinoid system together with earlier breakthroughs that have contributed to our present knowledge of the biochemistry and pharmacology of the endocannabinoids.

Figure 1

Established and newly proposed endocannabinoids. Chemical structures of the five endogenous cannabinoid ligands identified so far.

Figure 2

Proposed biosynthetic pathways of (a) anandamide and (b) 2-AG. P denotes a phosphate group, R₁ the acyl chain in arachidonic acid, R, R₂ and R₃ acyl chains of other fatty acids, and X the base in phosphoglycerides. In the case of 2-AG, the phosholipids mostly found to act as precursors for the sn-1-acyl-2-arachidonoyl-glycerol are phosphoinositides.

Figure 3

Inactivation (cellular reuptake and intracellular metabolism) of anandamide and 2-arachidonoylglycerol (2-AG). P denotes a phosphate group, R the head group of the endocannabinoid, R₃ the acyl chain of other fatty acids and X the base in phosphoglycerides. FAAH, fatty acid amide hydrolase; MAGL, monoacylglycerol lipase.