Biosynthesis and inactivation of endocannabinoids: relevance to their proposed role as neuromodulators.

The two putative endogenous ligands of cannabinoid receptors, anandamide and 2-arachidonoylglycerol, are synthesized by and released from neurons in a Ca2+-dependent fashion, and re-uptaken and catabolized by both neurons and astrocytes. These biochemical features of the endocannabinoids, as well as some of their pharmacological effects in both central and peripheral nervous systems, suggest a role as neuromodulators for these metabolites. This neuromodulatory role is supported by the brain regional distribution of anandamide, its biosynthetic precursor and its major inactivating enzyme, and by the existence of possible regulatory mechanisms for the biosynthesis and inactivation of endocannabinoids, which are reviewed in this article.