Biochemistry and pharmacology of arachidonylethanolamide, a putative endogenous cannabinoid

This review presents and explores the hypothesis that N-arachidonylethanolamine (AEA, also called anandamide) is synthesized in the brain and functions as an endogenous ligand of the cannabinoid receptor. Support for this hypothesis comes from in vitro experiments demonstrating that AEA binds and activates signaling through the cannabinoid receptor. In addition, in vivo AEA produces effects very similar to those of the classical agonists of the cannabinoid receptor. Evidence for the cellular synthesis and release of AEA is not as clear. Data are presented that suggest that AEA is synthesized via a two enzyme process. First, a novel phospholipid (N-arachidonylphosphatidylethanolamine) is formed by a calcium-dependent transacylase. This lipid is a substrate for a phosphodiesterase of the phospholipase D type which releases AEA. Although there is some evidence to support this hypothesis, it is clear that AEA is a very minor product of this enzymatic cascade. Several important questions remain to be answered, including whether the concentrations of AEA synthesized by cells are sufficient to support a signaling role in the brain.