New Advances in the Identification and Physiological Roles of the Components of the Endogenous Cannabinoid System

Abstract

Many aspects of the physiology and pharmacology of anandamide (arachidonoyl ethanolamide), the first endogenous cannabinoid ligand (“endocannabinoid”) isolated from pig brain, have been studied since its discovery in 1992. Ethanolamides from other fatty acids have also been identified as endocannabinoids with similar in vivo and in vitro pharmacological properties. 2-Arachidonoyl glycerol and noladin ether (2-arachidonyl glyceryl ether), isolated in 1995 and 2001, respectively, thus far display pharmacological properties in the central nervous system similar to those of anandamide. The endocanabinoids are widely distributed in brain, they are synthesized and released upon neuronal stimulation, and undergo reuptake and are hydrolyzed intracellularly by fatty acid amide hydrolase (FAAH). Pharmacological effects of the endocannabinoids are very similar, yet not identical, to those of the plant-derived and synthetic cannabinoid receptor ligands. In addition to pharmacokinetic explanations, direct or indirect interactions with other receptors have been considered to explain some of these differences, including activities at serotonin and γ-aminobutyric acid (GABA) receptors. Binding affinities for additional receptors such as the vanilloid receptor have to be taken into account in order to fully understand endocannabinoid physiology. Moreover, possible interactions with receptors for the lysophosphatidic acids deserve attention in future studies. Endocannabinoids have been implicated in a variety of physiological functions. These areas of central activity include pain reduction, motor regulation, learning/ memory, and reward. Neuroprotective effects of anandamide and 2-arachidonoyl glycerol have also been reported. Finally, the role of the endocannabinoid system in appetite stimulation in the adult organism, and perhaps more important, its critical involvement in milk ingestion and survival of the newborn, may further our understanding of the physiology of food intake and growth.