The lipid anandamide derived from arachidonic acid binds to the cannabinoid G-protein coupled receptors CB-1 and CB-2 to exert its biological effects. The CB-1 receptor is also the site of action of the psychoactive components of marijuana, including tetrahydrocannabinol (THC), and responsible for the effects of cannabinoids to repress learning, memory, and anxiety, relieve pain and nausea, and to stimulate appetite. The CB-2 receptor is expressed mainly in cells of the immune system and appears to modulate immune functions, but not to be involved in the effects of cannabinoids in the central nervous system. In addition to the illicit use of cannibinoids as drugs of abuse, the pharmaceutical use of natural and synthetic cannabinoids is being intensely studied, including a possible role in neurodegenerative diseases. Another therapeutic approach is the pharmacological modulation of levels of the endogenous cannabinoid anandamide. Although the subject of some controversy, the most likely route for the biosynthesis of anandamide starts with the formation of phosphatidylethanolamine from arachidonic acid and ethanolamine. Phosphatidylethanolamine is converted by N-acyltransferase to the phospholipid N-arachidonoyl-phosphatidylethanolamine (NAPE) and hydrolysis by phospholipase D releases phosphatidic acid and anandamide, which binds to the cannabinoid receptors. The signal it induces is terminated in part by degradation of anandamide by anandamide hydrolase (FAAH). 2-arachidonoyl-glycerol (2-AG) and 2-arachidonoyl glyceryl ether have also been shown to bind the cannabinoid receptors, and has been suggested to be important endocannabinoids. Also complicating cannabinoid pharmacology is the suggestion that some effects of cannabinoids might be moderated by additional receptor subtypes that have not yet been identified or by the vanilloid receptors.
