Pharmacological, physiological and clinical implications of the discovery of cannabinoid receptors.

It is now generally accepted that many of the known pharmacological effects of cannabinoids are mediated by receptors. These are CBI, that are expressed mainly by central and peripheral neurons, and CBz, that occur mainly in immune cells [1,2]. The discovery of these receptors has prompted the development of selective CB, and CBz receptor agonists and antagonists [ 1 , 3 4 1 and has also led to the demonstration that there are endogenous agonists for these receptors in mammalian tissues [ 1,2,6131. Cannabinoid receptors and their endogenous ligands together constitute what is referred to in this paper as 'the endogenous cannabinoid system'. The most important of the endogenous cannabinoids discovered to date are arachidonoylethanolamide (anandamide) and 2-arachidonoyl glycerol and there is evidence that both of these compounds serve as neuromodulators or neurotransmitters. This comes from demonstrations that they can be synthesized by neurons, that they can undergo depolarization-induced release from neurons and that, once released, they are rapidly removed from the extracellular space by tissue uptake processes andlor enzymic hydrolysis [1,2,10,14,15]. With regard to the biosynthesis of anandamide, there is growing evidence that this fatty acid amide is usually formed from 'V-arachidonoyl phosphatidylethanolamine (NAPE) by the action of a phospholipase D-like enzyme and that NAPE formation results from calcium-dependent, N-acyltransferase catalysed transfer of an arachdinonoyl group from the sn-1 position of phospholipids to the amino group of phosphatidylethanolamine [2,10,16,17]. Removal of anandamide from the extracellular space seems to depend on a carrier-mediated, saturable