The contribution of cyclooxygenase-2 to endocannabinoid metabolism and action.

The development of sensitive analytical methods for measurement of endocannabinoids, their metabolites, and related lipids, has underlined the complexity of the endocannabinoid system. A case can be made for an 'endocannabinoid soup' (akin to the inflammatory soup) whereby the net effect of a pathological state and/or a pharmacological intervention on this system is the result not only of changes in endocannabinoid levels but also of their metabolites and related compounds that affect their function. With respect to the metabolism of anandamide and 2-arachidonoylglycerol, the main hydrolytic enzymes involved are fatty acid amide hydrolase and monoacylglycerol lipase. However, other pathways can come into play when these are blocked. Cyclooxygenase-2 derived metabolites of anandamide and 2-arachidonoylglycerol have a number of properties, including effects upon cell viability, contraction of the cat iris sphincter (an effect mediated by a novel receptor), mobilization of calcium and modulation of synaptic transmission. Nonsteroidal anti-inflammatory agents, whose primary mode of action is the inhibition of cyclooxygenase, can also interact with the endocannabinoid system both in vitro and in vivo. Other enzymes, such as the lipoxygenase and cytochrome P450 oxidative enzymes, can also metabolize endocannabinoids and produce biologically active compounds. It is concluded that sensitive analytical methods, which allow for measurement of endocannabinoids and related lipids, should provide vital information as to the importance of these alternative metabolic pathways when the primary hydrolytic endocannabinoid metabolizing enzymes are inhibited.