Removal of endocannabinoids by the body: Mechanisms and therapeutic possibilities

Abstract

The actions of anandamide and 2-arachidonoylglycerol are terminated by cellular uptake followed by metabolism. In the case of anandamide, the uptake process was originally suggested to be achieved by a process of facilitated diffusion, but the mechanism(s) involved are a matter of controversy at present. The main hydrolytic enzyme for anandamide is fatty acid amide hydrolase, and inhibitors of this enzyme have been found to have beneficial effects in animal models of inflammatory pain, inflammation, anxiety and depression. Anandamide is also a substrate for cyclooxygenase-2 and lipoxygenases, and the cyclooxygenase-derived products, the prostamides have biological actions of their own. 2-Arachidonoylglycerol can be metabolized by a range of enzymes, including cyclooxygenase-2, monoacylglycerol lipase and fatty acid amide hydrolase. In the brain, monoacylglycerol lipase is probably the most important of these enzymes. However, no selective inhibitors of this enzyme are presently available with which to establish the potential of this enzyme as a target for drug development.