The cannabinoid system and its pharmacological manipulation - a review, with emphasis upon the uptake and hydrolysis of anandamide

Although cannabis has been used both recreationally and for medicinal purposes since ancient times, it was not until the 1990s that the receptors responsible for many of the actions of Delta(9)-tetrahydrocannabinol, the main psychoactive ingredient of cannabis, were cloned. Since then, our knowledge of the endogenous cannabinoid system, its physiology, pharmacology and therapeutic potential have expanded enormously. In the present review, the cannabinoid system is described, with particular emphasis on the mechanisms of removal and metabolism of the endocannabinoid signalling molecule anandamide. The current literature shows that cells can accumulate anandamide, and that this process can be disrupted pharmacologically, but that the nature of the mechanism(s) involved remains a matter of some debate. The main enzyme for the hydrolysis of anandamide, fatty acid amide hydrolase, is well characterized, and molecules selectively inhibiting this enzyme have potential therapeutic utility in a number of areas, in particular for the treatment of pain conditions.