Metabolism of the Endocannabinoids Anandamide and 2-Arachidonoyl Glycerol, A Review, with Emphasis on the Pharmacology of Fatty Acid Amide Hydrolase, A Possible Target for the Treatment of Neurodegenerative Diseases and Pain

There is a good evidence to suggest that activation of cannabinoid receptors may be beneficial not only in the treatment of conditions such as pain, but even in neurodegenerative states, such as in stroke and trauma. Nevertheless, the major obstacle to the development of cannabinoid receptor agonists as therapeutic agents for the treatment of such disorders the psychomotor are effects resulting from cannabinoid receptor activation. An alternative approach, which may avoid these problems is to bolster up tonically active endocannabinoid signalling by preventing the metabolism of the signalling molecules. In the present article, the metabolism of the endocannabinoids anandamide and 2-arachidonoylglycerol are reviewed, with the main emphasis being placed upon the pharmacology of fatty acid amide hydrolase (FAAH). This enzyme catalyses the hydrolysis of anandamide, as well as of the related N-acyl ethanolamines palmitoylethanolamide, stearoylethanolamide and oleoylethanolamide, which modulate the effects of anandamide as well as having cannabinoid receptor-independent actions of their own. A number of FAAH inhibitors have been synthesised and characterised pharmacologically. A case is made that such compounds may be useful for the treatment of pain and some neurodegenerative states. Although no FAAH inhibitors are as yet in clinical use, there is some evidence to suggest that FAAH inhibition contributes to the antinociceptive actions of spinally administered non-steroidal anti-inflammatory agents.