title: Targeting fatty acid amide hydrolase (FAAH) to treat pain and inflammation.
abstract: The endogenous cannabinoid N-arachidonoyl ethanolamine (anandamide; AEA) produces most of its pharmacological effects by binding and activating CB(1) and CB(2) cannabinoid receptors within the CNS and periphery. However, the actions of AEA are short lived because of its rapid catabolism by fatty acid amide hydrolase (FAAH). Indeed, FAAH knockout mice as well as animals treated with FAAH inhibitors are severely impaired in their ability to hydrolyze AEA as well as a variety of noncannabinoid lipid signaling molecules and consequently possess greatly elevated levels of these endogenous ligands. In this mini review, we describe recent research that has investigated the functional consequences of inhibiting this enzyme in a wide range of animal models of inflammatory and neuropathic pain states. FAAH-compromised animals reliably display antinociceptive and anti-inflammatory phenotypes with a similar efficacy as direct-acting cannabinoid receptor agonists, such as Delta(9)-tetrahydrocannabinol (THC), the primary psychoactive constituent of Cannabis sativa. Importantly, FAAH blockade does not elicit any apparent psychomimetic effects associated with THC or produce reinforcing effects that are predictive of human drug abuse. The beneficial effects caused by FAAH blockade in these models are predominantly mediated through the activation of CB(1) and/or CB(2) receptors, though noncannabinoid mechanisms of actions can also play contributory or even primary roles. Collectively, the current body of scientific literature suggests that activating the endogenous cannabinoid system by targeting FAAH is a promising strategy to treat pain and inflammation but lacks untoward side effects typically associated with Cannabis sativa.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, P.O. Box 980613, Richmond, Virginia 23298-0613, USA.
authors.forename: Joel E
authors.initials: JE
authors.lastname: Schlosburg
authors.forename: Steven G
authors.initials: SG
authors.lastname: Kinsey
authors.forename: Aron H
authors.initials: AH
authors.lastname: Lichtman
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000700:Analgesics / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000633:toxicity; D001095:Arachidonic Acids / Q000378:metabolism*; D004195:Disease Models, Animal; D013759:Dronabinol / Q000494:pharmacology / Q000633:toxicity; D016503:Drug Delivery Systems; D004353:Drug Evaluation, Preclinical; D063388:Endocannabinoids; D005989:Glycerides / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D010146:Pain / Q000188:drug therapy* / Q000503:physiopathology; D047492:Peroxisome Proliferator-Activated Receptors / Q000187:drug effects / Q000502:physiology; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D051381:Rats; D043882:Receptors, Cannabinoid / Q000187:drug effects / Q000378:metabolism; D011957:Receptors, Opioid / Q000187:drug effects / Q000502:physiology; D050916:TRPV Cation Channels / Q000187:drug effects / Q000502:physiology; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001095:Arachidonic Acids; D013759:Dronabinol; D063388:Endocannabinoids; D005989:Glycerides; D047492:Peroxisome Proliferator-Activated Receptors; D053284:Polyunsaturated Alkamides; D043882:Receptors, Cannabinoid; D011957:Receptors, Opioid; D050916:TRPV Cation Channels; D000099252:Fatty Acid Amide Hydrolases; C494484:TRPV1 receptor; C094503:glyceryl 2-arachidonate; C078814:anandamide