title: Mice lacking fatty acid amide hydrolase exhibit a cannabinoid receptor-mediated phenotypic hypoalgesia.
abstract: Although the N-arachidonoyl ethanolamine (anandamide) binds to cannabinoid receptors and has been implicated in the suppression of pain, its rapid catabolism in vivo by fatty acid amide hydrolase (FAAH) has presented a challenge in investigating the physiological functions of this endogenous cannabinoid. In order to test whether anandamide and other non-cannabinoid fatty amides modulate nociception, we compared FAAH (+/+) and (-/-) mice in the tail immersion, hot plate, and formalin tests, as well as for thermal hyperalgesia in the carrageenan and the chronic constriction injury (CCI) models. FAAH (-/-) mice exhibited a CB1 receptor-mediated phenotypic hypoalgesia in thermal nociceptive tests. These mice also exhibited CB1 receptor-mediated hypoalgesia in both phases of the formalin test accompanied with a phenotypic anti-edema effect, which was not blocked by either CB1 or CB2 antagonists. Additionally, FAAH (-/-) mice displayed thermal anti-hyperalgesic and anti-inflammatory effects in the carrageenan model that were mediated, in part, by CB2, but not CB1 receptors. In contrast, no genotype differences in pain behavior were evident following CCI, which was instead found to obliterate the phenotypic hypoalgesia displayed by FAAH (-/-) mice in the tail immersion and hot plate tests, suggesting that nerve injury may promote adaptive changes in these animals. Collectively, these findings demonstrate a cannabinoid receptor-mediated analgesic phenotype in FAAH (-/-) mice. In more general terms, these findings suggest that selective inhibitors of FAAH might represent a viable pharmacological approach for the clinical treatment of pain disorders.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298, USA The Skaggs Institute for Chemical Biology and Departments of Cell Biology and Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd, La Jolla, CA 92037, USA.
authors.forename: Aron H
authors.initials: AH
authors.lastname: Lichtman
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Shelton
authors.forename: Tushar
authors.initials: T
authors.lastname: Advani
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics / Q000502:physiology; D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D063387:Cannabinoid Receptor Antagonists; D004195:Disease Models, Animal; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D005838:Genotype; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010146:Pain / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D010147:Pain Measurement; D017288:Pain Threshold / Q000502:physiology*; D059348:Peripheral Nerve Injuries; D010525:Peripheral Nerves / Q000503:physiopathology; D010641:Phenotype; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D043882:Receptors, Cannabinoid / Q000378:metabolism*; D020886:Somatosensory Disorders / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D063387:Cannabinoid Receptor Antagonists; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D000099252:Fatty Acid Amide Hydrolases; C078814:anandamide