Fatty acid amide hydrolase blockade attenuates the development of collagen-induced arthritis and related thermal hyperalgesia in mice

Pharmacol Biochem Behav. 2011 Oct;99(4):718-25. doi: 10.1016/j.pbb.2011.06.022. Epub 2011 Jun 29.


Fatty acid amide hydrolase (FAAH) is the primary degradative enzyme of the endocannabinoid anandamide (N-arachidonoylethanolamine), which activates cannabinoid CB(1) and CB(2) receptors. FAAH disruption reduces nociception in a variety of acute rodent models of inflammatory pain. The present study investigated whether these actions extend to the chronic, collagen-induced arthritis (CIA) model. We investigated the anti-arthritic and anti-hyperalgesic effects of genetic deletion or pharmacological inhibition of FAAH in the CIA model. FAAH (-/-) mice, and FAAH-NS mice that express FAAH exclusively in nervous tissue, displayed decreased severity of CIA and associated hyperalgesia. These phenotypic anti-arthritic effects were prevented by repeated daily injections of the CB(2) receptor antagonist, SR144528, but not the CB(1) receptor antagonist rimonabant. Similarly, repeated administration of the FAAH inhibitor URB597 reduced CIA severity, and acute administration of rimonabant, but not SR144528, blocked the anti-hyperalgesic effects of prolonged FAAH inhibition, suggesting that prolonged CB(2) receptor activation reduces the severity of CIA, whereas acute CB(1) receptor activation reduces CIA-induced hyperalgesia. In contrast, acute administration of URB597 elicited a CB(1) receptor-dependent anti-hyperalgesic effect. The observed anti-arthritic and anti-hyperalgesic properties of FAAH inhibition, coupled with a lack of apparent behavioral alterations, suggest that endocannabinoid modulating enzymes offer a promising therapeutic target for the development of novel pharmacological approaches to treat rheumatoid arthritis and associated hyperalgesia.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amidohydrolases / antagonists & inhibitors*
  • Amidohydrolases / genetics
  • Amidohydrolases / physiology
  • Animals
  • Arthritis, Experimental / genetics
  • Arthritis, Experimental / pathology
  • Arthritis, Experimental / prevention & control*
  • Benzamides / pharmacology
  • Camphanes / pharmacology
  • Carbamates / pharmacology
  • Foot / pathology
  • Genotype
  • Hot Temperature*
  • Hyperalgesia / drug therapy*
  • Male
  • Mice
  • Mice, Inbred DBA
  • Mice, Knockout
  • Pain Measurement / drug effects
  • Phenotype
  • Pyrazoles / pharmacology
  • Receptor, Cannabinoid, CB1 / drug effects
  • Receptor, Cannabinoid, CB2 / drug effects


  • Benzamides
  • Camphanes
  • Carbamates
  • Pyrazoles
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2
  • SR 144528
  • cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester
  • Amidohydrolases
  • fatty-acid amide hydrolase