Local application of the endocannabinoid hydrolysis inhibitor URB597 reduces nociception in spontaneous and chemically induced models of osteoarthritis

Pain. 2011 May;152(5):975-981. doi: 10.1016/j.pain.2010.11.025. Epub 2010 Dec 24.


The present study examined whether enhancement of endogenous cannabinoid levels by administration of the fatty acid amide hydrolase inhibitor URB597 could modulate joint nociception in 2 rodent models of osteoarthritis (OA). OA-like changes were induced in male Wistar rats by intra-articular injection of monoiodoacetate, while Dunkin-Hartley guinea pigs (age 9-12 months) develop OA naturally and were used as a model of spontaneous OA. Joint nociception was measured by recording electrophysiologically from knee joint primary afferents in response to noxious hyper-rotation of the joint before and after close intra-arterial injection of URB597 (0.03 mg; 0.1 mL bolus); the CB(1) receptor antagonist AM251 (1 mg/kg intraperitoneally) or the CB(2) receptor antagonist AM630 (1 mg/kg intraperitoneally). The effect of systemic URB597 administration (5 mg/kg) on joint pain perception in the monoiodoacetate model was determined by hindlimb incapacitance. Peripheral injection of URB597 caused afferent firing rate to be significantly reduced by up to 56% in the rat OA model and by up to 69% in the guinea pig OA model. Systemic co-administration of AM251, but not AM630, abolished the antinociceptive effect of URB597 in both models. URB597 had no effect in saline-injected control rat joints or in nonarthritic guinea pigs. Systemic URB597 administration significantly reduced hindlimb incapacitance in monoiodoacetate joints and co-administration of the CB(1) antagonist abolished this effect. Local injection of URB597 into OA knee joints reduces mechanonociception and pain, and this response is mediated by CB(1) receptors. Targeting endocannabinoid-metabolizing enzymes in the peripheral nervous system could offer novel therapeutic approaches for the treatment of OA pain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Afferent Pathways / cytology
  • Afferent Pathways / drug effects
  • Age Factors
  • Animals
  • Arthralgia / drug therapy*
  • Arthralgia / etiology*
  • Benzamides / therapeutic use*
  • Carbamates / therapeutic use*
  • Diclofenac / therapeutic use
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / therapeutic use*
  • Guinea Pigs
  • Indoles / therapeutic use
  • Iodoacetic Acid / adverse effects*
  • Male
  • Nociceptors / drug effects
  • Osteoarthritis* / chemically induced
  • Osteoarthritis* / complications
  • Osteoarthritis* / drug therapy
  • Piperidines / pharmacology
  • Pyrazoles / pharmacology
  • Rats
  • Rats, Wistar
  • Time Factors
  • Weight-Bearing


  • Benzamides
  • Carbamates
  • Enzyme Inhibitors
  • Indoles
  • Piperidines
  • Pyrazoles
  • cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester
  • Diclofenac
  • AM 251
  • iodopravadoline
  • Iodoacetic Acid