The antinociceptive effects of intraplantar injections of 2-arachidonoyl glycerol are mediated by cannabinoid CB2 receptors

Background and purpose: 2- arachidonoyl glycerol ( 2- AG) is an endogenous cannabinoid with central antinociceptive properties. Its degradation is catalysed by monoacylglycerol lipase ( MGL) whose activity is inhibited by URB602, a new synthetic compound. The peripheral antinociceptive effects of 2- AG and URB602 in an inflammatory model of pain are not yet determined. We have evaluated these effects with and without the cannabinoid CB1 ( AM251) and CB2 ( AM630) receptor antagonists. Experimental approach: Inflammation was induced in rat hind paws by intraplantar injection of formalin. Nociception was assessed behaviourally over the next 60 min, in 19 experimental groups: ( 1) control; ( 2- 6) 2- AG ( 0.01- 100 mu g); ( 7) AM251 ( 80 mg); ( 8) AM251 + 2- AG ( 10 mg); ( 9) AM630 ( 25 mg); ( 10) AM630 + 2- AG ( 10 mg); ( 11-16) URB602 ( 0.1-500 mg); ( 17) 2- AG + URB602 ( ED50); ( 18) AM251 + URB602 ( ED50); ( 19) AM630 + URB602 ( ED50). Drugs were injected s. c. in the dorsal surface of the hind paw ( 50 mu l), 15 min before formalin injection into the same paw. Key results: 2- AG and URB602 produced dose-dependent antinociceptive effects for the late phases of the formalin test with ED50 of 0.65 +/- 0.455 mg and 68 +/- 14.3 mg, respectively. Their combination at ED50 doses produced an additive antinociceptive effect. These effects were inhibited by AM630 but not by AM251 for 2- AG and by the two cannabinoid antagonists for URB602. Conclusions and implications: Locally injected 2- AG and URB602 decreased pain behaviour in a dose-dependent manner in an inflammatory model of pain. The antinociceptive effect of 2- AG was mediated by the CB2 receptor.