The antinociceptive effects of intraplantar injections of 2‐arachidonoyl glycerol are mediated by cannabinoid CB 2 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 CB 1 (AM251) and CB 2 (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 μg); (7) AM251 (80 μg); (8) AM251+2‐AG (10 μg); (9) AM630 (25 μg); (10) AM630+2‐AG (10 μg); (11‐16) URB602 (0.1‐500 μg); (17) 2‐AG+URB602 (ED 50 ); (18) AM251+URB602 (ED 50 ); (19) AM630+URB602 (ED 50 ). Drugs were injected s.c. in the dorsal surface of the hind paw (50 μl), 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 ED 50 of 0.65±0.455 μg and 68±14.3 μg, respectively. Their combination at ED 50 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 CB 2 receptor. British Journal of Pharmacology (2007) 150 , 693–701. doi: 10.1038/sj.bjp.0706990