CB2 cannabinoid receptor mediation of antinociception

Management of acute pain remains a significant clinical problem. In preclinical studies, CB, cannabinoid receptor-selective agonists inhibit nociception without producing central nervous system side effects. The CB, receptor-selective agonist AM 1241 produces antinociceptive effects that are antagonized by CB2, but not CB1, receptor-selective antagonists.. suggesting that activation of CB, receptors results in antinociception. However, it has not been possible to definitively demonstrate that these effects are mediated by CB, receptors, because we have lacked the pharmacological tools to confirm the in vivo receptor selectivity of the antagonists used. Further, recent evidence for cannabinoid-like receptors beyond CB1 and CB2 raises the possibility that AM1241 exerts its antinociceptive effects at uncharacterized CB2-like receptors that are also inhibited by AM630. The experiments reported here further test the hypothesis that CB2 receptor activation inhibits nociception. They evaluated the antinociceptive actions of AM 1241 and the less-selective CB2 receptor agonist WIN55,212-2 in wild-type (CB2+/+) mice and in mice with genetic disruption of the CB2 receptor (CB2-/- mice). AM 1241 inhibited thermal nociception in CB2+/+ mice, but had no effect in CB2-/- littermates. WIN55,212-2 produced mice. while its antinociceptive effects were reduced in CB2-/- compared to CB2+/+ eqivalent antinociception in CB2+/+ and CB, I mice. The effects of morphine were not altered in CB2-/- compared to CB2+/+ mice. These data strongly suggest that AM 1241 produces antinociception in vivo by activating CB2 cannabinoid receptors. Further, they confirm the potential therapeutic relevance of CB2 cannabinoid receptors for the treatment of acute pain. (c) 2006 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.