Effects of the cannabinoid 2 receptor‐selective agonist GW405833 in assays of acute pain‐stimulated and paindepressed behavior in rats

Abstract

Cannabinoid 2 receptor (CB2R) agonists produce antinociception in many conventional preclinical assays of pain‐stimulated behavior, but effects of CB2R agonists on pain‐related behavioral depression are not known. GW405833 is a CB2R‐selective agonist with 1200‐fold selectivity for CB2R versus CB1R. This study compared effects of GW405833 in assays of acute pain‐stimulated and pain‐depressed in male Sprague Dawley rats. Intraperitoneal injection of dilute lactic acid (1.8% in 1 ml/kg) served as a noxious stimulus to stimulate a stretching response or depress intracranial self‐stimulation (ICSS) of the medial forebrain bundle. Effects of GW405833 on ICSS in the absence of the noxious stimulus were also examined as a measure of abuse liability. GW405833 (3.2–32 mg/kg IP) dose dependently attenuated both acid‐stimulated stretching and acid‐induced depression of ICSS without producing abuse‐related facilitation of ICSS in the absence of the noxious stimulus. However, significant antinociception was observed only at a relatively high dose (32 mg/kg), and in the assay of acid‐stimulated stretching, effects of GW4058333 were partially blocked by the CB1R antagonist rimonabant but not by the CB2R antagonist SR144528. These results suggest that antinociceptive effects of GW405833 in these assays were not mediated by CB2 receptors.