Cannabinoid CB$_2$ Agonist GW405833 Suppresses Inflammatory and Neuropathic Pain through a CB$_1$ Mechanism that is Independent of CB$_2$ Receptors in Mice

Abstract

GW405833, widely accepted as a cannabinoid receptor 2 (CB$_2$) agonist, suppresses pathologic pain in preclinical models without the unwanted central side effects of cannabinoid receptor 1 (CB$_1$) agonists; however, recent in vitro studies have suggested that GW405833 may also behave as a noncompetitive CB$_1$ antagonist, suggesting that its pharmacology is more complex than initially appreciated. Here, we further investigated the pharmacologic specificity of in vivo antinociceptive actions of GW405833 in models of neuropathic (i.e., partial sciatic nerve ligation model) and inflammatory (i.e., complete Freund’s adjuvant model) pain using CB$_2$and CB$_1$ knockout (KO) mice, their respective wild-type (WT) mice, and both CB$_2$ and CB$_1$ antagonists. GW405833 (3, 10, and 30 mg/kg i.p.) dose dependently reversed established mechanical allodynia in both pain models in WT mice; however, the antiallodynic effects of GW405833 were fully preserved in CB$_2$KO mice and absent in CB$_1$KO mice. Furthermore, the antiallodynic efficacy of GW405833 (30 mg/kg i.p.) was completely blocked by the CB$_1$ antagonist rimonabant (10 mg/kg i.p.) but not by the CB$_2$ antagonist SR144528 (10 mg/kg i.p.). Thus, the antinociceptive properties of GW405833 are dependent on CB$_1$ receptors. GW405833 (30 mg/kg i.p.) was also inactive in a tetrad of tests measuring cardinal signs of CB$_1$ activation. Additionally, unlike rimonabant (10 mg/kg i.p.), GW405833 (10 mg/kg, i.p.) did not act as a CB$_1$ antagonist in vivo to precipitate withdrawal in mice treated chronically with $\Delta^9$-tetrahydrocannabinol. The present results suggest that the antiallodynic efficacy of GW405833 is CB$_1$-dependent but does not seem to involve engagement of the CB$_1$ receptor’s orthosteric site.