Several recent reports have demonstrated a role for selective
cannabinoid CB2 receptor agonists in
pain modulation, showing both
analgesic and antihyperalgesic activities. While the mechanism of action is poorly understood, it has been postulated that these effects may be indirect, involving release of endogenous
opioids. We have previously reported that administration of the selective
cannabinoid CB2 receptor agonist
GW405833 (2,3-dichloro-phenyl)-[5-methoxy-2-methyl-3-(2-morpholin-4-yl-ethyl)-indol-1-yl]-methanone) to rats elicits potent and efficacious antihyperalgesic effects against neuropathic and inflammatory
pain and, at high dose (100 mg/kg), is
analgesic and ataxic [Valenzano, K.J., Tafesse, L., Lee, G., Harrison, J.E., Boulet, J., Gottshall, S.L., Mark, L., Pearson, M.S., Miller, W., Shan, S., Rabadi, L., Rotstheyn, Y., Chaffer, S.M., Turchin, P.I., Elsemore, D.A., Toth, M., Koetzner, L., Whiteside, G.T., 2005. Pharmacological and pharmacokinetic characterization of the
cannabinoid receptor 2 agonist,
GW405833, utilizing rodent models of acute and
chronic pain, anxiety,
ataxia and
catalepsy. Neuropharmacology 48, 658-672]. In the current study, we confirm these properties using mouse models and investigate the role of
cannabinoid CB2 receptors using knockout animals. Furthermore, we provide evidence that the antinociceptive properties of
GW405833 are
opioid independent.
GW405833 elicited robust antihyperalgesic effects in mouse models of inflammatory (Freund's complete adjuvant) and neuropathic (Seltzer)
pain. In contrast,
GW405833 showed no antihyperalgesic activity against Freund's complete adjuvant-mediated inflammatory
pain in
cannabinoid CB2 receptor knockout mice. As in rats, high-dose
GW405833 (100 mg/kg) showed both
analgesic and
sedative activities in wild-type mice, activities that were also apparent in
cannabinoid CB2 receptor knockout mice. In rats, neither the antihyperalgesic effect in the Freund's complete adjuvant model nor the
analgesic effects in tail flick and hot plate assays were inhibited by pre-treatment with the non-selective
opioid receptor antagonist,
naltrexone. These data demonstrate that the antihyperalgesic effects of
GW405833 are mediated via the
cannabinoid CB2 receptor, whereas the
analgesic and
sedative effects are not. Furthermore, these data suggest that the mechanism of action for
GW405833 does not depend on the release of endogenous
opioids.