Although Δ 9 -tetrahydrocannabinol (THC) and other mixed CB1/CB2 receptor agonists are well established to elicit antinociceptive effects, their psychomimetic actions and potential for abuse have dampened enthusiasm for their therapeutic development. Conversely, CB2 receptor-selective agonists have been shown to reduce pain and inflammation, without eliciting apparent cannabinoid behavioral effects. In the present study, we developed a novel ethyl sulfonamide THC analog, O-3223, and compared its pharmacological effects to those of the potent, mixed CB1/CB2 receptor
agonist, CP55,940, in battery of preclinical pain models. Competitive cannabinoid receptor
binding experiments revealed that O-3223 was approximately 80-fold more selective for CB2 than
CB1 receptors. Additionally, O-3223 behaved as full CB2 receptor agonist in [35S]GTPγS binding.
O-3223 reduced nociceptive behavior in both phases of the formalin test, reduced thermal
hyperalgesia in the chronic constrictive injury of the sciatic nerve (CCI) model, and reduced
edema and thermal hyperalgesia elicited by intraplantar injection of LPS. These effects were
blocked by pretreatment with the CB2 receptor-selective antagonist SR144528, but not by the CB1
receptor antagonist, rimonabant. Unlike CP55,940, O-3223 did not elicit acute antinociceptive
effects in the hot-plate test, hypothermia, or motor disturbances, as assessed in the rotarod test.
These data indicate that the CB2 receptor-selective agonist, O-3223, reduces inflammatory and
neuropathic nociception, without affecting basal nociception or eliciting overt behavioral effects.
Moreover, this compound can serve as a template to develop new CB2 receptor agonists with
increased receptor selectivity and increased potency in treating inflammatory and neuropathic