The CB2 cannabinoid receptor-selective agonist O-3223 reduces pain and inflammation without apparent cannabinoid behavioral effects

Abstract

Summary Although Δ9-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 pain.

Activation of cannabinoid receptor 2 inhibits experimental cystitis

“…These authors further demonstrated that activation of CB2 not only prevented, but also reversed, inflammation-induced edema (60). In other studies, treatment with a selective CB2 agonist reduced arachidonic acid-induced edema in the ear (31), and edema of hind paw elicited by intraplantar injection of lipopolysaccharide (38). These studies clearly support the antiinflammatory effects of CB2, although the precise mechanisms underlying CB2 activation-induced inhibition of inflammation remain to be clarified.…”

Treatment with a Cannabinoid Receptor 2 Agonist Decreases Severity of Established Cystitis

“…1,17–19 Pretreatment with selective CB2 agonists attenuated carrageenan induced edema in the hind paw of rats and the inhibitory effects were reversed by selective CB2 antagonists. 1 Similar treatments also decreased arachidonic acid induced edema in the ear 18 and edema of the hind paw elicited by intra-plantar injection of lipopolysaccharide.…”

CB1 Knockout Mice Unveil Sustained CB2-Mediated Antiallodynic Effects of the Mixed CB1/CB2 Agonist CP55,940 in a Mouse Model of Paclitaxel-Induced Neuropathic Pain

“…By contrast, chronic CP55,940, at a dose that produced CB 2 -mediated antiallodynic efficacy, failed to decrease body temperature in CB 1 KO mice, documenting that prolonged activation of CB 2 receptors does not result in hypothermia (Malan et al, 2001;Valenzano et al, 2005;Yao et al, 2009;Elliott et al, 2011;Kinsey et al, 2011;Amenta et al, 2012). Chronic CP55,940-treated WT, but not CB 1 KO mice, showed profound withdrawal signs when challenged with the CB 1 antagonist rimonabant, suggesting precipitation at CB 1 receptors produces withdrawal symptoms (Tsou et al, 1995;Aceto et al, 1996;Cook et al, 1998;Rubino et al, 1998;Lichtman et al, 2001).…”