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

• Published in: Neuropharmacology 2011-02, Vol.60 (2-3), p.244-251
• Main Authors: Kinsey, Steven G., Mahadevan, Anu, Zhao, Bingjun, Sun, Hang, Naidu, Pattipati S., Razdan, Raj K., Selley, Dana E., Imad Damaj, M., Lichtman, Aron H.
• Format: Article
• Language: English
• Subjects: Animals; Cannabinoids - pharmacology; Cannabinoids - therapeutic use; CB1; CB2; Cyclohexanols - pharmacology; Cyclohexanols - therapeutic use; Dose-Response Relationship, Drug; Dronabinol - analogs & derivatives; Dronabinol - chemistry; Dronabinol - pharmacology; Dronabinol - therapeutic use; Endogenous cannabinoid agonist; Inflammation; Inflammation - drug therapy; Inflammation - metabolism; Inflammation - psychology; Lipopolysaccharide induced edema; Male; Mice; Neuropathic pain; Pain - drug therapy; Pain - physiopathology; Pain Measurement; Piperidines - pharmacology; Pyrazoles - pharmacology; Receptor, Cannabinoid, CB2 - agonists; Receptor, Cannabinoid, CB2 - antagonists & inhibitors; Receptor, Cannabinoid, CB2 - physiology
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2010.09.004

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 a 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 a 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 constriction 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.