Background and purpose: Selective cannabinoid CB 2 receptor agonists have demonstrated analgesic activity across multiple preclinical pain models. AM1241 is an indole derivative that exhibits high affinity and selectivity for the CB 2 binding site and broad spectrum analgesic activity in rodent models, but is not an antagonist of CB 2 in vitro functional assays. Additionally, its analgesic effects are m-opioid receptor-dependent. Herein, we describe the in vitro and in vivo pharmacological properties of A-796260, a novel CB 2 agonist. Experimental approach: A-796260 was characterized in radioligand binding and in vitro functional assays at rat and human CB 1 and CB 2 receptors. The behavioural profile of A-796260 was assessed in models of inflammatory, post-operative, neuropathic, and osteoarthritic (OA) pain, as well as its effects on motor activity. The receptor specificity was confirmed using selective CB 1 , CB 2 and m-opioid receptor antagonists. Key results: A-796260 exhibited high affinity and agonist efficacy at human and rat CB 2 receptors, and was selective for the CB 2 vs CB 1 subtype. Efficacy in models of inflammatory, post-operative, neuropathic and OA pain was demonstrated, and these activities were selectively blocked by CB 2 , but not CB 1 or m-opioid receptor-selective antagonists. Efficacy was achieved at doses that had no significant effects on motor activity. Conclusions and implications: These results further confirm the therapeutic potential of CB 2 receptor-selective agonists for the treatment of pain. In addition, they demonstrate that A-796260 may be a useful new pharmacological compound for further studying CB 2 receptor pharmacology and for evaluating its role in the modulation of pain.

BACKGROUND AND PURPOSE Cannabinoid CB2 receptor activation by selective agonists has been shown to produce analgesic effects in preclinical models of inflammatory and neuropathic pain. However, mechanisms underlying CB2‐mediated analgesic effects remain largely unknown. The present study was conducted to elucidate the CB2 receptor expression in ‘pain relevant’ tissues and the potential sites of action of CB2 agonism in rats. EXPERIMENTAL APPROACH Expression of cannabinoid receptor mRNA was evaluated by quantitative RT‐PCR in dorsal root ganglia (DRGs), spinal cords, paws and several brain regions of sham, chronic inflammatory pain (CFA) and neuropathic pain (spinal nerve ligation, SNL) rats. The sites of CB2 mediated antinociception were evaluated in vivo following intra‐DRG, intrathecal (i.t.) or intraplantar (i.paw) administration of potent CB2‐selective agonists A‐836339 and AM1241. KEY RESULTS CB2 receptor gene expression was significantly up‐regulated in DRGs (SNL and CFA), spinal cords (SNL) or paws (CFA) ipsilateral to injury under inflammatory and neuropathic pain conditions. Systemic A‐836339 and AM1241 produced dose‐dependent efficacy in both inflammatory and neuropathic pain models. Local administration of CB2 agonists also produced significant analgesic effects in SNL (intra‐DRG and i.t.) and CFA (intra‐DRG) pain models. In contrast to A‐836339, i.paw administration of AM‐1241 dose‐relatedly reversed the CFA‐induced thermal hyperalgesia, suggesting that different mechanisms may be contributing to its in vivo properties. CONCLUSIONS AND IMPLICATIONS These results demonstrate that both DRG and spinal cord are important sites contributing to CB2 receptor‐mediated analgesia and that the changes in CB2 receptor expression play a crucial role for the sites of action in regulating pain perception.

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