Assessing CB1 and CB2 receptor agonist antinociception while exploring sex differences and 5-HT1A-dependent mechanisms

Introduction Inflammatory pain is a key component of both acute and chronic pain conditions that, when pathological, significantly decrease patient quality of life. There has been a recent interest in the use of cannabinoid-based compounds for analgesia and recent research has discovered functional connections between the CB 2 and 5-HT 1A receptors. Methods Therefore, we investigated the efficacy of CB 1 -selective agonism (ACEA) and CB 2 -selective agonism (AM1241), and their potential reliance on the 5-HT 1A receptor, in the formalin inflammatory pain model using female and male adult C57BL/6J mice. Potential dose- and sex-differences were assessed for ACEA (at 0.1-2.5 mg/kg) and AM1241 (at 1-10 mg/kg) in the formalin test. Subsequent experiments were conducted using either ACEA (0.5 mg/kg) or AM1241 (10 mg/kg), alone or with inhibition of 5-HT 1A via WAY-100635, in both the formalin model of inflammatory pain and the non-nociceptive components of the cannabinoid tetrad test (open field, rotarod, rectal temperature). Results ACEA provided significant pain relief at 0.5 mg/kg in female mice and at 0.5 and 0.75 mg/kg in male mice, with significant sex differences observed. ACEA (0.5 mg/kg) antinociception was unaltered by 5-HT 1A inhibition while AM1241 (10 mg/kg) antinociception was completely prevented in the acute phase by 5-HT 1A inhibition. Neither ACEA nor AM1241 significantly altered performance in the open field, rotarod, or rectal temperature assessments. Discussion These results demonstrate the antinociceptive benefit of CB1 and CB 2 agonism in a murine model of inflammatory pain while demonstrating further evidence of a functional link between the CB 2 and 5-HT 1A receptors. Further studies are needed to investigate the mechanism behind this connection and its potential clinical significance.