The Sigma1 receptor antagonist CM304 potentiates the antinociceptive effects of the cannabinoid receptor agonist delta9-tetrahydrocannabinol in rats and mice

Background: Mu opioid receptor (MOR) agonists are the primary medication class used to treat moderate to severe pain; however, the ongoing opioid overdose crisis underscores the need for alternatives to MOR agonists for pain treatment. Delta9-tetrahydrocannabinol (THC), a cannabinoid CB1 receptor (CB1R) agonist, and sigma1 receptor (σ1R) antagonists elicit antinociceptive effects albeit less effectively than MOR agonists. Co-administration of σ1R antagonists with THC may offer a safer alternative for pain management. Methods: Antinociception (warm water tail withdrawal in mice and hot plate assays in rats), hypothermia (mice and rats), locomotion (mice), and drug discrimination (rats) assays were employed to evaluate the effects of the σ1R antagonist CM304 alone and in combination with THC. Results: In naïve mice, CM304 (ip) shifted the antinociceptive time-effect function of 32 mg/kg (ip) THC upward. Similarly, greater hypothermia was observed with combinations of THC and CM304 than each compound alone. Only the high dose of CM304 (56 mg/kg) induced hypolocomotion. In naïve rats, CM304 (1.0 and 3.2 mg/kg, iv) dose-dependently shifted the antinociceptive dose-effect function of THC to the left. In rats trained to discriminate THC (3.2 mg/kg, ip), CM304 (10 and 17.8 mg/kg) did not elicit THC-like discriminative stimulus effects. In contrast to the antinociceptive experiments, CM304 (10 mg/kg) did not significantly shift the discrimination dose-effect function of THC. These results suggest that σ1R antagonists like CM304 can potentiate the antinociceptive effects of THC without potentiating its adverse effects, supporting their potential as adjuncts to CB1R agonists for acute pain treatment.