The Sigma1 receptor antagonist CM304 potentiates the antinociceptive effects of the cannabinoid receptor agonist delta9-tetrahydrocannabinol in rats and mice.
Elmira Zolali, Mallory Burns, Sebastiano Intagliata, Avi Patel, Nicholas P Ho, Luis F Restrepo, Lea R Gamez-Jimenez, Manuel A Alvarez, Lisa L Wilson, Stephen J Cutler, Lance R Mcmahon, Takato Hiranita, Samuel Obeng, Christopher R Mccurdy
Pharmacological reports : PR April 1, 2026 DOI: 10.1007/s43440-026-00834-w via PubMed
Summary
Combining the sigma1 receptor antagonist CM304 with delta9-tetrahydrocannabinol (THC) enhances pain relief without worsening THC's side effects. In mice, CM304 increased the pain-blocking effect of THC and caused greater body temperature drops when combined. A high dose of CM304 alone reduced movement. In rats, CM304 made THC's pain relief more potent. CM304 did not produce THC-like effects in rats trained to recognize THC, nor did it amplify THC's subjective effects. The findings suggest sigma1 receptor antagonists could be safer adjuncts to cannabinoid-based pain treatments, offering pain relief without increasing adverse effects like sedation or abuse potential.
Study at a glance
| Characteristics | Observational cohort Peer reviewed |
|---|---|
| Population | Naïve mice and rats; rats trained to discriminate THC |
| Interventions | CM304 Delta9-tetrahydrocannabinol (THC) |
| Dose | 32 mg/kg THC (mice); 1.0, 3.2 mg/kg CM304 (rats, iv); 10, 17.8 mg/kg CM304 (rats, discrimination); 56 mg/kg CM304 (mice, high dose) |
| Keywords | Antinociception Cm304 Cannabinoid Drug discrimination Sigma1 receptor |
| Key finding | The sigma1 receptor antagonist CM304 potentiates the antinociceptive effects of THC without potentiating its adverse effects such as hypolocomotion or THC-like discriminative stimulus effects. |
Abstract
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.