The Sigma1 Receptor Antagonist CM304 Enhances the Antinociceptive Effects of the Cannabinoid Receptor Agonists, but not Mu‐Opioid Receptor Full Agonists in Mice

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There is an overdose epidemic associated with the use of illicitly manufactured as well as prescription mu‐opioid receptor agonists. Sigma1 receptor (σ1R) antagonists in combination with other drugs may provide a viable, safer pharmacological option than opioids alone for treating pain. The present study compared pharmacological effects of the σ1R antagonist CM304 alone and in combination with high (fentanyl and morphine) and low (buprenorphine) efficacy opioid agonists and the cannabinoid CB (CP55,940 and THC) receptor agonists in C57BL/6J mice. Rectal temperature, tail withdrawal latency (10‐seconds cutoff) from warm water of various temperatures (45°C, 50°C and 55°C) and counts of unhabituated locomotor activity were measured in this order. Basal latency for tail withdrawal systematically decreased from 10 seconds at 45°C to 1.3 seconds at 55°C. Morphine, fentanyl and buprenorphine dose‐dependently increased maximum possible effects (MPEs) up to 100% at 55°C (ED50 values: 7.50, 0.068, and 1.13 mg/kg, respectively), whereas CP55,940 and THC were less effective at 55°C (Emax values: 56.6% and 58.2%, respectively). CM304 (56 mg/kg, i.p.) produced an upward shift in the CP55,940 dose‐effect function such that 100% MPE was achieved at 3.2 mg/kg CP55,940, while CM304 (56 mg/kg) produced a 3‐fold leftward shift in the dose‐effect curve of THC. On the other hand, CM304 did not enhance the antinociceptive effects of morphine and fentanyl but enhanced the effects of buprenorphine. In contrast to tail withdrawal latency, there were no consistent effects of CM304 on cannabinoid‐induced decreases in rectal temperature or locomotor activity. The present results may support the development of a σ1R antagonist as an adjunct to cannabinoid and low efficacy μ‐opioid receptor agonists for the treatment of acute pain.Support or Funding InformationThis work was supported by National Institute on Drug Abuse grants DA23205 and DA48353.