The overdose epidemic associated with the use of illicitly manufactured as well as prescription mu-opioid agonists. Sigma1 receptor (σ1R) antagonists in combination with other drugs may provide a viable, safe pharmacological option for treating pain. The present study compared pharmacological effects of the σ1R antagonist CM304 alone and in combination with morphine or the cannabinoid agonist CP55,940 in C57BL/6J mice. Rectal temperature, tail withdrawal latency 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 dose-dependently increased maximum possible effects (MPE) up to 100% at 55°C (ED50 value: 6.1 mg/kg). CP55,940 was less active at 55°C (Emax value: 53.9%). However, CM304 (56 mg/kg) dose-dependently produced an upward shift in the CP55,940 dose-effect function such that 100% MPE was achieved at 3.2 mg/kg CP55,940. In contrast, CM304 was inactive against the antinociceptive effects of morphine. While CM304 alone did not alter tail withdrawal latency at 55°C, it did decrease activity and rectal temperature. However, CM304 produced an upward shift in the dose-effect function of morphine-induced hyperactivity but without effects on CP55,940-induced hypothermia.