Female mice developed tolerance to THC pain relief faster than males in chronic pain model

Female mice developed tolerance to the anti-allodynic (pain-relieving) effects of both 6 mg/kg and 10 mg/kg THC faster than males. A mutation (S426A/S430A) designed to reduce CB1 receptor desensitization did not alter tolerance development in either sex. THC pain relief was blocked by the CB1 antagonist rimonabant and partially blocked by the CB2 inverse agonist SR144528.

Male and female S426A/S430A mutant mice and wild-type littermates received four weekly cisplatin injections (5 mg/kg) to induce chronic neuropathic pain. Mice were then tested for tolerance to THC anti-allodynic effects at 6 and 10 mg/kg doses. CB1 and CB2 receptor involvement was confirmed with selective antagonists.

Tolerance to cannabinoid pain relief is a major clinical limitation. The finding that females develop tolerance faster has direct relevance for dosing considerations, as women may need different treatment strategies for long-term cannabinoid pain management.

Sex differences in cannabinoid tolerance are increasingly recognized across preclinical research. If these findings translate to humans, they could explain why some clinical trials show inconsistent pain relief results when not accounting for sex as a variable.

Mouse model may not directly translate to human pain. Cisplatin-induced neuropathy is a specific pain type. Only two THC doses tested. The S426A/S430A mutation finding is negative, limiting mechanistic insight.