Sex differences in acute delta-9-tetrahydrocannabinol (Δ⁹-THC) response and tolerance as a function of mouse strain

Cannabinoids are increasingly used to alleviate pain; however, tolerance to their antinociceptive effects, including those of delta-9-tetrahydrocannabinol (Δ⁹-THC), may limit their therapeutic utility. With more women than men using medical cannabis for pain relief, it is crucial to understand how sex influences cannabinoid-mediated antinociception and tolerance. Though studies in rats consistently find females are more sensitive to the acute antinociceptive effects of cannabinoids, our work with mice consistently finds the converse. The present study examined whether our observed sex differences in Δ⁹-THC-induced antinociception and tolerance are consistent across multiple mouse strains or are strain-dependent. Male and female C57BL/6J (B6), DBA/2, AKR, and CBA/J mice were assessed for differences in acute Δ⁹-THC-induced antinociception and hypothermia prior to and following seven days of once-daily Δ⁹-THC administration. Consistent with our previous findings, male B6 mice were more sensitive to the acute antinociceptive effects of Δ⁹-THC than female littermates, an effect which dissipated with age. B6 males had decreased cannabinoid expression in the PAG compared to females. While DBA and CBA female mice showed increased Δ⁹-THC-antinociception compared to male littermates at 30 and 10 mg/kg Δ⁹-THC, respectively, these differences were less pronounced at higher doses, revealing that dose of Δ⁹-THC may also be important. Overall, CBA mice were more sensitive to Δ⁹-THC-induced antinociception while AKR mice were less responsive. These studies highlight the therapeutic potential of Δ⁹-THC in pain management and underscore the importance of considering not only Δ⁹-THC dose as a function of sex, but potentially genetic differences when evaluating their clinical utility.