Sex-Differences in Acute Cannabinoid Response and Tolerance as a Function of Mouse Strain

Cannabinoids have been increasingly used to alleviate chronic pain; however, tolerance to the antinociceptive effects of cannabinoids, including delta-9-tetrahydrocannabinol (Δ9 -THC), may limit their therapeutic utility. Likewise, with more women than men now using medical cannabis for pain relief, it is imperative that we understand how sex may influence cannabinoid-mediated antinociception and subsequent tolerance. While studies in rats have consistently found female rats to be more sensitive to the acute antinociceptive effects of cannabinoids compared to male rats, work in our lab consistently finds the opposite finding that male mice are more sensitive to the acute antinociceptive effects of both Δ9 -THC and CP55,940 compared to female littermates. Studies in our lab have consistently utilized mice on a C57BL6/J (B6) background. Therefore, the purpose of the present study is to examine 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 B6 and DBA mice were first assessed for differences in acute Δ9 -THC-induced antinociception using the tail-flick assay across a range of doses of (0-100 mg/kg). After a significant washout period, these mice were subsequently assessed for sex-differences in antinociceptive tolerance development to 30 mg/kg Δ9 -THC following once-daily treatment for seven consecutive days. Consistent with our previous findings, male B6 mice were more sensitive to the acute antinociceptive effects of Δ9 -THC than female B6 mice. Male and female DBA, however, mice did not differ in their antinociceptive response to Δ9 -THC, suggesting that sex-differences in cannabinoid-induced antinociception in mice is likely strain-specific. These studies highlight the therapeutic potential of Δ9 -THC in pain management and underscore the importance of considering sex when evaluating their clinical utility. © FASEB.