Psychopharmacology (Berl). 2021 Jun 24. doi: 10.1007/s00213-021-05886-9. Online ahead of print.
RATIONALE: Tolerance to cannabinoids could limit their therapeutic potential. Male mice expressing a desensitization-resistant form (S426A/S430A) of the type-1 cannabinoid receptor (CB1R) show delayed tolerance to delta-9-tetrahydrocannabinol (∆9-THC) but not CP55,940. With more women than men using medical cannabis for pain relief, it is essential to understand sex differences in cannabinoid antinociception, hypothermia, and resultant tolerance.
OBJECTIVE: Our objective was to determine whether female mice rely on the same molecular mechanisms for tolerance to the antinociceptive and/or hypothermic effects of cannabinoids that we have previously reported in males. We determined whether the S426A/S430A mutation differentially disrupts antinociceptive and/or hypothermic tolerance to CP55,940 and/or Δ9-THC in male and female S426A/S430A mutant and wild-type littermates.
RESULTS: The S426A/S430A mutation conferred an enhanced antinociceptive response for ∆9-THC and CP55,940 in both male and female mice. While the S426A/S430A mutation conferred partial resistance to ∆9-THC tolerance in male mice, disruption of CB1R desensitization had no effect on tolerance to ∆9-THC in female mice. The mutation did not alter tolerance to the hypothermic effects of ∆9-THC or CP55,940 in either sex. Interestingly, female mice were markedly less sensitive to the antinociceptive effects of 30 mg/kg ∆9-THC and 0.3 mg/kg CP55,940 compared with male mice.
CONCLUSIONS: Our results suggest that disruption of the GRK/βarrestin2 pathway of desensitization alters tolerance to Δ9-THC but not CP55,940 in male but not female mice. As tolerance to Δ9-THC appears to develop differently in males and females, sex should be considered when assessing the therapeutic potential and dependence liability of cannabinoids.
Source: ncbi 2