Sex-specific mechanisms of tolerance for the cannabinoid agonists CP55,940 and delta-9-tetrahydrocannabinol (Δ9-THC)

Rationale Tolerance to cannabinoids could limit their therapeutic potential. Male mice expressing a desensitization-resistant form (S426A/S430A) of the type-1 cannabinoid receptor (CB 1 R) 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 Δ 9 -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 CB 1 R 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 Δ 9 -THC but not CP55,940 in male but not female mice. As tolerance to Δ 9 -THC appears to develop differently in males and females, sex should be considered when assessing the therapeutic potential and dependence liability of cannabinoids.