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.

中文翻译：

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大麻素激动剂 CP55,940 和 delta-9-四氢大麻酚 (Δ9-THC) 的性别特异性耐受机制

基本原理

对大麻素的耐受性可能会限制其治疗潜力。_{表达 1 型大麻素受体 (CB 1} R)的脱敏抗性形式 (S426A/S430A) 的雄性小鼠表现出对 delta-9-四氢大麻酚 (Δ ⁹ -THC) 但对 CP55,940 的延迟耐受性。由于使用医用大麻缓解疼痛的女性多于男性，因此了解大麻素镇痛作用、体温过低和由此产生的耐受性方面的性别差异至关重要。

客观的

我们的目标是确定雌性小鼠是否依赖与我们之前在雄性小鼠中报告的相同的分子机制来耐受大麻素的镇痛作用和/或低温作用。我们确定了 S426A/S430A 突变是否差异性地破坏了雄性和雌性 S426A/S430A 突变体和野生型同窝小鼠对 CP55,940 和/或 Δ ⁹ -THC的镇痛作用和/或低温耐受性。

结果

S426A/S430A 突变增强了雄性和雌性小鼠对 Δ ^{9 -THC 和 CP55,940 的镇痛反应。}虽然 S426A/S430A 突变赋予雄性小鼠对 Δ ⁹ -THC 耐受性的部分抗性，但破坏 CB ₁ R 脱敏对雌性小鼠对 Δ ⁹ -THC耐受性没有影响。该突变并未改变对任一性别的 Δ ^{9 -THC 或 CP55,940 低温效应的耐受性。}有趣的是，与雄性小鼠相比，雌性小鼠对 30 mg/kg Δ ⁹ -THC 和 0.3 mg/kg CP55,940的镇痛作用的敏感性明显较低。

结论

我们的结果表明，破坏 GRK/βarrestin2 脱敏途径会改变对 Δ ⁹ -THC 的耐受性，但不会改变雄性小鼠而非雌性小鼠对 CP55,940 的耐受性。由于男性和女性对 Δ ⁹ -THC 的耐受性似乎不同，因此在评估大麻素的治疗潜力和依赖性时应考虑性别因素。