Department of Biomedical Sciences, Marshall University, Huntington, WV, 25755, USA.
Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA.
Psychopharmacology (Berl). 2023 Sep;240(9):1987-2003. doi: 10.1007/s00213-023-06421-8. Epub 2023 Jul 29.
Cannabinoids are increasingly used to alleviate pain; however, tolerance to their antinociceptive effects, including those of delta-9-tetrahydrocannabinol (Δ-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 Δ-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 Δ-THC-induced antinociception and hypothermia prior to and following seven days of once-daily Δ-THC administration. Consistent with our previous findings, male B6 mice were more sensitive to the acute antinociceptive effects of Δ-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 Δ-THC-antinociception compared to male littermates at 30 and 10 mg/kg Δ-THC, respectively, these differences were less pronounced at higher doses, revealing that dose of Δ-THC may also be important. Overall, CBA mice were more sensitive to Δ-THC-induced antinociception while AKR mice were less responsive. These studies highlight the therapeutic potential of Δ-THC in pain management and underscore the importance of considering not only Δ-THC dose as a function of sex, but potentially genetic differences when evaluating their clinical utility.
大麻素类药物越来越多地被用于缓解疼痛；然而，其镇痛作用（包括δ-9-四氢大麻酚（Δ-THC）的镇痛作用）的耐受性可能会限制其治疗效果。使用医用大麻缓解疼痛的女性多于男性，因此了解性别如何影响大麻素介导的镇痛和耐受性至关重要。尽管大鼠的研究一致发现女性对大麻素的急性镇痛作用更为敏感，但我们对小鼠的研究却发现了相反的结果。本研究旨在探讨我们在Δ-THC 诱导的镇痛和耐受方面观察到的性别差异是否在多个小鼠品系中一致，还是取决于品系。我们评估了雄性和雌性 C57BL/6J（B6）、DBA/2、AKR 和 CBA/J 小鼠在单次每日 Δ-THC 给药前后，急性 Δ-THC 诱导的镇痛和体温降低的差异。与我们之前的研究结果一致，雄性 B6 小鼠对Δ-THC 的急性镇痛作用比雌性同窝仔鼠更为敏感，这种作用随着年龄的增长而消失。与雌性相比，B6 雄性在 PAG 中的大麻素表达减少。虽然 DBA 和 CBA 雌性小鼠在 30 和 10 mg/kg Δ-THC 时分别表现出比雄性同窝仔鼠更高的Δ-THC 镇痛作用，但在更高剂量时，这些差异不那么明显，这表明Δ-THC 的剂量也可能很重要。总体而言，CBA 小鼠对Δ-THC 诱导的镇痛作用更为敏感，而 AKR 小鼠的反应性较低。这些研究突出了 Δ-THC 在疼痛管理中的治疗潜力，并强调了在评估其临床应用时，不仅要考虑Δ-THC 剂量作为性别的函数，还要考虑潜在的遗传差异。
