Kappa opioid receptor (KOR) agonists produce robust analgesia with minimal abuse liability and are considered promising pharmacological agents to manage chronic pain and itch. The KOR system is also notable for robust differences between the sexes, with females exhibiting lower analgesic response than males. Sexually dimorphic traits can be due to either the influence of gonadal hormones during development or adulthood, or due to the complement of genes expressed on the X or Y chromosome. Previous studies examining sex differences in KOR antinociception have relied on surgical or pharmacological manipulation of the gonads to determine whether sex hormones influence KOR function. While there are conflicting reports whether gonadal hormones influence KOR function, no study has examined these effects in context with sex chromosomes. Here, we use two genetic mouse models, the four core genotypes and XY*, to isolate the chromosomal and hormonal contributions to sex differences in KOR analgesia. Mice were treated with systemic KOR agonist (U50,488H) and thermal analgesia measured in the tail withdrawal assay. We found that KOR antinociception was influenced predominantly by the number of the X chromosomes. These data suggest that the dose and/or parental imprint on X gene(s) contribute significantly to the sexually dimorphism in KOR analgesia.

中文翻译：

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kappa 阿片受体抗伤害作用的性别差异受小鼠 X 染色体数量的影响

Kappa 阿片受体 (KOR) 激动剂产生强大的镇痛作用，且滥用可能性最小，被认为是治疗慢性疼痛和瘙痒的有前途的药物。KOR 系统还因性别之间的巨大差异而引人注目，女性表现出比男性更低的镇痛反应。性二态性状可能是由于发育或成年期间性腺激素的影响，或者是由于 X 或 Y 染色体上表达的基因互补。以前检查 KOR 抗伤害感受的性别差异的研究依赖于性腺的手术或药理学操作来确定性激素是否影响 KOR 功能。虽然性腺激素是否影响 KOR 功能的报道相互矛盾，但没有研究在性染色体的背景下检查这些影响。这里，我们使用两种遗传小鼠模型，即四种核心基因型和 XY*，来分离染色体和激素对 KOR 镇痛中性别差异的贡献。用全身性 KOR 激动剂 (U50,488H) 治疗小鼠，并在尾部退缩试验中测量热镇痛。我们发现 KOR 镇痛作用主要受 X 染色体数量的影响。这些数据表明 X 基因上的剂量和/或亲本印记对 KOR 镇痛中的性别二态性有显着贡献。我们发现 KOR 镇痛作用主要受 X 染色体数量的影响。这些数据表明 X 基因上的剂量和/或亲本印记对 KOR 镇痛中的性别二态性有显着贡献。我们发现 KOR 镇痛作用主要受 X 染色体数量的影响。这些数据表明 X 基因上的剂量和/或亲本印记对 KOR 镇痛中的性别二态性有显着贡献。