Pain is more prevalent in women for reasons that remain unclear. We have identified a mechanism of injury-free nociceptor sensitization and opioid-induced hyperalgesia (OIH) promoted by prolactin (PRL) in females. PRL signals through mutually inhibitory long (PRLR-L) and short (PRLR-S) receptor isoforms, and PRLR-S activation induces neuronal excitability. PRL and PRLR expression were higher in females. CRISPR-mediated editing of PRLR-L promoted nociceptor sensitization and allodynia in naïve, uninjured female mice that depended on circulating PRL. Opioids, but not trauma-induced nerve injury, decreased PRLR-L promoting OIH through activation of PRLR-S in female mice. Deletion of both PRLR-L and PRLR-S (total PRLR) prevented, whereas PRLR-L overexpression rescued established OIH selectively in females. Inhibition of circulating PRL with cabergoline, a dopamine D2 agonist, up-regulated PRLR-L and prevented OIH only in females. The PRLR-L isoform therefore confers protection against PRL-promoted pain in females. Limiting PRL/PRLR-S signaling pharmacologically or with gene therapies targeting the PRLR may be effective for reducing pain in a female-selective manner.

中文翻译：

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催乳素受体长亚型选择性地调节女性的伤害感受器致敏和阿片类药物诱导的痛觉过敏。

疼痛在女性中更为普遍，原因尚不清楚。我们已经确定了一种由女性催乳素 (PRL) 促进的无损伤伤害感受器致敏和阿片类药物诱导的痛觉过敏 (OIH) 的机制。PRL 通过相互抑制的长 (PRLR-L) 和短 (PRLR-S) 受体亚型发出信号，并且 PRLR-S 激活诱导神经元兴奋性。PRL 和 PRLR 表达在女性中较高。CRISPR 介导的 PRLR-L 编辑促进了依赖循环 PRL 的幼稚未受伤雌性小鼠的伤害感受器致敏和异常性疼痛。阿片类药物，但不是创伤引起的神经损伤，通过激活雌性小鼠的 PRLR-S 降低了促进 OIH 的 PRLR-L。PRLR-L 和 PRLR-S（总 PRLR）的删除阻止了，而 PRLR-L 过表达在女性中选择性地挽救了建立的 OIH。用多巴胺 D2 激动剂卡麦角林抑制循环 PRL，仅在女性中上调 PRLR-L 并预防 OIH。因此，PRLR-L 异构体可以保护女性免受 PRL 引起的疼痛。通过药理学或靶向 PRLR 的基因疗法限制 PRL/PRLR-S 信号传导可能对以女性选择性方式减轻疼痛有效。