Many clinical and preclinical studies report higher prevalence and severity of chronic pain in females. We used hyperalgesic priming with interleukin 6 (IL-6) priming and PGE₂ as a second stimulus as a model for pain chronicity. Intraplantar IL-6 induced hypersensitivity was similar in magnitude and duration in both males and females, while both paw and intrathecal PGE₂ hypersensitivity was more persistent in females. This difference in PGE₂ response was dependent on both circulating estrogen and translation regulation signaling in the spinal cord. In males, the duration of hypersensitivity was regulated by testosterone. Since the prolactin receptor (Prlr) is regulated by reproductive hormones and is female-selectively activated in sensory neurons, we evaluated whether Prlr signaling contributes to hyperalgesic priming. Using PRL, a competitive Prlr antagonist, and a mouse line with ablated Prlr in the Nav1.8 sensory neuronal population, we show that Prlr in sensory neurons is necessary for the development of hyperalgesic priming in female, but not male, mice. Overall, sex-specific mechanisms in the initiation and maintenance of chronic pain are regulated by the neuroendocrine system and, specifically, sensory neuronal Prlr signaling.

SIGNIFICANCE STATEMENT Females are more likely to experience chronic pain than males, but the mechanisms that underlie this sex difference are not completely understood. Here, we demonstrate that the duration of mechanical hypersensitivity is dependent on circulating sex hormones in mice, where estrogen caused an extension of sensitivity and testosterone was responsible for a decrease in the duration of the hyperalgesic priming model of chronic pain. Additionally, we demonstrated that prolactin receptor expression in Nav1.8⁺ neurons was necessary for hyperalgesic priming in female, but not male, mice. Our work demonstrates a female-specific mechanism for the promotion of chronic pain involving the neuroendrocrine system and mediated by sensory neuronal prolactin receptor.

许多临床和临床前研究报告，女性慢性疼痛的患病率和严重性较高。我们使用白细胞介素6（IL-6）引发的痛觉过敏引发和作为第二次刺激的PGE ₂作为慢性疼痛模型。在男性和女性中，足底内IL-6引起的超敏反应在强度和持续时间上均相似，而女性的爪和鞘内PGE ₂超敏反应则更为持久。PGE _2中的差异应答依赖于循环中的雌激素和脊髓中的翻译调节信号。在男性中，超敏反应的持续时间由睾丸激素调节。由于催乳素受体（Prlr）受生殖激素的调节，并在感觉神经元中被女性选择性激活，因此我们评估了Prlr信号传导是否有助于痛觉过敏的启动。使用PRL，一种竞争性Prlr拮抗剂和Nav1.8感觉神经元群体中具有消融Prlr的小鼠品系，我们表明，感觉神经元中的Prlr对于雌性而非雄性小鼠的痛觉过敏引发的发展是必需的。总体而言，慢性疼痛的发生和维持过程中的性别特异性机制受神经内分泌系统，特别是感觉神经元Prlr信号传导的调节。

意义声明女性比男性更容易遭受慢性疼痛，但是导致这种性别差异的机制尚不完全清楚。在这里，我们证明了机械性超敏反应的持续时间取决于小鼠体内循环性激素的水平，其中雌激素引起敏感性的延长，而睾丸激素则导致慢性疼痛的超痛觉敏模型的持续时间减少。此外，我们证明了Nav1.8 ⁺神经元中催乳素受体的表达对于雌性（而非雄性）小鼠的痛觉过敏引发是必需的。我们的工作证明了一种特定于女性的机制，可促进涉及神经内分泌系统并由感觉神经元催乳素受体介导的慢性疼痛。