A prolactin-mediated neuroendocrine link between stress-induced latent sensitization and female-selective pain

项目摘要： 许多患者在没有可识别的损伤的情况下遭受慢性疼痛。这种疼痛被称为“功能性疼痛” 包括肠易激综合征、颞下颌关节紊乱、纤维肌痛、偏头痛等。为 由于尚不清楚的原因，几乎所有的功能性疼痛综合征（FPS）都是女性流行的。FPS患者 经历无疼痛的发作间歇期，间歇期被疼痛的发作打断。袭击的频率预示着 慢性化的风险。因此，疼痛发作产生了启动效应，建立了一种脆弱性增加的状态 未来的攻击，可能反映了周边和中央敏感化。FPS患者通常认为压力是 疼痛的关键触发点因此，反复的压力可能会以一种性别二态的方式促进脆弱性和痛苦。 我们已经开发了一种基于重复应激的痛觉过敏启动的无损伤FPS啮齿动物模型。 痛觉过敏引发产生了一种无痛苦的状态，这种状态增加了脆弱性，被称为“潜伏性”。 致敏”（LS）。在诱导LS后，通常阈下触发可产生疼痛发作， FPS的发作间期和发作期。我们将使用这个模型来检验重复压力的新假设， 激活下丘脑中的κ阿片受体（KOR）信号传导，导致催乳素（PRL）的释放， 女性伤害感受器中催乳素受体（PRLR）亚型选择性表达失调。PRL信号 通过长和短PRLR的同源二聚体（即，PRLR-L和PRLR-S）同种型，其分别调节 转录和疼痛。反复应激下调PRLR-L，通过以下途径促进女性选择性疼痛 应激诱导的PRL/PRLR-S信号传导。因此，PRLR亚型的平衡可能会“调节”雌性伤害感受器 促进LS和正常阈下刺激引起的疼痛。 我们将使用遗传学和化学遗传学操作，沿着解剖学，神经化学， 在雄性和雌性小鼠中进行电生理学、药理学和行为学研究，以评价 背根神经节（DRG）PRLR-L下调和应激相关的下丘脑KOR激活， LS和女性压力相关疼痛的基本机制。目标1将建立重复的效果 应激对下丘脑KOR信号传导和PRL释放的影响。目标2将建立以下潜在因果关系： 重复应激或下丘脑KOR激活对DRG PRLR亚型表达、神经兴奋性、LS和 与压力有关的疼痛目的3将确定KOR拮抗剂、DA激动剂或PRL抗体是否会预防LS， 女性选择性的FPS样疼痛。 这项研究将描述一种以前未知的与压力相关的神经内分泌联系， 下丘脑KOR和PRL/PRLR信号通路促进女性选择性功能性疼痛。重要的是这些 这些研究将促进对以前未知的生物机制的了解，并可能揭示机制 用于治疗干预，以改善女性FPS的治疗。

Project Summary: Many patients suffer from chronic pain in the absence of identifiable injury. Such pains are termed “functional” and include irritable bowel syndrome, temporomandibular joint disorder, fibromyalgia, migraine and others. For reasons that are not understood, almost all functional pain syndromes (FPS) are female prevalent. FPS patients experience pain-free interictal periods punctuated by attacks of pain. The frequency of attacks is predictive of risk of chronification. Pain episodes thus produce a priming effect, establishing a state of increased vulnerability to future attacks, likely reflecting peripheral and central sensitization. FPS patients commonly identify stress as a key trigger of pain. Repeated stress may thus promote vulnerability and pain in a sexually dimorphic fashion. We have developed an injury-free rodent model of FPS based on hyperalgesic priming with repeated stress. Hyperalgesic priming produces a pain-free state of increased vulnerability that has been termed “latent sensitization” (LS). Following induction of LS, normally subthreshold triggers can produce pain attacks, modeling the interictal and ictal periods of FPS. We will use this model to test the novel hypothesis that repeated stress activates kappa opioid receptor (KOR) signaling in the hypothalamus resulting in release of prolactin (PRL) and dysregulation of prolactin receptor (PRLR) isoform expression selectively in female nociceptors. PRL signals through homodimers of PRLR long and short (i.e., PRLR-L and PRLR-S) isoforms that respectively regulate transcription and pain. Repeated stress down-regulates PRLR-L promoting female-selective pain through stress-induced PRL/PRLR-S signaling. The balance of PRLR isoforms may therefore “tune” female nociceptors to promote LS and pain from normally subthreshold stimuli. We will use genetic and chemogenetic manipulations along with anatomical, neurochemical, electrophysiological, pharmacological and behavioral studies in male and female mice to evaluate the role of dorsal root ganglion (DRG) PRLR-L down-regulation and stress-related hypothalamic KOR activation as essential mechanisms of LS and stress-related pain in females. Aim 1 will establish the effects of repeated stress on hypothalamic KOR signaling and PRL release. Aim 2 will establish a potential causal relationship of repeated stress or hypothalamic KOR activation on DRG PRLR isoform expression, neural excitability, LS and stress-related pain. Aim 3 will determine if KOR antagonists, DA agonists or a PRL antibody will prevent LS and FPS-like pain selectively in females. The proposed studies will characterize a previously unknown stress-related neuroendocrine link between hypothalamic KOR and PRL/PRLR signaling to promote female selective functional pain. Importantly, these studies will advance knowledge about previously unknown biological mechanisms and may unravel mechanisms for therapeutic interventions allowing improved therapy of FPS in women.