Meningeal prolactin signaling and female-selective migraine mechanisms

女性一贯报告头痛相关残疾较高，复发率较高，更频繁，时间更长 比男人更厉害，也更能吃苦。因此，迫切需要定制偏头痛 基于性别特异性疼痛机制的管理方案。因此，我们的长期目标是 定义偏头痛的性别特异性机制，并利用这些知识提供更有效的性- 基于个性化偏头痛管理方案。 头痛综合征，尤其是偏头痛的发病机制是性别依赖性的，这是公认的 由于性腺激素（GnH）的重要贡献。首先，一些报告显示， 在女性和男性中，伴随着催乳素（PRL）血浆水平的升高。第二，我们和 其他研究表明，疼痛通路中的PRL反应性是性别依赖的，并且受到严格控制 通过雌激素。关于催乳素系统是否以及如何与性别有关的知识存在着严重的差距- 依赖性地调节偏头痛。这项建议的目的是确定将临时立法会 系统对某些类型的偏头痛的压力和性别依赖性调节。我们的初步数据 证明PRL应用于硬脑膜会引起女性持久的面部异常性疼痛，但不会 男性。PRL也敏感芥子油引起的CGRP释放从女性，但不是男性硬脑膜。最后为 进一步将PRL系统与偏头痛联系起来，我们发现PRL受体（Prlr）拮抗剂阻断CGRP- 诱发女性偏头痛行为。因此，我们的中心假设是PRL通过Prlr起作用， 对硬脑膜支配的感觉神经元介导的女性特有的机制，有助于 偏头痛这项研究的基本原理是：1）极大地扩展了我们对性的认识 偏头痛机制的差异;和2）通过提供治疗靶点提供翻译潜力 治疗性偏头痛我们的假设是由相互关联但独立的目标来检验的。 目的1研究PRL和Prlr在三叉神经血管系统的性别特异性表达和调控。 目的2确定PRL和Prlr如何性别特异性地调节硬脑膜传入和偏头痛的活动。 类似于压力诱发的偏头痛模型中的行为。目的3：评估CGRP诱导的偏头痛 行为反应和硬膜PRL系统。这项研究是创新的，因为它定义了 基于PRL的某些偏头痛模型的概念性新的性别特异性调节机制 发信号。这项拟议中的研究意义重大，因为它促进了我们对性别差异的理解， 偏头痛机制-一个未充分研究的领域，增加基础科学知识有可能 从而带来更好的基于性别的个性化治疗。

Women consistently report higher headache-related disabilities, higher relapse rate, more frequent, longer lasting, and more severe headaches than men. Hence, there is an urgent need to customize migraine management schemes based on sex-specific pain mechanisms. Accordingly, our long-term goal is to define sex-specific mechanisms of migraine, and utilize this knowledge to provide more effective sex- based personalized migraine management schemes. It is well accepted that the pathogenesis of headache syndromes, especially migraine, are sex-dependent due to important contributions of gonadal hormones (GnH). First, some reports show that migraine attacks in female and males are accompanied by a rise in plasma levels of prolactin (PRL). Second, we and others demonstrated that PRL responsiveness in pain pathways is sex-dependent and strictly controlled by estrogen. There is a critical gap in knowledge pertaining to whether and how the PRL system sex- dependently regulates migraine. The objective of this proposal is to identify mechanisms linking the PRL system to stress- and sex-dependent regulation of certain types of migraine. Our preliminary data demonstrate that PRL applied to cranial dura induces long-lasting facial allodynia in females, but not males. PRL also sensitizes mustard oil-evoked CGRP release from female, but not male dura. Finally, to further link the PRL system to migraine, we showed that a PRL receptor (Prlr) antagonist blocks CGRP- induced migraine behavior in females. Thus, our central hypothesis is that PRL acting through the Prlr on dural-innervating sensory neurons mediates female-specific mechanisms contributing to migraine. The rationale for the proposed study is that it 1) greatly expands our knowledge of sex differences in migraine mechanisms; and 2) provides translational potential by offering therapeutic targets for sex-based migraine management. Our hypothesis is tested by interconnected yet independent aims. Aim 1 examines sex-specific expression and regulation of PRL and Prlr in the trigemino-vascular system. Aim 2 determines how PRL and Prlr sex-specifically modulate the activity of dural afferents and migraine- like behavior in stress-induced migraine models. Aim 3 assesses a link between CGRP-induced migraine behavioral responses and the dural PRL system. The proposed study is innovative since it defines conceptually novel sex-specific regulatory mechanisms for certain migraine models based on PRL signaling. The proposed research is significant as it advances our understanding of sex differences in migraine mechanisms – an understudied area where increasing basic science knowledge has the potential to lead to better sex-based personalized therapeutics.