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 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 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.