Meningeal prolactin signaling and female-selective migraine mechanisms

女性总是报告更高的头痛相关残疾，更高的复发率，更频繁，更长时间 持续的，比男性更严重的头痛。因此，迫切需要定制偏头痛 基于特定性别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，并利用这一知识提供更有效的性行为- 基于个性化偏头痛管理方案。 众所周知，头痛综合征，尤其是偏头痛的发病机制与性别有关。 由于性腺激素(GNH)的重要贡献。首先，一些报告显示偏头痛发作 在女性和男性中，伴随着血浆催乳素(PRL)水平的上升。第二，我们和 另一些研究表明，PRL在疼痛通路中的反应与性别有关，并且受到严格控制 由雌激素引起。关于PRL系统是否以及如何进行性行为方面的知识存在严重差距- 依赖地调节偏头痛。这项建议的目标是确定将PRL联系起来的机制 系统对某些类型的偏头痛进行应激和性别依赖性调节。我们的初步数据 证明PRL应用于颅脑硬脑膜会导致女性持久的面部痛觉异常，但不会 男性。PRL还能敏化芥子油引起的女性硬脑膜CGRP释放，但对男性硬脑膜不敏感。最后，为了 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- 在女性中诱发偏头痛行为。因此，我们的中心假设是PRL通过PRLR起作用 关于硬脑膜神经支配的感觉神经元介导女性特有的机制 偏头痛。提出这项研究的理由是：1)它极大地扩展了我们对性的认识 偏头痛机制的差异；以及2)通过提供治疗靶点提供翻译潜力 以性为基础的偏头痛治疗。我们的假设得到了相互关联但又相互独立的目标的检验。 目的1研究PRL和PrlR在三叉神经-血管系统中的性别特异性表达和调控。 目的2确定PRL和PrlR性别特异性地调节硬脑膜传入和偏头痛的活动。 类似于应激诱导的偏头痛模型中的行为。AIM 3评估降钙素基因相关肽引起的偏头痛 行为反应和硬脑膜催乳素系统。拟议的研究具有创新性，因为它界定了 基于催乳素的某些偏头痛模型的概念上的性别特异性调节机制 发信号。这项拟议的研究具有重要意义，因为它促进了我们对 偏头痛机制--一个研究不足的领域，不断增加的基础科学知识有可能 从而带来更好的基于性行为的个性化治疗。

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.