Meningeal prolactin signaling and female-selective migraine mechanisms

脑膜催乳素信号传导和女性选择性偏头痛机制

• 批准号: 10266762
• 负责人: ARMEN N AKOPIAN
• 金额: $ 47.62万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10266762
• 关键词: Acute; Afferent Neurons; Area; Basic Science; Behavior; Cephalic; Chronic; Clinical Data; Communication; Complex; Custom; Data; Development; Disease; Dura Mater; Endothelial Cells; Estrogens; Face; Female; Functional disorder; Goals; Gonadal Hormones; Headache; Human; Knowledge; Lead; Link; Literature; Mediating; Meningeal; Migraine; Modeling; Mus; Neurons; Neurosecretory Systems; Pain; Pathogenesis; Pathway interactions; Patients; Pattern; Pharmacology; Pituitary Gland; Plasma; Play; Population; Price; Principal Investigator; Prolactin; Prolactin Receptor; Regulation; Relapse; Reporting; Research; Role; Scheme; Sensory Receptors; Sex Differences; Signal Transduction; Stress; Syndrome; System; Testing; Vascular Endothelial Cell; Vascular System; Woman; Work; allodynia; base; behavioral response; burden of illness; disability; innovation; male; men; mustard oil; new therapeutic target; novel; personalized medicine; personalized predictions; personalized therapeutic; prepuberty; receptor expression; release factor; sex; therapeutic target; treatment strategy

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.

女性始终报告头痛相关残疾更高、复发率更高、频率更高、时间更长 比男性更持久、更严重的头痛因此迫切需要定制偏头痛。 因此，我们的长期目标是基于性别特异性疼痛机制的治疗方案。 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治疗 基于个性化偏头痛管理方案。 人们普遍认为，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，一些报告表明偏头痛发作。 其次，女性和男性的血浆催乳素（PRL）水平都会升高。 其他人证明疼痛通路中 PRL 的反应是性别依赖性的并且受到严格控制 关于 PRL 系统是否以及如何影响性别的知识存在严重差距。 该提案的目的是确定与 PRL 相关的机制。 我们的初步数据是对某些类型的偏头痛进行压力和性别依赖性调节的系统。 证明应用于硬脑膜的 PRL 会引起女性持久的面部异常疼痛，但不会 男性的 PRL 也会使女性的芥子油诱发的 CGRP 释放变得敏感，但对男性的硬脑膜则不会。 进一步将 PRL 系统与偏头痛联系起来，我们发现 PRL 受体 (Prlr) 拮抗剂可阻断 CGRP- 因此，我们的中心假设是 PRL 通过 Prlr 起作用。 硬脑膜支配感觉神经元介导女性特异性机制，有助于 这项研究的基本原理是：1）极大地扩展了我们对性的了解。 偏头痛机制的差异；2) 通过提供治疗靶点提供转化潜力 基于性别的偏头痛管理通过相互关联但独立的目标进行了检验。 目标 1 检查三叉血管系统中 PRL 和 Prlr 的性别特异性表达和调节。 目标 2 确定 PRL 和 Prlr 如何以性别特异性调节硬脑膜传入神经和偏头痛的活动 目标 3 评估 CGRP 诱发的偏头痛之间的联系。 拟议的研究具有创新性，因为它定义了行为反应和硬脑膜 PRL 系统。 基于 PRL 的某些偏头痛模型的概念性新颖的性别特异性调节机制 拟议的研究意义重大，因为它增进了我们对性别差异的理解。 偏头痛机制——一个尚未得到充分研究的领域，增加基础科学知识具有潜力 带来更好的基于性别的个性化治疗。