Mechanisms of Migraine

偏头痛的机制

• 批准号: 8703388
• 负责人: MICHAEL S GOLD
• 金额: $ 34.93万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-15 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8703388
• 关键词: Adrenal Glands; Adrenergic Agents; Adrenergic Receptor; Adult; Afferent Neurons; Biological Assay; Biological Response Modifiers; Blood Vessels; Blood flow; Brain; Caliber; Cells; Chemotaxis; Complex; Data; Disease; Dura Mater; Epinephrine; Estrogens; Evans blue stain; Fibromyalgia; Flow Cytometry; General Population; Goals; Gonadal Hormones; Headache; Health; High Prevalence; Histology; Hypothalamic structure; Image; Immune; Immune system; Intrinsic drive; Joints; Libido; Link; Mediator of activation protein; Migraine; Nature; Neurobiology; Neurons; Nitroglycerin; Nociception; Norepinephrine; Pain; Pain Disorder; Phase; Pituitary Gland; Population; Prevention; Productivity; Property; Receptor Activation; Recruitment Activity; Regulation; Relaxation; Sex Characteristics; Signaling Molecule; Site; Skin; Societies; Source; Staging; Stress; Structure; Syndrome; System; TNF gene; Techniques; Testing; Therapeutic; Therapeutic Intervention; Vascular Permeabilities; Viscera; Weight; Woman; adrenergic; base; biological adaptation to stress; cytokine; density; design; effective therapy; insight; macrophage; mast cell; men; nerve supply; nervous system disorder; novel strategies; patch clamp; prevent; public health relevance; research study; sex; stressor; therapy design; two-photon; voltage

Mechanisms of Migraine Migraine is a debilitating episodic pain disorder for which there are no consistently effective therapeutic interventions. It is also one of the most prevalent pain disorders afflicting as many as 10% of the general adult population and 18% of women. Identification of novel approaches for the treatment of migraine is therefore highly significant. The prevailing weight of evidence indicates that the primary afferent neurons innervating the dura and dural vasculature are the source of the pain of a migraine attack. The present proposal is therefore focused on components of the dura that can influence afferent activity. These components include resident and recruited immune cells in the dura and the dural vasculature. We will also study the afferents themselves. We have proposed to exploit two unique features of migraine as a means to identify mechanisms that enable the initiation of a migraine attack. One is that stress is the most common trigger of a migraine attack. A second is that migraine attacks occur during relaxation phase after stress has ended. We propose that sympathetic post-ganglionic neurons (SPGN) in the dura serve as a link between stress and migraine because they are a critical component of the stress response system, the dura is heavily innervated by SPGN terminals, and all three dural components to be studied are regulated by mediators released from SPGN terminals. Finally, we also propose that sex is a critical factor that influences the link between stress and migraine because of the higher prevalence of migraine in women and the fact that gonadal hormones, in particular estrogens co- regulate each of the dural components to be studied. Thus, the central hypothesis of this proposal is that that stress drives sex- and SPGN-dependent changes in the regulation of dural immune cells, vasculature and primary afferents, that set the stage for the initiation of a migraine attack. This hypothesis will be tested in experiments described under three specific aims. In the first, we will determine the impact of sex, SPGN innervation, and persistent stress on resident and recruited immune cells in the dura. In the second, we will determine the impact of sex and persistent stress on SPGN-dependent regulation of the dural vasculature. In the third, we will determine the impact of sex and persistent stress on SPGN-dependent changes in voltage-gated Ca2+ currents in dural afferents and dural afferent excitability. The proposed experiments will not only provide valuable insight into the neurobiology of the dura, a structure critical for the health of the brain, but suggest novel approaches for the treatment of migraine enabling the prevention an attack altogether.

偏头痛的发病机制 偏头痛是一种使人衰弱的发作性疼痛障碍， 治疗干预。它也是最普遍的疼痛疾病之一， 成年人和18%的女性。确定新的方法， 因此，治疗偏头痛是非常重要的。 目前的证据表明，支配硬脑膜的初级传入神经元 和硬脑膜脉管系统是偏头痛发作的疼痛来源。现时的建议是 因此，重点放在硬脑膜的成分，可以影响传入活动。这些组件 包括硬脑膜和硬脑膜脉管系统中的驻留和募集的免疫细胞。我们还将研究 传入神经本身。我们已经提出利用偏头痛的两个独特特征作为一种手段， 确定能够引发偏头痛发作的机制。一个是压力是 偏头痛发作的常见诱因第二个是偏头痛发作发生在放松阶段 压力结束后。我们认为硬脑膜中的交感节后神经元（SPGN） 作为压力和偏头痛之间的联系，因为它们是压力的关键组成部分 在反应系统中，硬脑膜受SPGN终末的严重支配，并且所有三个硬脑膜组件 被研究的神经元受SPGN终末释放的介质调节。最后，我们还建议， 性是影响压力和偏头痛之间联系的一个关键因素， 女性偏头痛的患病率和性腺激素，特别是雌激素共同作用的事实， 调节每个要研究的硬脑膜成分。因此，这一提议的核心假设是 压力驱动了硬膜免疫调节中性别和SPGN依赖性变化， 细胞、脉管系统和初级传入神经，为偏头痛的发生奠定了基础 攻击这一假设将在三个具体目标下描述的实验中进行测试。在第一个， 我们将确定性别、SPGN神经支配和持续压力对住院医师的影响， 在硬脑膜中募集免疫细胞。在第二部分，我们将确定影响性和持久性 强调硬脑膜血管系统的SPGN依赖性调节。第三，我们将确定 性别和持续应激对大鼠电压门控Ca 2+电流SPGN依赖性变化的影响 硬膜传入和硬膜传入兴奋性。这些实验不仅提供了宝贵的 深入了解硬脑膜的神经生物学，硬脑膜是大脑健康的关键结构，但建议 用于治疗偏头痛的新方法能够完全预防偏头痛发作。