Mechanisms of Migraine

偏头痛的机制

• 批准号: 9190386
• 负责人: MICHAEL S GOLD
• 金额: $ 35.08万
• 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/9190386
• 关键词: Adrenal Glands; Adrenergic Agents; Adrenergic Receptor; Adult; Afferent Neurons; Biological Assay; Biological Response Modifiers; Blood Vessels; Blood flow; Caliber; Cells; Chemotaxis; Complex; Data; Disease; Dura Mater; Electrophysiology (science); Epinephrine; Estrogens; Evans blue stain; 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; Phenotype; Pituitary Gland; Population; Prevention; Productivity; Property; Receptor Activation; Recruitment Activity; Regulation; Relaxation; Sex Characteristics; Signaling Molecule; Site; Skin; Societies; Source; Stress; Structure; Syndrome; System; TNF gene; Techniques; Testing; Therapeutic; Therapeutic Intervention; Treatment Efficacy; Vascular Permeabilities; Viscera; Weight; Woman; base; biological adaptation to stress; brain health; cytokine; density; design; effective therapy; experimental study; fibromyalgia pain; immunoregulation; insight; macrophage; mast cell; men; nerve supply; nervous system disorder; novel strategies; patch clamp; prevent; public health relevance; sex; stressor; therapy design; two-photon; voltage

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：偏头痛是一种使人衰弱的情节疼痛障碍，没有一贯有效的治疗干预措施。它也是最普遍的疼痛障碍之一，损害了多达10％的成人人群和18％的女性。因此，确定偏头痛治疗的新方法是非常重要的。 流行的证据表明，支配硬脑膜和硬脑膜脉管系统的主要传入神经元是偏头痛发作疼痛的根源。因此，本提案的重点是可以影响传入活动的硬脑膜组成部分。这些成分包括硬脑膜和硬脑膜脉管系统中的常驻和招募的免疫细胞。我们还将自己研究传入者。我们建议利用偏头痛的两个独特特征，以此来确定能够启动偏头痛攻击的机制。一种是压力是偏头痛攻击的最常见触发因素。第二个是在压力结束后放松阶段发生偏头痛攻击。我们提出，硬脑膜中的交感神经后神经元（SPGN）充当压力和偏头痛之间的联系，因为它们是应力响应系统的关键组成部分，硬脑膜由SPGN末端严重支配，并且所有三个要研究的硬膜组件都由从SPGN末端释放的中介器释放。最后，我们还建议性别是影响压力与偏头痛之间联系的关键因素，因为妇女偏头痛的患病率较高，并且性腺激素（尤其是雌激素）共同调节了每个硬膜成分。因此，该提议的中心假设是，压力驱动性别和SPGN依赖性的变化，在硬脑膜免疫细胞，脉管系统和主要传入的调节中，这为开始偏头痛攻击奠定了基础。该假设将在三个特定目标下描述的实验中进行检验。首先，我们将确定性别，SPGN神经支配以及持续的压力对硬脑膜中居民和招募的免疫细胞的影响。在第二个中，我们将确定性别和持续压力对硬脑膜脉管系统的依赖性调节的影响。在第三个中，我们将确定性别和持续应力对硬脑膜传入和硬膜传入兴奋性中电压门控Ca2+电流变化的影响。提出的实验不仅将提供对硬脑膜神经生物学的宝贵见解，这是对大脑健康至关重要的结构，而且建议对偏头痛的治疗方法进行新颖的方法，从而使预防完全发作。