Mechanisms of Migraine

偏头痛的机制

基本信息

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
项目类别：
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

项目摘要

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.

偏头痛的机制偏头痛是一种使人衰弱的阵发性疼痛疾病，目前尚无持续有效的治疗方法治疗干预。它也是最常见的疼痛疾病之一，影响多达 10% 占一般成年人口的 18%，以及 18% 的女性。确定新方法因此，治疗偏头痛非常重要。普遍的证据表明，支配硬脑膜的初级传入神经元硬脑膜血管系统是偏头痛发作时疼痛的根源。目前的建议是因此，重点关注硬脑膜中影响传入活动的成分。这些组件包括硬脑膜和硬脑膜脉管系统中驻留和招募的免疫细胞。我们也会学习传入物本身。我们建议利用偏头痛的两个独特特征作为一种手段确定引发偏头痛发作的机制。一是压力最大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神经节后神经元（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响应系统中，硬脑膜受到 SPGN 终端的严重支配，并且所有三个硬脑膜组件待研究的介质由 SPGN 终端释放的介质调节。最后我们还建议性别是影响压力与偏头痛之间联系的一个关键因素，因为性别较高女性偏头痛的患病率以及性腺激素，特别是雌激素共同作用的事实调节要研究的每个硬脑膜成分。因此，该提案的中心假设是这种压力会导致硬脑膜免疫调节中性别和 SPGN 依赖性的变化细胞、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得到检验。在第一个中，我们将确定性、SPGN 神经支配和持续压力对居民和在硬脑膜中招募免疫细胞。第二，我们将确定性的影响和持久性硬脑膜脉管系统 SPGN 依赖性调节的压力。在第三步中，我们将确定性别和持续压力对电压门控 Ca2+ 电流 SPGN 依赖性变化的影响硬脑膜传入和硬脑膜传入兴奋性。所提出的实验不仅将提供有价值的深入了解硬脑膜的神经生物学，硬脑膜是一种对大脑健康至关重要的结构，但建议治疗偏头痛的新方法能够完全预防偏头痛的发作。