Mechanisms of Migraine

偏头痛的机制

基本信息

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
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/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

项目摘要

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阵发性疼痛疾病，目前尚无持续有效的治疗干预措施。它也是最常见的疼痛疾病之一，困扰着多达 10% 的普通成年人和 18% 的女性。因此，确定治疗偏头痛的新方法非常重要。现有证据表明，支配硬脑膜和硬脑膜脉管系统的初级传入神经元是偏头痛发作的疼痛根源。因此，本提案的重点是可以影响传入活动的硬脑膜成分。这些成分包括硬脑膜和硬脑膜脉管系统中驻留和招募的免疫细胞。我们还将研究传入神经本身。我们建议利用偏头痛的两个独特特征作为识别偏头痛发作机制的手段。一是压力是偏头痛发作最常见的诱因。第二个是偏头痛发作发生在压力结束后的放松阶段。我们认为硬脑膜中的交感神经节后神经元（SPGN）是压力和偏头痛之间的联系，因为它们是压力反应系统的关键组成部分，硬脑膜受到 SPGN 末端的严重神经支配，并且所有三个硬脑膜成分都是研究受到 SPGN 终端释放的中介体的调节。最后，我们还提出，性别是影响压力和偏头痛之间联系的关键因素，因为女性偏头痛的患病率较高，而且性腺激素，特别是雌激素共同调节要研究的每个硬脑膜成分。因此，该提议的中心假设是，压力会导致硬脑膜免疫细胞、脉管系统和初级传入神经的调节发生性别和 SPGN 依赖性变化，从而为偏头痛发作奠定基础。这一假设将在三个具体目标下描述的实验中得到检验。首先，我们将确定性别、SPGN 神经支配和持续压力对硬脑膜中驻留和招募的免疫细胞的影响。第二步，我们将确定性别和持续压力对硬脑膜脉管系统 SPGN 依赖性调节的影响。第三，我们将确定性别和持续压力对硬脑膜传入电压门控 Ca2+ 电流和硬脑膜传入兴奋性中 SPGN 依赖性变化的影响。拟议的实验不仅将为硬脑膜（一种对大脑健康至关重要的结构）的神经生物学提供有价值的见解，而且还提出了治疗偏头痛的新方法，从而能够完全预防偏头痛的发作。