Cerebrovascular Afferent Mechanisms of Migraine

偏头痛的脑血管传入机制

• 批准号: 7629011
• 负责人: Andrea M Harriott
• 金额: $ 4.26万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7629011
• 关键词: Agonist; Automobile Driving; Blood Vessels; Body part; Bradykinin; Cells; Circle of Willis; Coculture Techniques; Data; Development; Drug Delivery Systems; Event; Feedback; Frequencies; Functional disorder; Headache; Heart; Histamine; Immunohistochemistry; In Vitro; Inflammation; Inflammation Mediators; Inflammatory Response; Internal carotid artery structure; Ion Channel; Label; Location; Mediator of activation protein; Meningeal; Meningeal Arteries; Migraine; Neurogenic Inflammation; Neurons; Neuropeptides; Nociception; Pain; Pattern; Peripheral; Pharmaceutical Preparations; Physiologic pulse; Population; Posterior Horn Cells; Property; Prostaglandins; Rattus; Sensory; Serotonin Receptor 5-HT1D; Signal Transduction; Site; Specificity; Spinal Ganglia; Stimulus; Structure; Synaptic Transmission; Testing; Therapeutic; Tissues; Treatment Efficacy; Trigeminal System; cerebrovascular; effective therapy; experience; follow-up; insight; nervous system disorder; neuronal cell body; novel; postsynaptic; pressure; presynaptic; receptor; research study; response; serotonin receptor; triptans; vasoconstriction; voltage clamp

DESCRIPTION (provided by the applicant) Migraine is a common neurological disorder characterized by severe head pain that is associated with autonomic and sensory dysfunction. Activation of cerebrovascular afferents and resultant neurogenic inflammation are thought to be essential for the development of migraine pain. Evidence suggests that inflammatory mediators such as histamine, bradykinin, and prostaglandin sensitize cerebrovascular afferents. Once sensitized, these afferents may be activated by normally innocuous stimuli, such as heart beat-induced changes in vascular pressure. Activated afferents not only release transmitters that are capable of directly stimulating afferent activity (i.e., feedback-excitation), but that drive an inflammatory response associated with the release of additional mediators that can further activate and sensitize afferent terminals. All of this afferent activity is thought to underlie at least the initiation of the pain experienced during a migraine attack. Administration of triptans is currently one of the most effective treatments for migraine pain. These drugs are serotonin receptor type 1B/1D (5-HT1B/1D) agonists. Although 5-HT1B/1D receptors are ubiquitously expressed in trigeminal and dorsal root ganglion neurons, triptans are not generally antinociceptive, having little efficacy for the treatment of pain arising from other parts of the body. Triptans have been shown to produce vasoconstriction and reduce peripheral neuropeptide expression but neither of these appears to be the primary mechanism of antinociception. Understanding the specificity associated with the anti-nociceptive action of 5-HT1B/1D receptors may provide insight into the mechanisms involved in migraine pain and help identify novel targets for drug treatment. The general hypothesis to be tested in this proposal is that the therapeutic actions of triptans reflect unique response properties of cerebrovascular afferents to inflammatory mediators. This hypothesis will be tested with experiments that examine the distribution of 5-HT1B/1D receptors among afferents innervating the intracranial vasculature and changes in excitability and synaptic transmission of cerebrovascular afferents following inflammation and triptan application. The results from these experiments should help provide unique targets for the treatment of migraine pain and increase the understanding of cerebrovascular afferent mechanisms in initiating migraine pain.

描述（由申请人提供） 偏头痛是一种常见的神经系统疾病，其特征是严重的头痛，与自主神经和感觉功能障碍有关。脑血管传入神经的激活和由此产生的神经源性炎症被认为对于偏头痛的发生至关重要。有证据表明，组胺、缓激肽和前列腺素等炎症介质可使脑血管传入变得敏感。一旦敏感，这些传入神经可能会被通常无害的刺激激活，例如心跳引起的血管压力变化。激活的传入神经不仅释放能够直接刺激传入活动（即反馈兴奋）的递质，而且还驱动与释放额外介质相关的炎症反应，这些介质可以进一步激活传入末梢并使其敏感。所有这些传入活动被认为至少是偏头痛发作期间疼痛开始的基础。曲坦类药物是目前治疗偏头痛最有效的方法之一。这些药物是 1B/1D 型血清素受体 (5-HT1B/1D) 激动剂。尽管 5-HT1B/1D 受体在三叉神经节和背根神经节神经元中普遍表达，但曲坦类药物通常不具有镇痛作用，对治疗身体其他部位产生的疼痛效果甚微。曲坦类药物已被证明可以产生血管收缩作用并减少外周神经肽的表达，但这似乎都不是镇痛的主要机制。了解与 5-HT1B/1D 受体抗伤害作用相关的特异性可能有助于深入了解偏头痛的机制，并有助于确定药物治疗的新靶点。该提案要测试的一般假设是曲坦类药物的治疗作用反映了脑血管传入细胞对炎症介质的独特反应特性。这一假设将通过实验进行检验，这些实验检查支配颅内脉管系统的传入神经中 5-HT1B/1D 受体的分布，以及炎症和曲坦类药物应用后脑血管传入神经的兴奋性和突触传递的变化。这些实验的结果应有助于为偏头痛的治疗提供独特的靶标，并增加对引发偏头痛的脑血管传入机制的理解。