Cerebrovascular Afferent Mechanisms of Migraine

偏头痛的脑血管传入机制

• 批准号: 7388958
• 负责人: Andrea M Harriott
• 金额: $ 4.24万
• 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/7388958
• 关键词: Agonist; Automobile Driving; Blood Vessels; Bradykinin; Cells; Circle of Willis; Coculture Techniques; Data; Development; Drug Delivery Systems; Event; Feedback; Frequencies; Functional disorder; Headache; Heart; Histamine; Immunohistochemistry; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Internal carotid artery structure; Ion Channel; Label; Localized; Location; Mediator of activation protein; Meningeal; Meningeal Arteries; Migraine; Neurogenic Inflammation; Neurons; Neuropeptides; Nociception; Other Body Part; Pain; Pattern; Peripheral; Pharmaceutical Preparations; Physiologic pulse; Population; Posterior Horn Cells; Property; Prostaglandins; Pulse taking; Rattus; Sensory; Serotonin Receptor 5-HT1D; Signal Transduction; Site; Specificity; Spinal Ganglia; Stimulus; Structure; Synaptic Transmission; Testing; Therapeutic; Thinking; Tissues; Treatment Efficacy; Trigeminal System; cerebrovascular; excitatory neuron; experience; follow-up; insight; nervous system disorder; neuronal cell body; novel; postsynaptic; pressure; presynaptic; receptor; research study; response; serotonin receptor; size; 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（申请人提供） 偏头痛是一种常见的神经系统疾病，其特征是与自主和感觉功能障碍有关的严重头部疼痛。脑血管传入和由此导致的神经源性炎症的激活被认为对于偏头痛疼痛的发展至关重要。有证据表明，炎症介质（例如组胺，心动激肽和前列腺素）使脑血管传入敏感。一旦敏感，这些传入可能会被正常无害的刺激激活，例如心跳引起的血管压力变化。活化的传入不仅释放能够直接刺激传入活动（即反馈激发）的发射机，而且会驱动与释放其他介体有关的炎症反应，这些炎症反应可以进一步激活并敏感传入终端。人们认为所有这些传入的活动至少是偏头痛攻击期间遭受的疼痛的启动。 triptans的给药目前是偏头痛疼痛的最有效治疗方法之一。这些药物是5-羟色胺受体1b/1d（5-HT1B/1D）激动剂。尽管5-HT1B/1D受体在三叉神经和背根神经神经元中普遍表达，但triptans通常并非具有抗伤害感受，对治疗体内其他部位引起的疼痛的疗效很小。曲霉已被证明会产生血管收缩并降低周围神经肽的表达，但它们似乎都不是抗伤害感受的主要机制。了解与5-HT1B/1D受体的抗伤心作用相关的特异性可能会洞悉偏头痛疼痛的机制，并有助于识别用于药物治疗的新靶标。在该提案中要检验的一般假设是，曲普（Triptans）的治疗作用反映了脑血管传入对炎症介体的独特反应特性。该假设将通过实验进行检验，这些实验检查了颅内脉管系统的传入中5-HT1B/1D受体的分布，以及炎症和Triptan应用后脑血管传入的兴奋性和突触传播的变化。这些实验的结果应有助于为偏头痛疼痛的治疗提供独特的目标，并在引发偏头痛疼痛时增加对脑血管传入机制的理解。