Cerebrovascular Afferent Mechanisms of Migraine

描述（由申请人提供） 偏头痛是一种常见的神经系统疾病，其特征是与自主神经和感觉功能障碍相关的严重头痛。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是偏头痛发生的关键。有证据表明，炎症介质，如组胺，缓激肽，前列腺素敏感脑血管传入。一旦被致敏，这些传入神经可能会被正常无害的刺激激活，如心跳引起的血管压力变化。激活的传入不仅释放能够直接刺激传入活动的递质（即，反馈-兴奋），但其驱动与额外介质的释放相关的炎症反应，所述额外介质可进一步激活和致敏传入末梢。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药物之一。这些药物是5-羟色胺受体1B/1D（5-HT 1B/1D）激动剂。虽然5-HT 1B/1D受体在三叉神经和背根神经节神经元中普遍表达，但曲坦类通常不是抗伤害感受的，对于治疗身体其他部位引起的疼痛几乎没有功效。曲坦类药物已被证明产生血管收缩和减少外周神经肽的表达，但这些似乎都不是抗伤害感受的主要机制。了解与5-HT 1B/1D受体的抗伤害性作用相关的特异性可能有助于了解偏头痛的机制，并有助于确定药物治疗的新靶点。在这个提议中要检验的一般假设是曲坦类的治疗作用反映了脑血管传入神经对炎症介质的独特反应特性。该假设将通过以下实验进行检验：检查支配颅内血管的传入神经中5-HT 1B/1D受体的分布，以及炎症和曲坦应用后脑血管传入神经兴奋性和突触传递的变化。这些实验的结果应该有助于为偏头痛的治疗提供独特的靶点，并增加对引发偏头痛的脑血管传入机制的理解。

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.