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，以严重的头痛为特征，并与自主神经和感觉功能障碍有关。脑血管传入的激活和由此产生的神经源性炎症被认为是偏头痛发展的关键。有证据表明，组胺、缓激肽和前列腺素等炎性介质会使脑血管传入变得敏感。一旦致敏，这些传入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。被激活的传入不仅释放能够直接刺激传入活动(即反馈-兴奋)的递质，而且驱动与释放额外介质相关的炎症反应，从而进一步激活和敏化传入终末。所有这些传入活动被认为至少是偏头痛发作期间疼痛的基础。曲普坦是目前治疗偏头痛最有效的方法之一。这些药物是5-羟色胺受体1B/1D(5-HT1B/1D)激动剂。尽管5-HT1B/1D受体在三叉神经节和背根神经节神经元中普遍表达，但Triptan通常不是抗伤害性的，对身体其他部位引起的疼痛几乎没有疗效。雷公藤红素已被证明可以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性感觉的主要机制。了解5-HT1B/1D受体与抗伤害性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。在这项建议中要检验的一般假设是，雷公藤多糖的治疗作用反映了脑血管传入对炎症介质的独特反应特性。这一假说将通过实验来验证，这些实验检测了5-HT1B/1D受体在支配颅内血管的传入神经元中的分布，以及炎症和曲普坦应用后脑血管传入神经元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，并增加对启动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.