Peroxynitrite and Migraine

世界卫生组织将偏头痛列为全球第三大流行病和第八大流行病。 致残（在女性中排名第四），使其成为最常见的神经系统疾病。的主要原因之一 偏头痛的致残性是目前可用的治疗方法的疗效差。低于50% 的患者使用曲坦类等急性药物后完全缓解，只有一半的患者达到50% 用预防剂缓解。新疗法的开发一直很缓慢，因为缺乏 了解偏头痛的潜在病理生理学。我们的长期目标是确定新的 这种常见的使人衰弱的疾病的治疗靶点。 偏头痛最一致的触发因素之一是一氧化氮（NO）供体的管理。约 75%的人类偏头痛患者将在施用NO供体的6小时内发生发作。 NO供体触发偏头痛的机制尚不清楚。本提案的目的是测试 NO和超氧化物的反应产物过氧亚硝酸盐（PN）是否有助于偏头痛 病理生理学过去十年的研究表明，PN是一种重要的激活剂/致敏剂， 神经性疼痛、炎性疼痛和癌症疼痛的临床前疼痛模型中的感觉神经元，以及 在临床前疼痛模型中证明了消除PN的有效性。然而，没有研究检查 PN是否有助于偏头痛，尽管观察到唯一的疼痛状态由 给予产生PN的刺激是偏头痛（NO供体不直接引起其他类型的疼痛）。 因此，我们建议测试的假设，NO对偏头痛的影响是由于PN的形成。 这项研究的基本原理是：1）极大地扩展了我们对潜在机制的认识。 最常见的偏头痛诱因之一; 2）通过提供新的 偏头痛的治疗目标。我们将使用临床前啮齿动物模型，以2个目的检验这一假设： 目的1将测试PN清除剂和分解催化剂对NO供体诱导的 偏头痛行为和三叉神经（硬脑膜）神经元中NO供体诱导的活性。目标2将测试功效 PN清除剂和分解催化剂对NO供体诱导的肥大细胞脱颗粒，CGRP 释放和硬脑膜中的蛋白质酪氨酸硝化。这项创新的研究将首次调查 PN在偏头痛中的作用，并将使用新的行为模型，模拟偏头痛相关的条件。的 该提案的意义在于它促进了我们对偏头痛机制的理解， 可能会带来更好的治疗方法。

The World Health Organization ranks migraine as the 3rd most prevalent disease worldwide and 8th most disabling (4th most in women) making it the most common neurological disorder. One of the primary reasons for the disabling nature of migraine is the poor efficacy of currently available therapeutics. Less than 50% of patients achieve complete relief with acute agents such as triptans and only half of patients achieve 50% relief with preventative agents. Development of new therapeutics has been slow due to a lack of understanding of the underlying pathophysiology of migraine. Our long-term goal is to identify new therapeutic targets for this common and debilitating disorder. One of the most consistent triggers for migraine is administration of a nitric oxide (NO) donor. Approximately 75% of human migraine patients will develop an attack within 6 hours of NO donor administration. Mechanisms by which NO donors trigger migraine are unknown. The objective of this proposal is to test whether the reaction product of NO and superoxide, peroxynitrite (PN), contributes to migraine pathophysiology. Studies over the last decade have shown that PN is an important activator/sensitizer of sensory neurons in preclinical pain models of neuropathic, inflammatory, and cancer pain and agents that eliminate PN have demonstrated efficacy in preclinical pain models. However, no studies have examined whether PN contributes to migraine despite the observation that the only pain state triggered by administration of a PN-producing stimulus is migraine (NO donors do not directly cause other types of pain). Thus, we propose to test the hypothesis that the effects of NO on migraine are due to PN formation. The rationale for the proposed study is that it 1) greatly expands our knowledge of mechanisms underlying one of the most common migraine triggers; and 2) provides translational potential by offering new therapeutic targets for migraine. We will test this hypothesis with 2 Aims using preclinical rodent models: Aim 1 will test the efficacy of PN scavengers and decomposition catalysts against NO donor-induced migraine behavior and NO donor-induced activity in trigeminal (dural) neurons. Aim 2 will test the efficacy of PN scavengers and decomposition catalysts against NO donor-induced mast cell degranulation, CGRP release, and protein tyrosine nitration in the dura. This innovative study will for the first time investigate the role of PN in migraine and will use novel behavioral models that mimic conditions relevant to migraine. The significance of the proposal is that it advances our understanding of migraine mechanisms and has the potential to lead to better therapeutics.