Mechanistic Assessment of Osteopathic Manipulation inRelieving Migraine Headache Using a Novel Translational Rodent Model

项目概要： 经验证据表明，应用正骨手法治疗（OMT）偏头痛， 患者可以减少头痛发作的频率和疼痛强度， 偏头痛发作然而，OMT的好处还没有经过严格的测试。这项提案的目的是 确定OMT作为预防性或急性治疗的可能疗效和作用机制， 偏头痛我们的项目是创新的，因为我们使用了一个临床前模型， 病理学，包括公认的“生物标志物”和临床相关的输出措施，增加信心 in translation翻译across横过species物种.这些研究将为确定OMT的可能效用提供坚实的证据 用于偏头痛的临床治疗。偏头痛发作通常伴随恶心、呕吐和 对包括轻触在内的各种外部刺激过敏。患者大多被迫减少 他们的日常活动，并躺在一个安静，黑暗的房间，等待症状通过。的 偏头痛的病理生理学还没有很好地理解，但最终，偏头痛被认为是由以下原因引起的： 在易感个体中激活三叉神经复合物。三叉神经血管激活可能 引起和/或源于多种神经递质释放 （CGRP）。现在认为三叉神经系统的激活和血液中CGRP释放的增强 偏头痛的病理生理学特征。偏头痛的常见临床诱因之一是颈部疼痛。我们有 描述了一种大鼠偏头痛模型，该模型概括了三叉神经颈会聚的临床特征 采取“两击”策略我们通过给大鼠注射CFA（完全弗氏）来引起偏头痛样疼痛 佐剂，第一次打击），造成轻微的颈部炎症，然后应用伞形酮（第二次打击），主要挥发性 头痛树释放的一种分子，引发头痛。这两种侮辱都需要引起偏头痛样 疼痛，类似于人类偏头痛患者，当遭受疼痛时， 颈部疼痛。我们将使用该模型来确定OMT在预防和/或治疗中的可能功效。 缓解偏头痛样疼痛，以及阐明OMT的潜在潜在机制， 对治疗偏头痛有好处。人体软组织的跨种属等效性， 发音技术将被用作大鼠的松弛促进方法，以确定 OMT对伞形酮引起的头痛的影响。令人信服的初步数据表明， OMT能显著抑制伞形酮引起的头触诱发痛的发生。我们将进一步 追求两个具体的目标，以阐明OMT在a）预防和B）逆转中的治疗窗口 “偏头痛样”变化，包括触摸过敏，自愿轮运行活动减少，增强 CGRP在血液中释放，并激活三叉神经组织。这些研究的结果是高度 因为它们将为OMT治疗偏头痛提供强有力的神经生物学原理。

PROJECT SUMMARY: Empirical evidence suggests that application of osteopathic manipulative treatment (OMT) to migraine patients may reduce the frequency and pain intensity of headache episodes and provide abortive relief during the migraine episode. The benefit of OMT has not been rigorously tested, however. The goal of this proposal is to determine the possible efficacy and mechanisms of action of OMT as a preventative or acute therapy for migraine. Our project is innovative because we use a preclinical model that recapitulate aspects of migraine pathology including well-accepted “biomarkers” and clinical-relevant output measures that increase confidence in translation across species. These studies will provide solid evidence to determine the possible utility of OMT for clinical management of migraine. Migraine attacks commonly associate with nausea, vomiting and hypersensitivity to a variety of external stimuli including light touch. The sufferers are mostly forced to reduce their daily routine activities and lay down in a quiet, dark room to wait for the symptoms pass. The pathophysiology of migraine is not well understood but ultimately, migraine pain is believed to arise from activation of the trigeminocervical complex in susceptible individuals. Trigeminovascular activation may provoke and/or arise from release of multiple neurotransmitters including calcitonin gene-related peptide (CGRP). Activation of the trigeminal system and enhanced CGRP release in the blood are now considered hallmarks of migraine pathophysiology. One of the common clinical triggers of migraine is neck pain. We have characterized a rat model of migraine that recapitulates clinical features of the trigeminal cervical convergence with a “two-hit” strategy. We provoke migraine-like pain by injecting the rats with CFA (Complete Freund Adjuvant, 1st hit) to cause mild neck inflammation and then apply umbellulone (2nd hit), the major volatile molecule emitted by “headache trees”, to trigger cephalic pain. Both insults are required to elicit migraine-like pain, resembling human migraineurs who have increased susceptibility to the migraine triggers when suffering from neck pain. We will use this model to determine the possible efficacy of OMT in preventing and/or relieving migraine-like pain as well as to shed insight on the potential underlying mechanisms by which OMT could provide benefit in treatment of migraine. Trans-species equivalence of the human soft tissue and articulatory techniques will be used as the relaxation-promoting approach in rats to determine the effects of OMT on umbellulone-evoked cephalic pain. Compelling preliminary data indicate that multiple application of OMT can largely inhibit the development of cephalic allodynia triggered by umbellulone. We will further pursue two specific aims to elucidate the therapeutic window of OMT in a) preventing and b) reversing “migraine-like” changes including touch hypersensitivity, reduced voluntary wheel-running activity, enhanced CGRP release in the blood, and activation of trigeminal tissues. The results from these studies are highly significant because they will provide a strong neurobiological rationale for use of OMT in managing migraine.