Mechanisms of CSD-evoked persistent activation of meningeal nociceptors

CSD 诱发脑膜伤害感受器持续激活的机制

• 批准号: 9055775
• 负责人: DAN LEVY
• 金额: $ 34.26万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9055775
• 关键词: ASIC channel; Accounting; Acidosis; Affect; Afferent Neurons; Arginine; Astrocytes; Auras; Blood Vessels; Breathing; Cerebrovascular Circulation; Cerebrum; Data; Development; Electrophysiology (science); Event; Glutamates; Headache; Health; Hydroxyeicosatetraenoic Acids; Hyperoxia; Hypoxia; Intervention; Lead; Lidocaine; Local Anesthetics; Measurement; Mediating; Mediator of activation protein; Meningeal; Meninges; Metabolic; Migraine; Modeling; Monitor; Neurogenic Inflammation; Neurons; Nociception; Nociceptors; Oxygen; Pain; Papaverine; Phase; Physiological; Play; Potassium Glutamate; Process; Property; Prostaglandins; Protons; Rattus; Role; Series; Spreading Cortical Depression; Substance P; Sumatriptan; Testing; Time; Tissues; Topical application; Vasodilator Agents; Visual; Work; base; cerebral hypoperfusion; evidence base; glycogenolysis; in vivo; inhibitor/antagonist; nociceptive response; receptive field; response; theories; triptans

DESCRIPTION (provided by applicant): Over the past two decades, evidence has gradually accumulated in support of the cortical spreading depression (CSD) theory of migraine, which proposes that CSD is the physiological event that underlies the visual aura that precedes the migrainous headache. According to this theory, CSD is also the endogenous process that triggers the migraine headache, presumably through the activation of meningeal nociceptors via the release of excitatory molecules from the parenchyma. Recently, it has been shown that CSD indeed can promote persistent activation of meningeal nociceptors. However, the observed time course of the nociceptor activation following CSD does not easily fit with the mechanisms typically proposed in the CSD theory or the known properties of CSD. First, the onset of this nociceptor activation cannot be accounted for solely by the propagation time of the CSD wave, because in the majority of cases there is a substantial delay between the end of the CSD and the onset of activation. Second, once initiated, the nociceptor activation persists for much longer than can be accounted for by the known actions of the excitatory agents that are released during the CSD wave. Our preliminary data had led us to hypothesize that the persistent and often delayed activation of meningeal nociceptors that occurs in the wake of CSD does not depend upon the brief release of excitatory mediators or a resultant brief nociceptor activation, but rather occurs due to the CSD-evoked vascular and metabolic changes, in particular the cerebral oligemia, hypoxia, and parenchymal lactate elaboration. This working hypothesis will be tested using a series of in vivo electrophysiological recordings of meningeal nociceptors' activity combined with multi-parametric measurements of changes in regional cerebral blood flow (rCBF), parenchymal tissue oxygen tension (tpO2) and lactate concentration as well pharmacological interventions. Specific Aim 1 will determine whether the CSD-related persistent activation of meningeal nociceptors is mediated by the local brief elaboration of excitatory molecules during the CSD phase b) a coinciding brief nociceptor excitation and c) resultant meningeal neurogenic inflammation. Specific Aim 2 will examine the relative contribution of the CSD-evoked cerebral oligemia and hypoxia to the persistent activation of meningeal nociceptors using treatments that inhibit these processes. Specific Aim 3 will employ pharmacological blockers to examine whether CSD-evoked lactate elaboration and ensuing activation of the acid-sensing ion channel 3 (ASIC3) mediates the persistent activation of meningeal nociceptors following CSD. We hope that these studies will provide a better understanding of the endogenous mechanism that play a role in the genesis of migraine headache, which can propel the development of much needed evidence-based approaches to treat this type of pain.

描述（申请人提供）：在过去的二十年中，逐渐积累了支持偏头痛的皮质扩散性抑制（CSD）理论的证据，该理论认为 CSD 是偏头痛之前视觉先兆的生理事件。根据这一理论，CSD 也是引发偏头痛的内源性过程，可能是通过从实质中释放兴奋性分子来激活脑膜伤害感受器。最近，研究表明CSD确实可以促进脑膜伤害感受器的持续激活。然而，观察到的 CSD 后伤害感受器激活的时间过程并不容易符合 CSD 理论中通常提出的机制或 CSD 的已知特性。首先，这种伤害感受器激活的开始不能仅由 CSD 波的传播时间来解释，因为在大多数情况下，CSD 结束和激活开始之间存在相当大的延迟。其次，一旦启动，伤害感受器的激活就会持续更长时间 这可以通过 CSD 波期间释放的兴奋剂的已知作用来解释。我们的初步数据使我们推测，CSD 后发生的脑膜伤害感受器的持续且经常延迟的激活并不取决于兴奋性介质的短暂释放或由此产生的短暂伤害感受器激活，而是由于 CSD-引起血管和代谢变化，特别是脑供血不足、缺氧和脑实质乳酸的变化。这一工作假设将通过脑膜伤害感受器活动的一系列体内电生理记录结合局部脑血流量（rCBF）、实质组织氧张力（tpO2）和乳酸浓度变化的多参数测量以及药物干预进行测试。具体目标 1 将确定与 CSD 相关的脑膜伤害感受器持续激活是否是由 CSD 阶段 b）同时发生的短暂伤害感受器兴奋和 c）由此产生的脑膜神经源性炎症期间兴奋性分子的局部短暂阐述介导的。具体目标 2 将检查 CSD 引起的脑供血不足和缺氧对脑膜伤害感受器持续激活的相对影响，使用抑制这些过程的治疗方法。具体目标 3 将采用药理学阻断剂来检查 CSD 诱发的乳酸生成和随后的酸敏感离子通道 3 (ASIC3) 激活是否介导 CSD 后脑膜伤害感受器的持续激活。我们希望这些研究能够更好地了解在偏头痛发生过程中发挥作用的内源性机制，从而推动开发治疗此类疼痛的急需的循证方法。