Mechanisms of CSD-evoked persistent activation of meningeal nociceptors

描述（由申请人提供）：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，该理论提出CSD是偏头痛之前视觉先兆的生理事件。根据该理论，CSD也是触发偏头痛的内源性过程，推测是通过从实质释放兴奋性分子来激活脑膜伤害感受器。最近的研究表明，CSD确实可以促进脑膜伤害感受器的持续激活。然而，所观察到的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的已知性质。首先，这种伤害感受器激活的开始不能仅仅由CSD波的传播时间来解释，因为在大多数情况下，在CSD结束和激活开始之间存在相当大的延迟。第二，一旦启动，伤害感受器激活持续更长时间 这比CSD波期间释放的兴奋性物质的已知作用所能解释的要多。我们的初步数据使我们假设，持续和经常延迟激活的脑膜伤害感受器，发生在清醒的CSD不依赖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，而是发生由于CSD引起的血管和代谢的变化，特别是脑少血，缺氧，和实质乳酸的阐述。将使用脑膜伤害感受器活性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）和乳酸浓度变化以及药理学干预的多参数测量来测试该工作假设。具体目标1将确定CSD相关的脑膜伤害感受器的持续激活是否由CSD阶段期间兴奋性分子的局部短暂加工介导，B）同时发生的短暂伤害感受器兴奋和c）导致的脑膜神经源性炎症。具体目标2将使用抑制这些过程的治疗来检查CSD诱发的脑少血和缺氧对脑膜伤害感受器持续激活的相对贡献。具体目标3将采用药理学阻断剂来检查CSD诱发的乳酸盐加工和随后的酸敏感离子通道3（ASIC 3）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中发挥作用的内源性机制，这可以推动急需的循证方法的发展来治疗这种类型的疼痛。

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.