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，越来越多的证据支持偏头痛的皮质扩张性抑制（CSD）理论，该理论提出CSD是偏头痛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，可能是通过从实质释放兴奋性分子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，观察到的痛觉感受器在痛觉感受器激活后的时间过程并不容易与痛觉感受器理论中通常提出的机制或已知的痛觉感受器特性相吻合。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大量延迟。其次，伤害感受器的激活一旦启动，就会持续更长的时间

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.