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: 8697153
• 负责人: DAN LEVY
• 金额: $ 33.91万
• 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 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8697153
• 关键词: ASIC channel; Accounting; Acidosis; Affect; Afferent Neurons; Arginine; Astrocytes; Auras; Blood Vessels; Breathing; Cerebrovascular Circulation; Cerebrum; Data; Development; Event; Glutamates; Headache; 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 measurement, partial pressure, arterial; Pain; Papaverine; Phase; Physiological; Play; Potassium Glutamate; Process; Property; Prostaglandins; Protons; Rattus; Relative (related person); 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; public health relevance; 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（由申请人提供）：在过去的二十年中，证据逐渐积累，以支持偏头痛的皮质扩散抑郁症（CSD）理论，该理论提出CSD是生理事件，其基于偏头痛之前的视觉光环的基础。根据这一理论，CSD也是触发偏头痛的内源过程，大概是通过脑膜伤害感受器通过从实质中释放兴奋性分子而激活的。最近，已经表明，CSD确实可以促进脑膜伤害感受器的持续激活。但是，在CSD后观察到的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发作不能仅由CSD波的传播时间来解释，因为在大多数情况下，CSD结束与激活的发作之间存在很大的延迟。其次，一旦开始，伤害感受器的激活持续了更长的时间 比CSD波中释放的兴奋剂的已知作用可以解释。我们的初步数据使我们假设我们在CSD之后发生的脑膜伤害感受器的持续且经常被延迟激活不取决于兴奋性介体的短暂释放或由此导致的短暂伤害感受器激活，而是由于CSD诱发的血管和新近的杂种，尤其是由于CSD诱发的序言而发生的杂种症状，尤其是发生的。精心设计。该工作假设将使用一系列脑膜伤害感受器活动的体内电生理记录，结合了局部脑血流变化（RCBF），实质性氧气氧气张力（TPO2）和乳酸浓度以及乳酸浓度以及药理学介绍的多种参数测量。具体的目标1将确定脑膜伤害感受器的与CSD相关的持续激活是否是通过在CSD期间对兴奋分子的局部简要阐述介导的，b）同时发生的短暂伤害感受器激发和C）导致的脑膜神经起源炎症。具体目标2将使用抑制这些过程的治疗方法来检查CSD诱发的脑寡血症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将采用药理学阻滞剂检查CSD诱发的乳酸阐述，并随之而来的激活酸性离子通道3（ASIC3）介导了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理解内源性机制，该机制在偏头痛的起源中发挥作用，这可以推动急需的基于循证的方法来治疗这种类型的疼痛。