Mast Cells: Role in the Pathophysiology of Headache

描述（由申请人提供）：颅内源性头痛被认为是由支配颅内血管和脑膜的初级传入伤害感受神经元激活引起的。这种神经元激活背后的内源性因素仍然知之甚少。肥大细胞与许多慢性疼痛疾病有关，包括颅内头痛。鉴于肥大细胞释放大量痛觉介质的能力及其与伤害感受器的接近性，建议了一种功能关系。然而，肥大细胞激活，释放介质和增强的伤害感受器兴奋性，导致激活的伤害性通路之间的直接联系仍然没有探索。基于我们的初步数据，我们假设，硬膜肥大细胞脱粒，释放介质和随后的白细胞募集促进颅内硬膜伤害感受器的激活，增强其机械敏感性，并诱导激活背角神经元，处理颅内伤害性输入。我们建议使用多学科的方法，包括电生理学，药理学，组织学和免疫细胞化学方法来验证我们的假设。提出了三个具体目标。在具体目标1中，将使用三叉神经节硬脑膜伤害感受器的单单位记录来确定肥大细胞脱粒是否促进硬脑膜伤害感受器的激活和机械致敏。在具体目标2中，使用电生理单单位记录和c-fos表达作为伤害性神经元激活的标志物，我们将确定硬脑膜肥大细胞脱粒是否足以促进三叉神经血管背角神经元的激活/敏化。在具体目标3中，将使用单单位记录结合药理学方法来检查肥大细胞介质的相对贡献;一氧化氮、TNF-α和类胰蛋白酶以及白细胞募集对硬脑膜肥大细胞诱导的伤害感受器激活和机械致敏的作用。这些研究结果有助于我们更好地了解肥大细胞与深部组织伤害感受器，尤其是支配颅内脑膜的伤害感受器之间的联系。结果可能有助于确定药理学靶点，从而开发用于治疗头痛和其他顽固性疼痛综合征的新型镇痛药物。

DESCRIPTION (provided by applicant): Headaches of intracranial origin have been suggested to result from the activation of primary afferent nociceptive neurons innervating intracranial blood vessels and the meninges. Endogenous factors underlying this neuronal activation remain poorly understood. Mast cells were implicated in numerous chronic painful conditions, including intracranial headaches. Given the ability of mast cells to release an abundance of algesic mediators and their proximity to nociceptors, a functional relationship is suggested. However, a direct link between mast cell activation, release of mediators and enhanced nociceptor excitability leading to activation of nociceptive pathways remained unexplored. Based on our preliminary data we hypothesized that dural mast cell degranulation, release of mediators and subsequent leukocyte recruitment promote activation of intracranial dural nociceptors, enhance their mechanosensitivity, and induce activation of dorsal horn neurons that process intracranial nociceptive input. We propose to use a multidisciplinary approach including electrophysiological, pharmacological, histological, and immunocytochemical methods to test our hypothesis. Three specific aims are proposed. In specific aim 1, single-unit recording of dural nociceptors from the trigeminal ganglion will be used to determine whether mast cell degranulation promotes activation and mechanical sensitization of dural nociceptors. In specific Aim 2, using both electrophysiological single unit recording, and c-fos expression as a marker of nociceptive neuronal activation, we will determine whether dural mast cell degranulation is sufficient to promote activation/sensitization of trigeminovascular dorsal horn neurons. In specific aim 3, single-unit recording combined with a pharmacological approach will be used to examine the relative contribution of the mast cell mediators; nitric oxide, TNF-alpha and tryptase and the role of leukocyte recruitment to dural mast cell-induced nociceptor activation and mechanical sensitization. Data obtained in these studies could provide a better understanding on the link between mast cells and deep tissue nociceptors, especially those innervating the intracranial meninges. Results may help identify pharmacological targets that could lead to the development of novel analgesic drugs for the treatment of headaches and possibly other intractable pain syndromes.