Mast Cells: Role in the Pathophysiology of Headache

描述(申请人提供)：颅内起源的头痛被认为是由于支配颅内血管和脑膜的初级传入伤害性神经元的激活所致。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，以及它们与伤害性感受器的接近程度，提出了一种函数关系。然而，肥大细胞激活、介质释放和伤害性感受器兴奋性增强导致伤害性通路激活之间的直接联系仍未被探索。根据我们的初步数据，我们假设硬脑膜肥大细胞脱颗粒、介质释放和随后的白细胞募集促进了硬脑膜伤害性感受器的激活，增强了它们的机械敏感性，并诱导了处理颅内伤害性输入的背角神经元的激活。我们建议使用包括电生理学、药理学、组织学和免疫细胞化学方法在内的多学科方法来检验我们的假设。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性感受器的单一单位记录来确定肥大细胞脱颗粒是否促进硬脑膜伤害性感受器的激活和机械敏化。在具体目标2中，我们将同时使用电生理单位记录和c-fos表达作为伤害性神经元激活的标志，以确定硬膜肥大细胞脱颗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，将使用单一单位记录结合药理学方法来研究肥大细胞介质、一氧化氮、肿瘤坏死因子-α和类胰蛋白酶的相对贡献，以及白细胞募集在硬膜肥大细胞诱导的伤害性感受器激活和机械敏化中的作用。这些研究中获得的数据可以更好地了解肥大细胞和深层组织伤害性感受器之间的联系，特别是那些支配颅内脑膜的伤害性感受器。结果可能有助于确定可能导致开发新型止痛药的药理靶点，用于治疗头痛和其他可能的顽固性疼痛综合征。

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.