Mast Cells: Role in the Pathophysiology of Headache

描述（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觉神经元的激活引起的。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，提出了一种功能关系。然而，肥大细胞激活、介质释放和伤害感受器兴奋性增强导致伤害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颅内硬脑膜伤害感受器的激活，增强了它们的机械敏感性，并诱导了处理颅内伤害感受器输入的背角神经元的激活。我们建议采用多学科方法，包括电生理、药理学、组织学和免疫细胞化学方法来检验我们的假设。提出了三个具体目标。在特定目的1中，来自三叉神经节的硬脑膜伤害感受器的单单元记录将用于确定肥大细胞脱颗粒是否促进硬脑膜伤害感受器的激活和机械致敏。在特定的Aim 2中，使用电生理单单元记录和c-fos表达作为伤害性神经元激活的标记，我们将确定硬脑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。在特定目标3中，单单位记录结合药理学方法将用于检查肥大细胞介质的相对贡献；一氧化氮、tnf - α和胰蛋白酶以及白细胞募集在硬脑膜肥大细胞诱导的伤害感受器激活和机械致敏中的作用。在这些研究中获得的数据可以更好地理解肥大细胞和深层组织伤害感受器之间的联系，特别是支配颅内脑膜的那些。结果可能有助于确定药理学靶点，从而开发出治疗头痛和其他难治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.