Peripheral Mechanisms of Posttraumatic Headache

描述（由申请人提供）：持续性头痛是轻度创伤性头部损伤后最常见的症状之一，但对于许多创伤后头痛（PTH）患者来说，整体疼痛管理仍然不理想，导致痛苦和生活质量差。不能有效地控制甲状旁腺疼痛可部分归因于对甲状旁腺的病理生理基础的不了解。由于缺乏动物模型来模拟最常见的头部创伤类型，并表现出与持续头痛和持续疼痛相关的行为，甲状旁腺激素的临床前研究一直受到阻碍。以下建议的目的是检查可能导致PTH疼痛发展的关键外周机制。基于令人兴奋的初步数据，我们的工作假设是轻微的头部创伤导致炎症驱动的初级传入神经元的持续激活和敏化，这些神经元支配颅外骨膜和颅内硬脑膜，进而促进与PTH疼痛相关的感觉和情感变化的发展。我们提出了一系列的研究，利用电生理学、行为测试、组织学、药理学和缺乏免疫细胞的突变动物来研究我们的工作假设，通过解决以下开放性问题：1)头部创伤是否会导致控制颅骨骨膜和/或颅内硬脑膜的初级传入神经元的持续激活和机械和化学敏感性的增加（具体目标1）？2)如果是这样，这些神经生理变化是否与颅周皮肤异常性痛的发展相关并有所贡献？颅周皮肤异常性痛是一种与持续性头痛相关的感觉变化，而挖洞抑制是一种反映持续性疼痛的情感（厌恶）维度的先天行为变化（Specific Aim 2）？3)创伤后外周炎症反应，特别是颅骨骨膜和颅内硬脑膜内免疫细胞的募集和激活，是否有助于创伤后神经生理变化以及随之而来的与甲状旁腺疼痛相关的行为改变？该项目的结果将为PTH的发病机制提供重要的见解，包括PTH疼痛可能产生的外周组织，头痛的神经生理相关性及其潜在机制。这一新的信息可能会导致干预目标的扩大，可以用来减轻这种知之甚少的创伤相关的疼痛。

DESCRIPTION (provided by applicant): Persistent headache is one of the most common symptoms following a mild traumatic head injury, but for many individuals with posttraumatic headache (PTH) overall pain management remains unsatisfactory, leading to suffering and poor quality of life. The inability to effectively control PTH pain can be attributed in part to the poo understanding of the pathophysiology underlying PTH. Preclinical research on PTH has been hampered by the lack of an animal model that mimics the most common type of head trauma and exhibits behaviors that can be linked to ongoing headache and persistent pain. The goal of following proposal is to examine key peripheral mechanisms that could contribute to the development of PTH pain. Based on exciting preliminary data, our working hypothesis is that mild head trauma leads to inflammatory-driven persistent activation and sensitization of primary afferent neurons that innervate the extracranial calvarial periosteum and intracranial dura mater, which in turn promote the development of sensory and affective changes that can be linked to PTH pain. We propose a series of studies that employ electrophysiology, behavioral testing, histology, pharmacology and mutant animals that lack immune cells to study our working hypothesis by addressing the following open questions: 1) Does head trauma lead to persistent activation and increased mechanical and chemical sensitivities of primary afferent neurons that innervate the calvarial periosteum and/or intracranial dura (Specific Aim 1)? 2) If so, do these neurophysiological changes correlate and contribute to the development of pericranial cutaneous allodynia, a sensory change linked to persistent headache, and suppression of burrowing, a change in innate behavior that reflects an affective (aversive) dimension of persistent pain (Specific Aim 2)? 3) Does a posttraumatic peripheral inflammatory response, in particular the recruitment and activation of immune cells within the skull's periosteum and intracranial dura, contribute to the posttraumatic neurophysiological changes and the ensuing behavioral changes linked to PTH pain. Results from this project will provide important insights into the pathogenesis of PTH, including the peripheral tissues from which PTH pain likely arise, the neurophysiological correlate of the headache and its underlying mechanisms. This novel information could lead to the expansion of the targets of interventions that can be used to alleviate this poorly understood trauma-related pain.