Peripheral Mechanisms of Posttraumatic Headache

描述(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，但对于许多创伤性头痛(PTH)患者来说，整体疼痛管理仍然不令人满意，导致痛苦和生活质量下降。无法有效控制甲状旁腺激素疼痛的部分原因可以归因于对甲状旁腺激素潜在的病理生理学的理解。甲状旁腺激素的临床前研究一直受到阻碍，因为缺乏模拟最常见类型的头部创伤的动物模型，并表现出与持续性头痛和持续性疼痛有关的行为。以下建议的目的是研究可能有助于甲状旁腺素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，轻度头部创伤导致初级传入神经元在炎症驱动下持续激活和敏化，这些传入神经元支配颅外颅骨骨膜和颅内硬脑膜，进而促进与甲状旁腺素疼痛相关的感觉和情感变化的发展。我们提出了一系列研究，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说，解决以下开放问题：1)头部创伤是否导致支配颅骨骨膜和/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增加(特定目标1)？2)如果是这样的话，这些神经生理变化是否与颅周皮肤异位痛的发展相关并有助于发展，这是一种与持续性头痛有关的感觉变化，并抑制了挖洞，反映持续性疼痛的情感(厌恶)维度的先天行为的改变(特定目标2)？3)创伤后的外周炎症反应，特别是颅骨骨膜和颅内硬脑膜内免疫细胞的招募和激活，是否有助于创伤后的神经生理变化以及随后与甲状旁腺素疼痛相关的行为变化。该项目的结果将为甲状旁腺激素的发病机制提供重要的见解，包括甲状旁腺激素疼痛可能产生的外周组织，头痛的神经生理学关联及其潜在机制。这一新信息可能导致可用于缓解这种鲜为人知的创伤相关疼痛的干预目标的扩大。

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.