Calvarial periosteal afferents in post-traumatic headache

描述（由申请人提供）：每年大约有200万美国人遭受创伤性头部损伤，其中大多数被认为是轻微的。尽管创伤持续的比例看似轻微，但许多受伤的人在头痛后不久就会出现令人虚弱的头痛，这种头痛可能持续数月甚至数年。在许多创伤后头痛（PTH）患者中，治疗仍然不能令人满意，导致痛苦和生活质量差。尽管PTH的患病率相对较高，但其潜在的病理生理学仍不清楚。这种理解的缺乏极大地阻碍了以证据为基础的疼痛管理的发展，以减轻甲状旁腺痛。在初步实验中，我们使用了轻度外伤性闭合性颅脑损伤大鼠模型。我们发现，这种相对轻微的创伤可以促进支配颅骨骨膜衬里的推定伤害性传入神经元的激活。我们的数据还表明，与患有PTH的患者相似，大鼠头部创伤也可导致颅周触觉痛超敏反应。最后，我们的数据表明，轻微的头部创伤促进颅骨骨膜内的持续炎症，这一过程可以作为启动和维持颅骨膜传入神经的激活和随后的甲状旁腺激素及其相关的颅周疼痛超敏反应的机制。基于这些试点数据，我们提出了一系列探索性的单单元电生理记录、行为学、组织学和药理学研究，这些研究将开始解决我们的工作假设，即在头部创伤时，颅骨骨膜是促进PTH发展的关键外周部位。我们建议采用一个轻度闭合性头部损伤的大鼠模型来解决以下3个具体目的：目的1将检验轻度头部创伤后，颅骨膜传入神经发展持续活动并对机械刺激变得超敏感的假设。目的2将验证轻度头部损伤诱发的颅骨膜传入神经激活和超敏反应在PTH患者中表现为颅周触觉超敏反应。目的3将检验轻度头部创伤导致颅骨骨膜内持续炎症的假设，这一过程，特别是炎症肥大细胞的局部作用，有助于骨膜传入激活/敏化和颅周触觉超敏反应的发展。这项研究的结果将开始更多地阐明PTH的病理生理学，并可能导致干预目标的扩大，可用于减轻PTH的疼痛。收集的数据将导致进一步的可测试的假设，细胞和分子的变化，有助于甲状旁腺激素的发展。

DESCRIPTION (provided by applicant): Approximately 2 million American sustain traumatic head injuries annually, most of which are considered mild. Despite the seemingly mild proportions of the trauma sustained, many injured individuals develop shortly after a debilitating headache, which can persist for months and even years. In many patients with post traumatic headache (PTH), treatment remains unsatisfactory leading to suffering and poor quality of life. Despite the relatively high prevalence of PTH, its underlying pathophysiology remains poorly defined. This lack of understanding greatly hinders the development evidence-based pain management to alleviate PTH pain. In preliminary experiments, we have used a rat model of mild traumatic closed-head injury. We have found that such relatively mild trauma can promote the activation of putative nociceptive afferent neurons that innervate the periosteal lining of the skull. Our data also indicate that similar to patients suffering from PTH, head trauma in rats can also lead to pericranial tactile pain hypersensitivity. Finally, our data suggests that mild head trauma promotes persistent inflammation within the skull's periosteum, a process which could serve as a mechanism that initiates and sustains the activation of calvarial periosteal afferents and the ensuing PTH and its related pericranial pain hypersensitivity. Based on this pilot data, we propose a series of exploratory single-unit electrophysiological recording, behavioral, histological and pharmacological studies that will begin to address our working hypothesis that upon head trauma, the skull's periosteum serves as a key peripheral site that contributes to the development of PTH. We propose to employ a rat model of mild closed-head injury to address the following 3 specific aims: Aim 1 will test the hypothesis that following mild head trauma, calvarial periosteal afferents develop persistent ongoing activity and become hypersensitive to mechanical stimuli. Aim 2 will test the hypothesis that mild head injury-evoked activation and hypersensitivity of calvarial periosteal afferents is manifested behaviorally as pericranial tactile hypersensitivity as seen in PTH patients. Aim 3 will to test the hypothesis that mild head trauma leads to persistent inflammation within the calvarial periosteum, and that this process, in particular local action of inflammatory mast cells, contributes to the development of periosteal afferent activation/sensitization and pericranial tactile hypersensitivity. Results from this study will begin to shed more light on the pathophysiology of PTH and potentially lead to the expansion of the targets of interventions that can be used to alleviate the pain of PTH. Data collected will lead to further testable hypotheses on the cellular and molecular changes that contribute to the development of PTH. PUBLIC HEALTH RELEVANCE: Persistent post traumatic headache (PTH) after mild head injury remains hard to manage in part due to the poor understanding of the pathophysiology underlying this headache syndrome. The proposed study will employ a rodent model of traumatic closed-head injury to examine the relative contribution of the skull's periosteum in mediating PTH pain. As a result of this research, new targets and pharmacological interventions may be explored to alleviate the pain of PTH.