Calvarial periosteal afferents in post-traumatic headache

描述(由申请人提供)：每年约有200万美国人遭受创伤性头部损伤，其中大部分被认为是轻微的。尽管遭受的创伤看起来很轻微，但许多受伤的人在令人衰弱的头痛后不久就会发展起来，头痛可能会持续几个月甚至几年。在许多创伤性头痛(PTH)患者中，治疗仍然不令人满意，导致患者痛苦和生活质量下降。尽管甲状旁腺激素的患病率相对较高，但其潜在的病理生理机制仍不清楚。这种认识的缺乏极大地阻碍了循证疼痛管理缓解PTH疼痛的发展。在初步实验中，我们使用了一种轻度创伤性闭合性头部损伤的大鼠模型。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伤害性传入神经元的激活。我们的数据还表明，与PTH患者类似，大鼠头部创伤也可导致颅周触觉疼痛超敏反应。最后，我们的数据表明，轻度头部创伤促进了颅骨骨膜内的持续性炎症，这一过程可能是启动和维持颅骨骨膜传入和随后的甲状旁腺激素及其相关的颅周疼痛超敏反应的一种机制。基于这一先导数据，我们提出了一系列探索性的单单位电生理记录、行为学、组织学和药理学研究，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。我们建议使用一种轻度闭合性头部损伤的大鼠模型来解决以下三个具体目标：目的1将验证以下假设：轻度头部创伤后，颅骨骨膜传入细胞发展持续的持续活动，并对机械刺激变得超敏。目的2验证轻度颅脑损伤诱发的头盖骨骨膜传入的激活和超敏反应在行为上表现为甲状旁腺功能亢进的假说。目的3验证轻度颅脑损伤导致颅骨骨膜持续炎症的假说，以及这一过程，特别是炎性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的发展。这项研究的结果将开始更多地阐明甲状旁腺激素的病理生理学，并可能导致扩大可用于缓解甲状旁腺激素疼痛的干预靶点。收集的数据将导致关于细胞和分子变化的进一步可验证的假说，这些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.