Peripheral Mechanisms of Posttraumatic Headache

创伤后头痛的外周机制

• 批准号: 8814839
• 负责人: DAN LEVY
• 金额: $ 38.06万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8814839
• 关键词: Address; Affect; Affective; Afferent Neurons; American; Animal Model; Animals; Behavior; Behavioral; Calvaria; Cell Degranulation; Cells; Cephalic; Chemicals; Closed head injuries; Communication; Craniocerebral Trauma; Craniotomy; Cutaneous; Data; Development; Dimensions; Dura Mater; Electrophysiology (science); Exhibits; Functional disorder; Genetically Modified Animals; Goals; Headache; Histology; Hypersensitivity; Immune; Immune Cell Activation; Individual; Inflammation Mediators; Inflammatory; Inflammatory Response; Instinct; Intervention; Lead; Lidocaine; Light; Link; Local Anesthetics; Local anesthesia; Manuscripts; Mechanics; Mediating; Migraine; Modeling; Motivation; Nerve; Neurons; Nociception; Nociceptive Stimulus; Pain; Pain management; Pathogenesis; Pathway interactions; Periosteum; Peripheral; Persistent pain; Personal Satisfaction; Pharmaceutical Preparations; Pharmacology; Population; Preparation; Quality of life; Rattus; Relative (related person); Research; Role; Sensory; Series; Soldier; Stimulus; Symptoms; Tactile; Test Result; Testing; Time; Tissues; Trauma; Trigeminal System; Veterans; Work; allodynia; base; behavior test; cranium; cutaneous allodynia; density; dorsal horn; evidence base; frovatriptan; in vivo; insight; mast cell; mutant; neurophysiology; novel; pain behavior; pre-clinical research; public health relevance; receptive field; response; triptans

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.

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，但对于许多患有创伤后头痛 (PTH) 的人来说，整体疼痛管理仍然不令人满意，导致痛苦和生活质量差。无法有效控制 PTH 疼痛的部分原因是粪便对 PTH 病理生理学的理解。由于缺乏模拟最常见头部创伤类型并表现出与持续性头痛和持续性疼痛相关的行为的动物模型，PTH 的临床前研究受到了阻碍。以下提案的目的是检查可能导致 PTH 疼痛发生的关键外周机制。基于令人兴奋的初步数据，我们的工作假设是，轻度头部创伤会导致炎症驱动的初级传入神经元持续激活和敏化，这些神经元支配颅外颅骨骨膜和颅内硬脑膜，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，解决以下开放性问题：1）头部创伤是否会导致支配颅骨骨膜和/或颅内硬脑膜的初级传入神经元持续激活并增加机械和化学敏感性（具体目标1）？ 2) 如果是这样，这些神经生理学变化是否与颅周皮肤异常性疼痛（一种与持续性头痛相关的感觉变化）和挖洞抑制（反映持续性疼痛的情感（厌恶）维度的先天行为的变化）的发展相关并促成（具体目标 2）？ 3) 创伤后周围炎症反应，特别是颅骨骨膜和颅内硬脑膜内免疫细胞的募集和激活，是否会导致创伤后神经生理变化以及随后与 PTH 疼痛相关的行为变化。该项目的结果将为 PTH 的发病机制提供重要的见解，包括可能引起 PTH 疼痛的外周组织、头痛的神经生理学相关性及其潜在机制。这一新颖的信息可能会导致干预目标的扩大，这些干预措施可用于减轻这种人们知之甚少的创伤相关疼痛。