Peripheral Mechanisms of Posttraumatic Headache

创伤后头痛的外周机制

• 批准号: 8912557
• 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/8912557
• 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; Health; 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; behavioral study; cranium; cutaneous allodynia; density; dorsal horn; evidence base; frovatriptan; in vivo; insight; mast cell; mutant; neurophysiology; novel; pain behavior; pre-clinical research; 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受伤后最常见的症状之一，但是对于许多患有创伤后头痛（PTH）的人来说，总体疼痛管理仍然不满意，导致痛苦和生活质量差。无法有效控制PTH疼痛的部分可以归因于对PTH基础生理学的便便理解。缺乏模仿最常见类型的头部外伤类型和展示行为的动物模型，对PTH的临床前研究受到了阻碍，这些模型可能与持续的头痛和持续性疼痛有关。遵循建议的目的是检查可能有助于PTH疼痛发展的关键外围机制。基于令人兴奋的初步数据，我们的工作假设是，轻度的头部创伤会导致炎症驱动的持续激活和原发性传入神经元的敏感性，从而支配颅外钙颅骨骨膜和颅内硬脑膜内膜，从而促进了感觉和情感变化的发展和情感变化，从而可以链接到PTH疼痛。我们提出了一系列研究，该研究采用电生理学，行为测试，组织学，药理学和突变动物，缺乏免疫细胞来通过解决以下问题来研究我们的工作假说：1）头部创伤是否会导致持续的激活，并提高机械和化学敏感性，使钙质和内部或内在尿液的一级神经元（或化学）的化学敏感性提高（ 2）如果是这样，这些神经生理学的变化是否相关并有助于肾上腺皮肤异常性异常的发展，与持续性头痛有关的感觉变化以及对挖洞的抑制，天生行为的变化，反映了情感（厌恶的）持续性疼痛的情感（厌恶）维度（特定目标2）？ 3）会做创伤后外周炎症反应，特别是在颅骨骨膜和颅内硬脑膜内募集和激活，有助于创伤后神经生理学变化，以及随之而来的行为变化与PTH疼痛有关。该项目的结果将为PTH的发病机理提供重要的见解，包括可能出现PTH疼痛的周围组织，头痛及其潜在机制的神经生理学相关性。这种新的信息可能会导致干预措施的靶标扩大，以减轻这种与创伤相关的疼痛。