Nociceptive Mechanisms in Whiplash Injury

颈部扭伤的伤害感受机制

• 批准号: 8213693
• 负责人: Beth A Winkelstein
• 金额: $ 28.59万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8213693
• 关键词: Affect; Arthritis; Attenuated; Behavioral; Biochemical; Biological Models; Biomechanics; Brain-Derived Neurotrophic Factor; C Fiber; Cervical; Cervical spinal cord injury; Clinical; Clinical Research; Cytokine Activation; Data; Development; Etiology; Event; Facet joint structure; Fiber; Foundations; Functional disorder; Future; GDNF gene; Goals; Health; Immune response; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Inflammatory Response Pathway; Injury; Joint Capsule; Joints; Link; Maintenance; Measures; Mechanics; Mediating; Modeling; Modification; Molecular; Motion; Neck; Neck Injuries; Neck Pain; Nerve Fibers; Nervous system structure; Neuraxis; Neurons; Neuropeptides; Nociception; Nociceptors; Outcome; Pain; Painless; Pathway interactions; Persistent pain; Physiological; Prevention; Production; Public Health; Rattus; Regulation; Relative (related person); Research; Research Proposals; Role; Sensory; Simulate; Source; Spinal; Spinal Anesthesia; Spinal Cord; Spinal Ganglia; Substance P; Symptoms; Syndrome; Testing; Therapeutic Intervention; Time; Tissues; Toxin; Whiplash Injuries; Work; capsule; chronic pain; cytokine; disability; in vivo; in vivo Model; injured; joint injury; joint loading; macrophage; neurochemistry; neurotrophic factor; nociceptive response; novel; prevent; programs; receptor; research study; response; therapy development

Description (provided by applicant): Whiplash and its associated syndromes continue to be ranked among the most common and debilitating nonfatal injuries. Painful injury of the cervical facet capsule occurs because altered neck motions during whiplash results in mechanical injury to the sensory afferents in the facet joint's capsule. However, due to a lack of relevant in vivo systems modeling biomechanical neck injuries, little is known about the mechanisms of neck pain resulting from whiplash. We recently developed a rat model that simulates the biomechanical loading conditions of the cervical facet joint during whiplash. It is the long-term objective of this application to use that model to define the effects of local joint biomechanics on capsule afferent responses, spinal mechanisms of nociception, and the resulting behavioral sensitivity. We hypothesize that: (1) whiplash-like loading of the facet joint produces persistent pain via altered neurochemical function of the peptidergic and non-peptidergic C- fibers in the facet capsule, (2) the biochemical responses of those capsule afferents have permanent effects on neuropeptides, neurotrophins and immune responses (i.e. glial activation, pro-inflammatory cytokines) in the spinal cord, and (3) whiplash loading produces inflammation in the facet joint that also exacerbates spinal modifications and pain symptoms. We have pilot data demonstrating that a transient whiplash-like loading scenario produces both persistent behavioral sensitivity in the neck and sustained spinal modifications in our rat model. In this proposal we will define the temporal relationship between joint biomechanics, neuropeptide and neurotrophin regulation and immune responses in the dorsal root ganglion and spinal cord, and behavioral sensitivity. In Aim 1 we will define these responses for painful whiplash loading to the C6/C7 facet joint. In Aim 2 we use saporin conjugates in separate studies to selectively eliminate NK1 receptor-bearing and IB4-positive neurons in the facet joint and define their relative contributions to pain and nociception by comparison to outcomes in Aim 1. In Aim 3 we will impose a non-painful joint loading scenario and also ablate NK1 receptor- bearing neurons in the spinal cord to identify which spinal responses are specific for painful joint biomechanics. Lastly, in Aim 4 we will test if inhibiting the inflammatory cascade in the facet joint can prevent or attenuate sensitivity and/or modulate associated spinal responses. By accomplishing the specific aims of this research, we will directly link the initial mechanical conditions of the facet joint to pain pathways in the central nervous system. In turn, we will define the etiology for persistent pain from neck loading, leading to the development of potential treatments to treat whiplash-related neck pain. PUBLIC HEALTH RELEVANCE: Whiplash is a public health burden, with staggering annual societal and financial consequences. This research proposal will define mechanisms of whiplash injury that produce persistent pain and will identify how sensory fibers in the facet joint contribute to the onset and maintenance of such symptoms. Physiologic correlates of these injuries and symptoms are also characterized to guide future development of preventions and treatments for neck pain from this common class of injuries for vehicle occupants.

描述（由申请人提供）：颈椎扭伤及其相关综合征仍然被列为最常见且使人衰弱的非致命伤害之一。颈椎小关节囊会发生疼痛性损伤，因为颈椎扭伤期间颈部运动的改变会导致小关节囊内感觉传入的机械损伤。然而，由于缺乏模拟生物力学颈部损伤的相关体内系统，人们对颈椎扭伤引起的颈部疼痛机制知之甚少。我们最近开发了一种大鼠模型，可以模拟颈椎小关节扭伤期间的生物力学负荷条件。本应用的长期目标是使用该模型来定义局部关节生物力学对胶囊传入反应、伤害感受的脊柱机制以及由此产生的行为敏感性的影响。我们假设：（1）小关节的鞭打样负荷通过改变小关节囊中肽能和非肽能 C 纤维的神经化学功能产生持续性疼痛，（2）这些囊传入神经的生化反应对神经肽、神经营养蛋白和免疫反应（即神经胶质激活、 (3) 脊髓中的促炎细胞因子)，以及 (3) 挥鞭性损伤会在小关节中产生炎症，这也会加剧脊柱变形和疼痛症状。我们的试验数据表明，短暂的鞭打样加载场景会在我们的大鼠模型中产生持续的颈部行为敏感性和持续的脊柱改变。在本提案中，我们将定义关节生物力学、神经肽和神经营养蛋白调节以及背根神经节和脊髓中的免疫反应以及行为敏感性之间的时间关系。在目标 1 中，我们将定义对 C6/C7 小关节疼痛性鞭打负荷的这些反应。在目标 2 中，我们在单独的研究中使用皂草素缀合物选择性地消除小关节中的 NK1 受体和 IB4 阳性神经元，并通过与目标 1 中的结果进行比较来定义它们对疼痛和伤害感受的相对贡献。在目标 3 中，我们将施加无痛的关节负荷场景，并消融脊髓中的 NK1 受体神经元，以确定哪些脊髓反应是特定的 疼痛的关节生物力学。最后，在目标 4 中，我们将测试抑制小关节中的炎症级联是否可以预防或减弱敏感性和/或调节相关的脊柱反应。通过实现这项研究的具体目标，我们将直接将小关节的初始机械条件与中枢神经系统的疼痛通路联系起来。反过来，我们将确定颈部负荷引起的持续性疼痛的病因，从而开发出治疗颈部扭伤相关疼痛的潜在疗法。公共卫生相关性：颈部扭伤是一种公共卫生负担，每年都会造成惊人的社会和经济后果。该研究计划将定义产生持续疼痛的颈部扭伤的机制，并将确定小关节中的感觉纤维如何导致此类症状的发生和维持。这些损伤和症状的生理相关性也被表征，以指导未来开发针对车辆乘员常见损伤类型的颈部疼痛的预防和治疗。