Nociceptive Mechanisms in Whiplash Injury

颈部扭伤的伤害感受机制

基本信息

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
项目类别：
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

项目摘要

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）：鞭打及其相关综合症继续被评为最常见和令人衰弱的非致命伤害。颈椎胶囊的疼痛受伤会发生，因为鞭打过程中的颈部运动改变会导致小股关节胶囊中的感觉传入机械损伤。但是，由于缺乏相关的体内系统建模生物力学颈部损伤，对鞭打引起的颈部疼痛机制知之甚少。我们最近开发了一个大鼠模型，该模型模拟了鞭打过程中宫颈小平台的生物力学载荷条件。该应用程序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所得的行为敏感性的影响。 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,脊髓中的促炎性细胞因子），（3）鞭打负荷会在小平关节中产生炎症，这也会加剧脊柱修饰和疼痛症状。我们有试验数据表明，瞬态鞭打状的载荷方案在我们的大鼠模型中会产生颈部持续的行为敏感性和持续的脊柱修饰。在此提案中，我们将定义关节生物力学，神经肽和神经营养蛋白调节与背根神经节和脊髓中的免疫反应与行为敏感性之间的时间关系。在AIM 1中，我们将定义这些响应，以使其对C6/C7 Facet接头的痛苦鞭打负载。在目标2中，我们在单独的研究中使用saporin conjugates来选择性地消除刻面关节中的NK1受体和IB4阳性神经元，并通过与AIM 1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。痛苦的关节生物力学。最后，在AIM 4中，我们将测试是否抑制小相接头中的炎症性级联反应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的，我们将直接将Facet关节的初始机械条件与中枢神经系统中的疼痛途径联系起来。反过来，我们将因颈部负荷而定义持续性疼痛的病因，从而导致潜在治疗以治疗与鞭打相关的颈部疼痛。公共卫生相关性：鞭打是一种公共卫生负担，年度社会和财务后果惊人。该研究建议将定义鞭打损伤的机制，该机制会导致持续的疼痛，并确定方面关节中的感觉纤维如何有助于这种症状的发作和维持。这些损伤和症状的生理相关性也被特征在于指导未来的预防和治疗颈部疼痛治疗这种常见的车辆乘员伤害类别。