Nociceptive Mechanisms in Whiplash Injury

描述（由申请人提供）：挥鞭样损伤及其相关综合征仍然是最常见和使人衰弱的非致命性损伤之一。颈椎小关节囊疼痛性损伤的发生是因为在挥鞭过程中颈部运动的改变导致小关节囊感觉传入的机械损伤。然而，由于缺乏相关的生物力学颈部损伤的体内系统建模，颈部疼痛的机制所知甚少，从挥鞭样损伤。我们最近开发了一个大鼠模型，模拟生物力学的负载条件下颈椎小关节在挥鞭样损伤。本申请的长期目标是使用该模型来定义局部关节生物力学对关节囊传入反应、伤害性感受的脊髓机制以及由此产生的行为敏感性的影响。我们假设：（1）小关节的挥鞭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）这些囊传入的生化反应对神经肽、神经营养因子和免疫反应具有永久性影响（即神经胶质活化、促炎细胞因子），和（3）挥鞭样负荷在小关节中产生炎症，这也加剧了脊柱变形和疼痛症状。我们有试验数据表明，一个短暂的挥鞭样负载的情况下产生持久的行为敏感性在颈部和持续的脊柱修改在我们的大鼠模型。在这个建议中，我们将定义关节生物力学，神经肽和神经营养因子调节和免疫反应在背根神经节和脊髓，和行为敏感性之间的时间关系。在目标1中，我们将定义C6/C7小关节疼痛性挥鞭样载荷的这些反应。在目标2中，我们在单独的研究中使用皂草素缀合物来选择性地消除小关节中的NK 1受体承载和IB 4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，我们将施加无疼痛的关节负荷场景，并消融脊髓中的NK 1受体承载神经元，以确定哪些脊髓反应是疼痛关节生物力学特有的。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。通过完成本研究的特定目标，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疼痛的病因，从而开发治疗挥鞭样损伤相关颈部疼痛的潜在治疗方法。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。这项研究计划将定义产生持续疼痛的挥鞭样损伤机制，并确定小关节中的感觉纤维如何有助于这些症状的发生和维持。这些损伤和症状的生理相关性也被表征，以指导未来对车辆乘员这种常见损伤的颈部疼痛的预防和治疗的发展。

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.