Nociceptive Mechanisms in Whiplash Injury

描述（由申请人提供）：鞭打及其相关综合征仍然是最常见和使人衰弱的非致命伤害之一。颈椎小关节囊疼痛损伤的发生是由于颈部运动的改变导致小关节囊内感觉传入神经的机械损伤。然而，由于缺乏相关的体内系统模拟生物力学颈部损伤，对颈部扭伤引起的颈部疼痛的机制知之甚少。我们最近开发了一个大鼠模型来模拟颈椎小关节在鞭打过程中的生物力学载荷条件。该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的影响，伤害感觉的脊柱机制，以及由此产生的行为敏感性。我们假设：(1)小关节的鞭状负荷通过改变小关节囊中多肽能和非多肽能C-纤维的神经化学功能而产生持续疼痛；(2)这些小关节囊传入的生化反应对脊髓中的神经肽、神经营养素和免疫反应（即神经胶质激活、促炎细胞因子）具有永久性影响；(3)鞭笞载荷会在关节突关节产生炎症，这也会加剧脊柱变形和疼痛症状。我们的试验数据表明，在我们的大鼠模型中，短暂的鞭状加载情景会在颈部产生持续的行为敏感性和持续的脊柱改变。在这个提议中，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。在目的1中，我们将定义C6/C7关节突关节疼痛的颈椎扭伤反应。在Aim 2中，我们在单独的研究中使用皂苷偶联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Aim 1中的结果进行比较，确定它们对疼痛和伤害感觉的相对贡献。在Aim 3中，我们将施加非疼痛关节负荷情景，并切除脊髓中携带NK1受体的神经元，以确定哪些脊髓反应是疼痛关节生物力学的特异性反应。最后，在Aim 4中，我们将测试抑制小关节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。通过完成本研究的具体目标，我们将直接将小关节的初始力学条件与中枢神经系统的疼痛通路联系起来。反过来，我们将定义由颈部负荷引起的持续疼痛的病因，从而导致治疗鞭扭伤相关颈部疼痛的潜在治疗方法的发展。公共卫生相关性：鞭伤是一项公共卫生负担，每年造成惊人的社会和经济后果。本研究计划将确定产生持续性疼痛的鞭扭伤损伤机制，并将确定小关节中的感觉纤维如何参与此类症状的发生和维持。这些损伤和症状的生理学相关性也被表征，以指导未来预防和治疗车辆乘员这类常见损伤引起的颈部疼痛的发展。

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.