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最令人衰弱的非致命损伤之一。颈椎小关节囊疼痛损伤的发生是因为颈椎抽动时颈部运动的改变导致小关节囊内感觉神经传入的机械损伤。然而，由于缺乏相关的活体系统模拟颈部生物力学损伤，对颈椎扭伤引起的颈部疼痛的机制知之甚少。我们最近开发了一种模拟颈椎扭伤过程中颈椎小关节生物力学负荷情况的大鼠模型。这项应用的长期目标是使用该模型来确定局部关节生物力学对包膜传入反应的影响、脊髓伤害性反应的机制以及由此产生的行为敏感性。我们假设：(1)鞭击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而产生持续性疼痛，(2)这些囊传入的生化反应对脊髓中的神经肽、神经营养因子和免疫反应(即胶质激活、促炎细胞因子)具有永久性影响，以及(3)鞭击负荷在小关节产生炎症，这也加剧了脊柱的改变和疼痛症状。我们有试验数据表明，在我们的大鼠模型中，瞬时鞭子样负荷情景会在颈部产生持久的行为敏感性，并产生持续的脊柱修改。在这个提案中，我们将定义关节生物力学、神经肽和神经营养素调节以及背根神经节和脊髓中的免疫反应之间的时间关系，以及行为敏感性。在目标1中，我们将定义对C6/C7小关节的疼痛鞭打负荷的这些反应。在目标2中，我们在不同的研究中使用皂苷结合物来选择性地消除小关节中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确定它们对疼痛和伤害性感觉的相对贡献。在目标3中，我们将施加非痛性关节负荷情景，并消融脊髓中的NK1受体神经元，以确定哪些脊髓反应是痛性关节生物力学所特有的。最后，在目标4中，我们将测试抑制小关节炎症级联是否可以防止或减弱敏感性和/或调节相关的脊髓反应。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中的疼痛通路联系起来。反过来，我们将确定颈部负荷性持续性疼痛的病因，从而开发出治疗与颈鞭相关的颈部疼痛的潜在疗法。与公共卫生相关：鞭打是一种公共卫生负担，每年都会造成惊人的社会和财政后果。这项研究计划将确定产生持续性疼痛的鞭打损伤的机制，并将确定小关节中的感觉神经纤维如何有助于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用来指导未来预防和治疗这种常见的车辆乘员伤害类别的颈部疼痛的发展。

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.