Investigating the role of osteoarthritic pain and inflammation in autonomic nervous system shifts using preclinical models

项目总结/摘要 骨关节炎（OA）是一种常见的肌肉骨骼疾病，其特征是局部低度炎症， 受影响的关节OA中的炎症通过降低神经元的可塑性来调节局部和高阶神经可塑性。 炎症滑膜的神经支配和背角神经元的阈值降低。失调 自主神经系统（ANS）的启动和发展已被认为是其他神经系统的启动和发展 炎症性和慢性疼痛疾病，如类风湿性关节炎，但尚未在OA中探索。然而，在这方面， 我的初步数据表明，在8-10周的手术大鼠膝关节OA模型中， 启动后。不幸的是，自主神经功能障碍与病理生理和症状有关， 膝关节OA的进展尚不清楚。 疼痛是OA的主要症状。在疾病的早期阶段，使用关节时会出现疼痛，表明 伤害感受成分。在幼稚动物中，来自外周的伤害性传入反馈相互作用， 方向与ANS。例如，刺激孤束核抑制伤害性信号 而伤害性反馈通过阻尼迷走神经传导来减弱副交感神经系统。 活动然而，这些疼痛-伤害感受的关系尚未在膝关节中进行探索。 为了解决这些差距，本提案的中心目标是缩小膝关节伤害性感受之间的差距 和迷走神经激活，并研究伤害性感受和ANS在症状性和 OA的病理生理进展。在目标1中，将通过量化迷走神经来研究关节-脑轴 对急性伤害性膝关节刺激的反应。在目标2中，由于慢性炎症引起的迷走神经反应的变化 将定量大鼠中OA疼痛和炎症的进展。这扩展了目标1，将疼痛与 相关的步态补偿和病理性关节损伤，以改变迷走神经反应。因为OA是一个 异质性疾病与不同的发病机制和症状的严重程度，两种模型的OA将是 研究了这项研究是重要的和创新的，因为它将提供第一个定量证据， OA啮齿动物模型中的副交感神经变化。具体地说，迷走神经输出对伤害性感觉的反应 刺激将被量化以建立自主关节-脑轴的存在。这些反应的变化 将与OA啮齿动物模型中疼痛相关的行为变化一起进行评估，以证明 OA症状进展中的自主神经系统。该提案将利用专门的定量 技术，以了解新的机制，有助于OA疼痛和残疾，从而成为其中 首次研究阐明ANS在OA发病机制和OA症状进展中的作用。

Project Summary/Abstract Osteoarthritis (OA) is a prevalent musculoskeletal disease characterized by local, low-grade inflammation in the affected joints. Inflammation in OA modulates both local and higher-order neuroplasticity through decreased innervation in the inflamed synovium and lowered thresholds of dorsal horn neurons, respectively. Dysregulation of the autonomic nervous system (ANS) has been considered in the initiation and progression of other inflammatory and chronic pain disorders such as rheumatoid arthritis, but has not been explored in OA. However, my preliminary data demonstrate widespread ANS dysregulation in a surgical rat knee OA model 8-10 weeks after initiation. Unfortunately, autonomic dysfunction related to the pathophysiologic and symptomatic progression of knee OA is not well understood. Pain is the cardinal symptom of OA. In early stages of the disease, pain arises with use of the joint, indicating a nociceptive component. In naïve animals, nociceptive afferent feedback from the periphery interacts bi- directionally with the ANS. For example, stimulation of the nucleus tractus solitaries inhibits nociceptive signal transmission while nociceptive feedback attenuates the parasympathetic nervous system by damping vagal activity. However, these autonomic-nociceptive relationships have not been explored in the knee joint. To address these gaps, the central goal of this proposal is to close the gap between nociception at the knee and vagal nerve activation and to investigate the role of nociception and the ANS in symptomatic and pathophysiologic progression of OA. In Aim 1, I the joint-brain axis will be investigated by quantifying vagal nerve response to acute nociceptive knee stimulations. In Aim 2, shifts in vagal nerve response due to chronic progression of OA pain and inflammation in the rat will be quantified. This expands on Aim 1 to correlate pain- related gait compensations and pathologic joint damage to shifts in vagal nerve responses. Because OA is a heterogeneous disease with varied mechanisms of onset and severity of symptoms, two models of OA will be investigated. This research is significant and innovative because it will provide the first quantitative evidence of parasympathetic changes in rodent models of OA. Specifically, vagal output in response to nociceptive sensory stimuli will be quantified to establish the presence of the autonomic joint-brain axis. Shifts in these responses will be assessed alongside pain-related behavioral changes in rodent models of OA to evidence a role for the autonomic nervous system in OA symptomatic progression. This proposal will utilize specialized quantitative techniques to understand novel mechanisms contributing to OA pain and disability, thereby becoming among the first studies to elucidate the role of the ANS in OA pathogenesis and OA symptom progression.