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

使用临床前模型研究骨关节炎疼痛和炎症在自主神经系统转变中的作用

• 批准号: 10240289
• 负责人: Taylor Yeater
• 金额: $ 4.07万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-16 至 2022-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10240289
• 关键词: Acute; Address; Affect; Agonist; Animals; Area; Attenuated; Autonomic Dysfunction; Autonomic nervous system; Behavioral; Blood Pressure; Brain; Brain Stem; Cell Nucleus; Chronic; Data; Degenerative polyarthritis; Disease; Drops; Electrophysiology (science); Etiology; Feedback; Financial compensation; Functional disorder; Gait; Goals; Heart Rate; Heterogeneity; Inflammation; Inflammatory; Injections; Joints; Knee; Knee Injuries; Knee Osteoarthritis; Knee joint; Knowledge; Kynurenic Acid; Measurement; Measures; Methods; Modeling; Motivation; Musculoskeletal Diseases; Nerve; Nervous System Physiology; Neuronal Plasticity; Nociception; Nociceptive Stimulus; Operative Surgical Procedures; Output; Pain; Parasympathetic Nervous System; Pathogenesis; Pathologic; Posterior Horn Cells; Pre-Clinical Model; Rattus; Research; Rheumatoid Arthritis; Rodent Model; Role; Sensory; Severities; Signal Transduction; Spinal; Sprague-Dawley Rats; Stimulus; Surgical Models; Symptoms; Synovitis; Tactile; Techniques; Testing; Time; Vagus nerve structure; Weight; chronic inflammatory disease; chronic painful condition; disability; dorsal horn; experimental study; gait examination; inflammatory pain; innovation; joint injury; knee pain; meniscal tear; nerve supply; novel; osteoarthritis pain; receptive field; relating to nervous system; response; sensory stimulus; transmission process

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.

项目概要/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 骨关节炎中的炎症通过降低局部和高阶神经可塑性来调节。 分别导致发炎滑膜的神经支配和背角神经元的阈值降低。 自主神经系统（ANS）的功能被认为是其他疾病的发生和进展的原因 炎症和慢性疼痛疾病，如类风湿性关节炎，但尚未在 OA 中进行探索。 我的初步数据表明，手术大鼠膝关节 OA 模型中 8-10 周存在广泛的 ANS 失调 不幸的是，在开始后，自主神经功能障碍与病理生理和症状有关。 膝关节骨关节炎的进展尚不清楚。 疼痛是 OA 的主要症状。在疾病的早期阶段，随着关节的使用而出现疼痛，这表明疼痛。 在幼稚的动物中，来自周围的伤害性传入反馈相互作用。 例如，刺激孤束核会抑制伤害性信号。 传递，而伤害性反馈通过抑制迷走神经来削弱副交感神经系统 然而，这些自主神经-伤害感受的关系尚未在膝关节中得到探索。 为了解决这些差距，该提案的中心目标是缩小膝盖伤害感受之间的差距 和迷走神经激活，并研究伤害感受和 ANS 在症状和症状中的作用 在目标 1 中，我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，由于慢性迷走神经反应发生变化。 大鼠 OA 疼痛和炎症的进展将被量化，这扩展了目标 1，将疼痛关联起来。 相关的步态补偿和病理性关节损伤与迷走神经反应的变化有关，因为 OA 是一种 具有不同发病机制和症状严重程度的异质性疾病，将有两种 OA 模型 这项研究具有重要意义和创新性，因为它将提供第一个定量证据。 OA 啮齿动物模型中副交感神经的变化具体来说是对伤害性感觉的迷走神经输出。 刺激将被量化以确定这些反应中自主关节-大脑轴的变化。 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 的作用 该提案将利用专门的定量方法来分析 OA 症状进展中的自主神经系统。 技术来了解导致 OA 疼痛和残疾的新机制，从而成为其中之一 首次研究阐明 ANS 在 OA 发病机制和 OA 症状进展中的作用。

项目成果

Measures of cardiovascular function suggest autonomic nervous system dysregulation after surgical induction of joint injury in the male Lewis rat.

• DOI: 10.1016/j.joca.2021.12.008
• 发表时间: 2022-04
• 期刊: OSTEOARTHRITIS AND CARTILAGE
• 影响因子: 7
• 作者: Yeater, T. D.;Zubcevic, J.;Allen, K. D.
• 通讯作者: Allen, K. D.

Age alters gait compensations following meniscal injury in male rats.

• DOI: 10.1002/jor.25306
• 发表时间: 2022-12
• 期刊: JOURNAL OF ORTHOPAEDIC RESEARCH
• 影响因子: 2.8
• 作者: Chan, Kiara M.;Yeater, Taylor D.;Allen, Kyle D.
• 通讯作者: Allen, Kyle D.

Autonomic Nervous System Dysregulation and Osteoarthritis Pain: Mechanisms, Measurement, and Future Outlook.

• DOI: 10.1007/s11926-022-01071-9
• 发表时间: 2022-06
• 期刊: Current rheumatology reports
• 影响因子: 5
• 作者: Yeater TD;Cruz CJ;Cruz-Almeida Y;Allen KD
• 通讯作者: Allen KD

Hypertension contributes to exacerbated osteoarthritis pathophysiology in rats in a sex-dependent manner.

• DOI: 10.1186/s13075-022-02966-9
• 发表时间: 2023-01-12
• 期刊: Arthritis research & therapy
• 影响因子: 4.9

Chronic Pain is Associated With Reduced Sympathetic Nervous System Reactivity During Simple and Complex Walking Tasks: Potential Cerebral Mechanisms.

• DOI: 10.1177/24705470211030273
• 发表时间: 2021-01
• 期刊: Chronic stress (Thousand Oaks, Calif.)
• 作者: Yeater TD;Clark DJ;Hoyos L;Valdes-Hernandez PA;Peraza JA;Allen KD;Cruz-Almeida Y
• 通讯作者: Cruz-Almeida Y