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.

项目摘要/摘要 骨关节炎（OA）是一种普遍的肌肉骨骼疾病，其特征是局部低级炎症 受影响的关节。 OA中的炎症可通过改进来调节局部和高阶神经可塑性 分别在发炎的滑膜和背角神经元的阈值中神经支配。失调 自主神经系统（ANS）的主动性和进展已被考虑 炎症性和慢性疼痛障碍，例如类风湿关节炎，但在OA中尚未探索。然而， 我的初步数据显示了8-10周的手术大鼠膝关节中的宽度和失调 启动后。不幸的是，与病理生理和症状有关的自主功能障碍 膝盖OA的进展尚不清楚。 疼痛是OA的基本症状。在疾病的早期，使用关节会出现疼痛，表明 伤害性成分。在幼稚的动物中，周围的伤害感受传入反馈相互作用 用ANS方向。例如，刺激巨核孤子的刺激抑制伤害性信号 伤害感受反馈通过抑制迷走神经来减轻副交感神经系统 活动。但是，这些自主神经关系尚未在膝关节中探索。 为了解决这些差距，该提案的核心目标是缩小膝盖伤害感受的差距 和迷走神经激活，并研究伤害感受和ANS在有症状和 OA的病理生理进展。在AIM 1中，将通过量化迷走神经来研究联合脑轴 对急性伤害性膝关节刺激的反应。在AIM 2中，由于慢性而引起的迷走神经神经反应的变化 大鼠的OA疼痛和炎症的进展将被量化。这扩展了AIM 1以相关的疼痛 - 相关收集的补偿和病理关节损害对迷走神经反应的转变。因为OA是一个 异质性疾病具有不同机制的发作和症状严重程度，OA的两个模型将是 调查。这项研究具有重要和创新性，因为它将提供第一个定量证据 OA啮齿动物模型的副交感神经变化。具体而言，对伤害感受感官的迷走神经输出 刺激将被量化以确定自主神经脑轴的存在。这些回应的转变 将与OA啮齿动物模型中与疼痛相关的行为变化进行评估，以证明 OA有症状进展的自主神经系统。该建议将利用专业定量 了解有助于OA疼痛和残疾的新型机制的技术，从而成为其中的 阐明ANS在OA发病机理和OA症状进展中的作用的第一批研究。

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