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)是一种流行的肌肉骨骼疾病，其特征是局部的、低级别的炎症 受影响的关节。骨性关节炎的炎症通过降低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。调控失调 自主神经系统(ANS)的启动和进展被认为是 炎症性和慢性疼痛障碍，如类风湿性关节炎，但尚未在骨性关节炎中探索。然而， 我的初步数据显示，在8-10周的手术大鼠膝骨性关节炎模型中普遍存在ANS失调。 印心后。不幸的是，自主神经功能障碍与病理生理和症状有关 膝骨性关节炎的进展情况尚不清楚。 疼痛是骨性关节炎的主要症状。在疾病的早期阶段，关节的使用会引起疼痛，这表明 一种伤害感受器成分。在幼稚的动物中，来自外围的伤害性传入反馈相互作用。 直接与澳大利亚国民警卫队合作。例如，刺激孤束核抑制了伤害性信号。 伤害性反馈时的传递通过抑制迷走神经来减弱副交感神经系统 活动。然而，这些自主神经-伤害性关系在膝关节中还没有被探索过。 为了解决这些差距，这项提议的中心目标是弥合膝盖上的伤害性感觉之间的差距 和迷走神经的激活，并探讨伤害性感觉和ANS在症状性和非典型肺炎中的作用。 骨性关节炎的病理生理进展。在目标1中，将通过量化迷走神经来研究关节-脑轴。 对急性膝部伤害性刺激的反应。在目标2中，迷走神经反应由于慢性 将量化大鼠骨性关节炎疼痛和炎症的进展情况。这在目标1的基础上进行了扩展，以关联疼痛- 迷走神经反应移位的相关步态代偿和病理性关节损伤。因为办公自动化是一个 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 调查过了。这项研究具有重要意义和创新性，因为它将提供第一个量化证据 OA啮齿动物模型中的副交感神经改变。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，以确定自主关节-脑轴的存在。这些反应的转变 将与疼痛相关的行为变化一起在OA啮齿动物模型中进行评估，以证明 自主神经系统在骨性关节炎症状进展中的作用。这项提议将利用专门的量化 理解导致骨性关节炎疼痛和残疾的新机制的技术，从而成为 首次研究阐明ANS在骨性关节炎的发病机制和症状进展中的作用。

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

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

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