A Novel Model of TMJ Osteoarthritis to Define Glial Reactivity in Chronic Pain

描述（由申请人提供）：与颞下颌关节（TMJ）疾病相关的慢性疼痛是美国的一个主要问题，病理生理机制不明确。本研究的长期目标是建立一种新的大鼠机械疼痛性TMJ骨关节炎的体内模型，并利用该模型来确定神经胶质反应性和细胞因子表达对TMJ疼痛的影响机制。在本研究计划中，我们将结合生物工程方法、行为测试仪器和生化分析来确定颞下颌关节疼痛性骨关节炎（OA）的机制。我们有初步的数据支持稳定的张嘴在大鼠中产生持续的机械异常性疼痛。在本提案中，我们扩展了这些研究，以确定与颞下颌关节软骨退变发展相关的持续行为敏感性的发病机制。本课题旨在通过非侵入性和非辅助的方法建立一种新的TMJ骨关节炎疼痛模型，并利用该模型了解CMS中骨关节炎变化、行为敏感性和神经胶质激活之间的关系。我们假设重复的张嘴方案可以诱导TMJ软骨的永久性骨关节炎改变，这取决于加载频率和施加的力。此外，TMJ软骨的这种变化引起中枢神经系统胶质促炎细胞因子表达升高，从而导致持续的异位性疼痛的开始和维持，模仿持续的口面部疼痛症状。本研究的具体目的是：(1)建立反复张口导致TMJ骨关节炎病变和持续行为敏感的大鼠体内模型；(2)利用免疫表型和细胞分选技术分离胶质细胞和神经元细胞群，并利用实时PCR检测慢性行为敏感性发病和维持过程中这些细胞的细胞因子表达谱。这项发展研究项目的发现将为确定TMJ疼痛的病因和潜在的未来治疗策略建立一种新的大鼠模型。相关性：由于美国人口老龄化，TMJ骨关节炎的发病率持续上升。这给美国医疗保健系统带来了越来越大的压力，使“2010年健康人口”的目标难以实现。本研究方案为明确与颞下颌关节慢性疼痛相关的关节和中枢神经系统的细胞机制奠定了基础。该研究还确定了这些疾病的生理机制的时间进程，为今后研究慢性TMJ疼痛的潜在药物治疗方法提供了基础。

DESCRIPTION (provided by applicant): Chronic pain associated with temporomandibular joint (TMJ) disorders is a major problem in the United States, with poorly defined pathophysiological mechanisms. It is the long-term objective of this application to develop a novel in vivo model of painful mechanically-induced TMJ osteoarthritis in the rat and utilize this model to define mechanisms of glial reactivity and cytokine expression that contribute to TMJ pain. In this proposed research plan, we will integrate bioengineering approaches, behavioral test instruments and biochemical assays to define mechanisms of painful osteoarthritis (OA) in the TMJ. We have preliminary data supporting steady mouth-opening as producing sustained mechanical allodynia in the rat. In this proposal we extend those studies to define the pathogenesis of persistent behavioral sensitivity associated with the development of cartilage degeneration in the TMJ. The goals of the proposed research project are to develop a novel pain model of osteoarthritis in the TMJ via non-invasive and non-adjuvant methods, and to utilize this model to understand the relationship between osteoarthritic changes, behavioral sensitivity, and glial activation in the CMS. We hypothesize that a repeated mouth-opening protocol can induce permanent osteoarthritic changes in TMJ cartilage that depend on loading frequency and applied force. Further, such changes in TMJ cartilage give rise to elevated glial pro-inflammatory cytokine expression in the CNS which contribute to the initiation and maintenance of sustained allodynia, mimicking persistent orofacial pain symptoms. The specific aims of this research are to: (1) develop an in vivo rat model of repeated mouth-opening which produces TMJ osteoarthritic lesions and persistent behavioral sensitivity; and (2) utilize immunophenotyping and cell sorting techniques to separate glial and neuronal cell populations, and real-time PCR to probe cytokine expression profiles in those cells during the onset and maintenance of chronic behavioral sensitivity. Findings from this developmental research project will establish a novel rat model for defining the etiology of TMJ pain and potential future treatment strategies. Relevance: The incidence of TMJ osteoarthritis continues to rise due to the aging United States population. This places growing strain on the United States healthcare system, making it difficult to achieve the objective of 'Healthy People 2010.' This research proposal lays the foundation for defining the cellular mechanisms in the joint and central nervous system associated with chronic pain in the TMJ. It also identifies the time course of physiologic mechanisms of these disorders, and will provide the basis for future studies to investigate potential pharmacologic therapies for chronic TMJ pain.