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，其病理生理机制定义不清。本申请的长期目标是在大鼠中开发疼痛的机械诱导的TMJ骨关节炎的新型体内模型，并利用该模型来定义导致TMJ疼痛的神经胶质反应性和细胞因子表达的机制。在这项拟议的研究计划中，我们将整合生物工程方法，行为测试仪器和生化分析，以确定疼痛性骨关节炎（OA）在颞下颌关节的机制。我们有初步的数据支持大鼠稳定的张口产生持续的机械性异常性疼痛。在这个建议中，我们扩展了这些研究，以确定持续的行为敏感性与颞下颌关节软骨变性的发展的发病机制。拟议的研究项目的目标是通过非侵入性和非辅助方法开发一种新的TMJ骨关节炎疼痛模型，并利用该模型来了解CMS中骨关节炎变化，行为敏感性和胶质细胞激活之间的关系。我们假设，一个重复的张口协议可以诱导颞下颌关节软骨的永久性骨关节炎的变化，这取决于加载频率和施加的力量。此外，TMJ软骨中的这种变化引起CNS中神经胶质促炎细胞因子表达升高，这有助于引发和维持持续异常性疼痛，模拟持续性口面疼痛症状。本研究的具体目的是：（1）建立一个体内大鼠模型，重复张口，产生TMJ骨关节炎病变和持续的行为敏感性;和（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，并实时PCR探针细胞因子表达谱在这些细胞在慢性行为敏感性的发病和维持。这项发展研究项目的结果将建立一种新的大鼠模型，用于确定TMJ疼痛的病因和未来潜在的治疗策略。相关性：由于美国人口老龄化，颞下颌关节骨关节炎的发病率持续上升。这给美国的医疗保健系统带来了越来越大的压力，使其难以实现“2010年健康人”的目标。“这项研究提案为定义与TMJ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。它还确定了这些疾病的生理机制的时间过程，并将为未来的研究提供基础，以调查潜在的药物治疗慢性颞下颌关节疼痛。

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.