Central Mechanisms of Orofacial Pain

摘要与颞下颌关节紊乱病相关的疼痛是一种非常常见的口腔面部疾病。 疼痛，一种使人虚弱的慢性疼痛状况。慢性口腔面部疼痛难以治疗 因为其机制在很大程度上仍不清楚。此前的研究表明， 神经元和非神经元(神经胶质)成分在细胞中都起着关键作用。 病理性疼痛的机制。已有研究表明，周围神经损伤和 炎症可以诱导脊髓神经胶质细胞激活，而促炎细胞因子可以 上调脊髓N-甲基-D-天冬氨酸受体(NMDAR)的表达 至少部分是通过激活细胞内蛋白激酶C。我们的初步数据 已经证明了完全弗洛因德引起的疼痛行为的发展 大鼠颞下颌关节(TMJ)内注射佐剂可引起 白介素6和NMDAR在同侧的表达增加 三叉神经尾侧亚核。这些发现支持这样的观点，即相互作用 神经元和神经胶质分子之间也可能在细胞内发挥关键作用 口腔面部疼痛的机制。在这项拨款中，我们建议有系统地研究 三叉神经胶质细胞激活与神经元NMDAR表达的相互作用 及其在大鼠TMJ疼痛行为发病机制中的作用。我们的主要假设是 TMJ炎症会诱导神经胶质细胞的激活和促炎反应的增加 三叉神经尾侧亚核内的IL-6等细胞因子，将导致 包括IL-6在内的一系列细胞事件上调神经元NMDAR 受体信号、蛋白激酶C和转录核因子-kappaB， 导致了TMJ的疼痛行为。这一假设将通过行为测试来检验。 以及药理工具，免疫组织化学，蛋白质印迹，原位杂交， 实时RT-PCR、蛋白激酶活性分析、凝胶迁移率改变分析 实现三个特定目的的酶联免疫吸附试验：1)评估 神经胶质-神经元相互作用在TMJ疼痛行为中的功能作用；2)检查 三叉神经胶质细胞的表达及其与促炎细胞因子变化的关系 由TMJ炎症诱导；以及3)研究导致TMJ炎症的细胞机制 神经胶质细胞激活后三叉神经细胞NMDAR的表达预期中的 结果可能会为治疗口腔面部疼痛提供新的治疗选择。项目叙事 非甾体抗炎药治疗口腔面部疼痛的疗效观察 三环类抗抑郁药和阿片类止痛药往往受到这些药物的限制 影响，在某些情况下，还会产生不受欢迎的长期后果。这样做的结果是 研究可能导致开发新的治疗工具来治疗通常难以治愈的疾病 和衰弱的临床口腔面部疼痛。

Pain related to temporomandibular disorders is a highly prevalent entity of orofacial pain, a debilitating chronic pain condition. Chronic orofacial pain is difficult to treat because its mechanisms remain largely unclear. Previous studies have indicated that both neuronal and non-neuronal (glial) elements play a critical role in the cellular mechanisms of pathological pain. It has been shown that peripheral nerve injury and inflammation can induce spinal glial activation and that proinflammatory cytokines can upregulate the expression of spinal N-methyl-D-aspartate receptors (NMDAR) mediated at least in part through activation of intracellular protein kinase C. Our preliminary data have demonstrated that the development of pain behavior induced by complete Freund's adjuvant injected into the temporomandibular joint (TMJ) in rats was associated with an increased expression of both interleukin-6 (IL-6) and NMDAR within the ipsilateral trigeminal subnucleus caudalis. These findings support the notion that interactions between neuronal and glial elements may also play a critical role in the cellular mechanisms of orofacial pain. In this grant, we propose to systematically examine the interaction between trigeminal glial activation and the expression of neuronal NMDAR and its role in the pathogenesis of TMJ pain behavior in rats. Our main hypothesis is that TMJ inflammation would induce glial activation and increases in proinflammatory cytokines such as IL-6 within trigeminal subnucleus caudalis, which would lead to the upregulation of neuronal NMDAR through a chain of cellular events including IL-6 receptor signaling, protein kinase C, and transcriptional nuclear factor-kappa B, contributing to TMJ pain behavior. This hypothesis will be examined using behavioral and pharmacological tools, immunohistochemistry, Western blot, in situ hybridization, real-time RT-PCR, protein kinase activity assay, electrophoretic mobility shift assay, and enzyme-linked immunosorbent assay to accomplish three specific aims: 1) to evaluate the functional role of glial-neuronal interactions in TMJ pain behavior; 2) to examine trigeminal glial expression and its relationship to proinflammatory cytokine changes induced by TMJ inflammation; and 3) to investigate a cellular mechanism contributing to the expression of trigeminal neuronal NMDAR following glial activation. The anticipated results could suggest new therapeutic options for managing orofacial pain. Project Narrative The effectiveness of treating orofacial pain with non-steroidal anti-inflammatory drugs, tricyclic antidepressants, and opioid analgesics is often limited by these drugs' side effects and, in some cases, unwanted long-term consequences. The outcome of this study could lead to the development of new therapeutic tools to treat often intractable and debilitating clinical orofacial pain.