Glial Response in a Jaw Muscle Pain Model

描述(由申请人提供)：大约12%的美国人口患有颞下颌关节紊乱病(TMD)，主要是育龄妇女。虽然超过60%的TMD患者以下颌肌肉疼痛为主要症状，但研究尚未对这些患者发现的持续性肌肉疼痛的生物学基础提供太多见解。在过去的十年里，神经胶质细胞在神经元-神经胶质细胞信号和调节持续性疼痛中的作用引起了人们的关注。然而，只有少数关于神经胶质细胞参与口面部疼痛的研究，这些研究集中在三叉神经损伤和神经病理性疼痛或牙源性疼痛上。我们已经在小鼠身上建立了一种模型，通过反复向咬肌注射酸性盐水，在不对肌肉造成明显损害的情况下，导致持续性的颌部肌肉疼痛。在初步数据中，我们提出了用该模型获得的证据，支持神经胶质在调节和/或维持持续性颌骨肌肉疼痛中的作用。基于这一数据，我们提出了以下假设：单侧重复酸性生理盐水注射到咬肌后，胶质细胞的激活是一系列事件的一部分，这些事件导致三叉神经系统中具有性别特异性的双侧初级传入神经元神经可塑性改变，并导致持续性颌肌疼痛。为了检验这一假设，我们提出了三个具体目标。(1)三叉神经节和感觉核复合体内神经胶质细胞的时空激活与三叉神经节神经肽表达的神经塑性变化以及颌肌疼痛的行为指标之间存在相关性；研究目的：(1)确定米诺环素和普罗布林对三叉神经感觉核复合体内小胶质细胞和星形胶质细胞的激活、三叉神经节神经肽表达的神经塑性变化和颌肌疼痛的行为指标的影响；以及(3)三叉神经节和颌肌疼痛行为指标中促炎细胞因子和金属蛋白酶的时空表达与胶质细胞激活、三叉神经节和颌肌痛神经肽表达的神经塑性变化之间的关联。这些研究的结果应该提供关于三叉神经初级传入和节段性细胞对轻度、重复的疼痛刺激的反应的新数据，这些刺激会导致持续性的颌骨肌肉疼痛，以及这些反应的性别差异。这项在R21应用中提出的研究将为未来研究神经胶质细胞在咀嚼肌疼痛中的作用提供基础。未来的研究将包括调查性别差异的基础，咀嚼肌损伤后神经胶质细胞激活的机制，以及测试潜在的治疗干预靶点。

DESCRIPTION (provided by applicant): Approximately 12% of the US population have temporomandibular disorders (TMD) and are predominately women in their childbearing years. Although greater than 60% of those affected by TMD have jaw muscle pain as their main complaint, research has not provided much insight into the biological basis of the persistent muscle pain found in these patients. In the past decade, the role of glial cells has gained attention for their role in neuron-glia signaling and in modulating persistent pain. However, there are only a few studies of glial cell involvement in orofacial pain and these have focused on trigeminal nerve injury and on neuropathic pain or odontogenic pain. We have developed a model in the mouse using repetitive acidic saline injections into the masseter muscle to cause persistent jaw muscle pain without significant damage to the muscle. In preliminary data, we present evidence obtained with this model in support of a glial role in mediating and/or maintaining persistent jaw muscle pain. Based on this data we propose the following hypothesis: Glial cell activation after a unilateral repetitive acidic saline injection into the masseter muscle is part of a cascade of events that elicit gender-specific, bilateral primary afferent neuron neuroplastic changes in the trigeminal system and result in persistent jaw muscle pain. To test this hypothesis, we propose three specific aims. (1) Correlate the temporal and spatial activation of glia within the trigeminal ganglion and sensory nuclear complex with neuroplastic changes in neuropeptide expression in the trigeminal ganglia and with behavioral measures of jaw muscle pain; (2). Determine the effects of minocycline and propentofylline on the activation of microglia and astrocytes within the trigeminal sensory nuclear complex, on neuroplastic changes in neuropeptide expression in the trigeminal ganglia and on behavioral measures of jaw muscle pain; and (3) Correlate the temporal and spatial expression of pro-inflammatory cytokines and metalloproteinases within the trigeminal sensory nuclear complex with glial activation, neuroplastic changes in neuropeptide expression in the trigeminal ganglia and jaw muscle pain. The results of these studies should provide new data on trigeminal primary afferent and segmental cellular responses to mild, repetitive pain stimuli which induce a persistent jaw muscle pain and on gender-based differences in these responses. The research proposed in this R21 application will provide a foundation for future investigations into the role of glial cells in masticatory muscle pain. Future studies will include investigation into the basis for gender differences, mechanisms of glial cell activation after masticatory muscle injury and testing of potential targets for therapeutic intervention.