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疾病（TMD），并且主要是育龄期的女性。尽管超过60%的TMD患者以下颌肌肉疼痛为主要主诉，但研究并没有提供很多关于这些患者持续肌肉疼痛的生物学基础的见解。在过去的十年中，神经胶质细胞在神经元-神经胶质信号传导和调节持续性疼痛中的作用引起了人们的关注。然而，关于神经胶质细胞参与口面部疼痛的研究很少，这些研究主要集中在三叉神经损伤和神经性疼痛或牙源性疼痛上。我们在老鼠身上建立了一个模型，反复向咬肌注射酸性盐水，造成持续的下颌肌肉疼痛，而不会对肌肉造成明显损害。在初步数据中，我们提出了通过该模型获得的证据，以支持神经胶质在介导和/或维持持续性颚肌疼痛中的作用。基于这些数据，我们提出以下假设：单侧反复注射酸性生理盐水后，咬肌神经胶质细胞的激活是引发三叉神经系统性别特异性、双侧初级传入神经元神经可塑性改变的一系列事件的一部分，并导致持续的颚肌疼痛。为了验证这一假设，我们提出了三个具体目标。(1)三叉神经节内胶质细胞和感觉核复合体的时空激活与三叉神经节神经肽表达的神经可塑性变化和下颌肌肉疼痛的行为测量相关；(2)。确定二甲胺四环素和丙烯茶碱对三叉神经感觉核复合体内小胶质细胞和星形胶质细胞激活的影响，对三叉神经节神经肽表达的神经可塑性变化的影响，以及对颌骨肌肉疼痛行为测量的影响；(3)三叉神经感觉核复合体内促炎细胞因子和金属蛋白酶的时空表达与神经胶质活化、三叉神经节神经肽表达的神经可塑性变化和颚肌疼痛的相关性。这些研究的结果应该为三叉神经初级传入神经和节段细胞对引起持续性颚肌疼痛的轻度重复性疼痛刺激的反应以及这些反应的性别差异提供新的数据。本R21申请的研究将为进一步研究胶质细胞在咀嚼肌疼痛中的作用奠定基础。未来的研究将包括研究性别差异的基础，咀嚼肌损伤后神经胶质细胞激活的机制，以及测试治疗干预的潜在靶点。

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.