Glial Response in a Jaw Muscle Pain Model

下颌肌肉疼痛模型中的神经胶质反应

• 批准号: 8070507
• 负责人: JOYCE A MORRIS-WIMAN
• 金额: $ 6.25万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-07 至 2012-06-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8070507
• 关键词: Affect; Afferent Neurons; Animal Model; Astrocytes; Attention; Behavioral; Bilateral; Biological; Cells; Characteristics; Chronic; Complex; Data; Event; Foundations; Future; Gender; Glial Fibrillary Acidic Protein; ITGAM gene; Inflammation; Inflammatory; Injection of therapeutic agent; Injury; Interstitial Collagenase; Investigation; Jaw; Knowledge; Lead; Masseter Muscle; Masticatory muscles; Matrix Metalloproteinases; Mediating; Metalloproteases; Microglia; Minocycline; Modeling; Mus; Muscle; Myalgia; Necrosis; Neuroglia; Neurons; Neuropeptides; Nuclear; Orofacial Pain; Pain; Patients; Persistent pain; Population; Reagent; Research; Role; Saline; Sensory; Sex Characteristics; Signal Transduction; Stimulus; Structure of trigeminal ganglion; Study models; Temporomandibular Joint Disorders; Testing; Therapeutic Intervention; Tissues; Trigeminal System; Trigeminal nerve structure; Western Blotting; Woman; base; behavior measurement; child bearing; cytokine; design; insight; nerve injury; painful neuropathy; prevent; propentofylline; public health relevance; response; therapeutic target

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.

描述（由申请人提供）：大约 12% 的美国人患有颞下颌关节紊乱病 (TMD)，并且主要是育龄妇女。尽管超过 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持续性肌肉疼痛的生物学基础提供深入的了解。在过去的十年中，神经胶质细胞因其在神经元-胶质细胞信号传导和调节持续性疼痛中的作用而受到关注。然而，关于神经胶质细胞参与口面部疼痛的研究很少，这些研究都集中在三叉神经损伤和神经性疼痛或牙源性疼痛上。我们开发了一种小鼠模型，通过向咬肌重复注射酸性盐水来引起持续的下颌肌肉疼痛，而不会对肌肉造成明显损伤。在初步数据中，我们提供了通过该模型获得的证据，支持神经胶质在介导和/或维持持续性下颌肌肉疼痛中的作用。基于这些数据，我们提出以下假设：单侧重复向咬肌注射酸性盐水后，胶质细胞激活是一系列事件的一部分，这些事件引起三叉神经系统中性别特异性、双侧初级传入神经元的神经塑性变化，并导致持续性下颌肌肉疼痛。为了检验这一假设，我们提出了三个具体目标。 (1) 将三叉神经节和感觉核复合体内神经胶质细胞的时间和空间激活与三叉神经节神经肽表达的神经塑性变化以及下颌肌肉疼痛的行为测量相关联； （2）。确定米诺环素和丙戊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活化、三叉神经节神经肽表达的神经可塑性变化以及下颌肌肉疼痛行为测量的影响； (3)将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间和空间表达与神经胶质活化、三叉神经节中神经肽表达的神经塑性变化以及颌肌疼痛相关联。这些研究的结果应该提供关于三叉神经初级传入和节段细胞对轻微、重复性疼痛刺激的反应的新数据，这些刺激会引起持续的下颌肌肉疼痛，以及这些反应中基于性别的差异。 R21 申请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奠定基础。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治疗干预的潜在目标。