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Role of purinergic signaling and glia in TMJ nociception

嘌呤能信号和神经胶质细胞在 TMJ 伤害感受中的作用

基本信息

批准号：
9507148
负责人：
DAVID A BEREITER
金额：
$ 47.91万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9507148
关键词：
Address Affect Anatomy Animals Arthritis Behavior Behavioral Cells Communication Coupled Couples Craniofacial Pain Data Dose Electrophysiology (science)Etiology Exposure to Family Female Food Freund&apos s Adjuvant Goals High Prevalence Human Hyperalgesia Hypertrophy Inflammasome Inflammation Inflammatory Injection of therapeutic agent Injury Jaw Maintenance Mastication Masticatory muscles Methods Microglia Modeling Molecular Muscle Neuroglia Neurons Nociception Orofacial Pain P2X-receptor Pain Pain intensity Pathway interactions Patients Peripheral Pharmacology Phenotype Physiological Play Property Proteins Protocols documentation Purinergic P2 Receptors Purinoceptor RNA Interference Rattus Receptor Cell Receptor Signaling Reflex action Reporting Research Design Role Sampling Sensory Signal Transduction Stimulus Structure of trigeminal ganglion Study models Synovial Fluid Temporomandibular Joint Temporomandibular Joint Disorders Temporomandibular joint disorder pain Test Result Testing Time Tissues Woman awake base extracellular glial activation jaw movement male men nerve injury neuromechanism neuronal circuitry pressure receptor relating to nervous system response sex somatosensory therapeutic target tool treatment effect

项目摘要

Temporomandibular joint disorders (TMD) include a family of conditions that present with pain in the temporomandibular joint (TMJ) and muscles of mastication. TMD is the most common non-dental orofacial pain, yet the underlying physiological and cellular mechanisms are poorly understood. Painful TMD is notable for a higher prevalence in women than men, and poor correlation between overt signs of injury and ratings of pain intensity. Reports of elevated levels of pro-inflammatory molecules in synovial fluid samples of non-osteoarthritic TMD patients suggest that low grade TMJ inflammation is a common feature of TMD, but likely goes undetected without direct synovial fluid sampling. The central hypothesis is that low grade TMJ inflammation primes trigeminal ganglion (TG) neurons and induces persistent hyperalgesia seen as altered response properties of spinomedullary (Vc/C1-2) neurons and jaw muscle activity. We propose that purinergic (P2) receptors and glial cell activation play key roles in TMJ priming and maintain hyperalgesia in a stimulus- and sex-dependent manner. The long-term goal of this project is to determine if interference with specific P2 receptors on neurons and glia are therapeutic targets for managing TMJ nociception and TMD pain in humans. A quantitative sensory testing (QST) protocol is developed to assess treatment effects on TMJ-responsive neurons. Converging lines of evidence using electrophysiological, behavioral, molecular, and anatomical approaches address three issues: 1) is transient low grade TMJ inflammation sufficient to cause persistent changes in the properties of TMJ-responsive TG and Vc/C1-2 neurons, jaw muscle activity and jaw movement; 2) what is the role of purinergic receptors in TMJ priming; and 3) what is the role of glial cells in maintenance of TMJ nociception? Unlike previous studies, this model uses a single exposure to a non-tissue damaging inflammatory agent to prime TMJ-responsive neuronal circuits in male and female rats and couples this insult to the responses of TMJ-responsive neurons with identified phenotypes. Aim 1 establishes the QST protocol under TMJ primed conditions and determines the effects of priming on the properties of TG neurons, Vc/C1-2 neurons, on MMemg activity and jaw movement. Aim 2 determines the expression and protein levels of P2 receptors closely associated with TG and Vc/C1-2 neurons and the role of those receptors on neural activity, jaw muscle activity and jaw movement. Aim 3 determines the expression and protein levels of P2 receptors closely associated with satellite glia in TG and microglia at Vc/C1-2 neurons and the role of glial cell activation in TMJ hyperalgesia. Neuron-glia communication is a critical feature of persistent inflammatory hyperalgesia in other models, but remains poorly defined in TMJ nociception. When coupled with neural recording and jaw muscle reflexes, inhibition of P2 receptors closely associated with neurons or glia, inhibition of inflammasome formation by microglia and blockade of glia-specific secretory products by pharmacological and interference RNA approaches will enhance the understanding of neural mechanisms underlying persistent TMJ hyperalgesia.

颞下颌关节紊乱病（TMD）包括一个家族的条件，目前与疼痛的颞下颌关节（TMJ）和咀嚼肌。TMD是最常见的非牙科疾病口面疼痛，但基本的生理和细胞机制知之甚少。值得注意的是，疼痛性TMD在女性中的患病率高于男性，损伤的明显迹象和疼痛强度的评级。报告称促炎因子水平升高非骨关节炎TMD患者滑液样本中的分子表明，炎症是TMD的一个共同特征，但在没有直接滑液的情况下可能无法被发现取样.中心假设是，低度颞下颌关节炎症引发三叉神经节 (TG)神经元和诱导持续性痛觉过敏被视为改变的反应特性，脊髓（Vc/C1-2）神经元和颌肌活动。我们建议嘌呤能（P2）受体和胶质细胞活化在颞下颌关节启动和维持痛觉过敏中起关键作用，刺激和性别依赖的方式。该项目的长期目标是确定干扰神经元和神经胶质细胞上的特异性P2受体是管理人类的颞下颌关节伤害感受和TMD疼痛。定量感觉测试（QST）开发方案以评估对TMJ反应性神经元的治疗效果。汇聚的线条使用电生理学、行为学、分子学和解剖学方法的证据，三个问题：1）短暂的低度TMJ炎症是否足以引起持续的变化， TMJ反应性TG和Vc/C1-2神经元的特性、颌肌活动和颌运动; 2）嘌呤能受体在颞下颌关节启动中的作用是什么; 3）胶质细胞在颞下颌关节启动中的作用是什么？ TMJ伤害感受的维持？与以前的研究不同，该模型使用单一暴露于非组织损伤性炎性剂，以引发男性和女性的TMJ反应神经元回路，雌性大鼠，并将这种损伤与TMJ反应神经元的反应结合起来，表型目的1建立TMJ预处理条件下的QST协议，并确定预激对TG神经元、Vc/C1-2神经元特性、MMemg活性和下颌骨的影响运动目的2确定与P2受体的表达和蛋白水平密切相关，与TG和Vc/C1-2神经元以及这些受体对神经活动、颌肌活动的作用和下颌运动。目的3密切测定P2受体的表达和蛋白水平与TG中的卫星胶质细胞和Vc/C1-2神经元中的小胶质细胞相关，激活TMJ痛觉过敏。神经元-胶质细胞通信是持续性神经元-胶质细胞通信的一个重要特征。炎性痛觉过敏，但在TMJ伤害性感受中仍然定义不清。当 P2受体抑制与神经记录和颌肌反射密切相关与神经元或神经胶质细胞，抑制炎性小体形成的小胶质细胞和阻断胶质细胞特异性通过药理学和干扰RNA方法产生的分泌产物将增强持续性颞下颌关节痛觉过敏的神经机制的理解。