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.

颞下颌关节疾病（TMD）包括一个疾病的家族，这些疾病会出现疼痛颞下颌关节（TMJ）和咀嚼肌肉。 TMD是最常见的非牙科口服疼痛，但是对潜在的生理和细胞机制知之甚少。痛苦的TMD在女性中的患病率高于男性，而在疼痛强度的明显迹象和疼痛强度的等级。促炎水平升高的报告非稳定性关节炎TMD患者的滑液样品中的分子表明低级TMJ 炎症是TMD的常见特征，但可能没有直接滑液未检测到采样。中心假设是低级TMJ炎症素三叉神经节（TG）神经元和诱导持续性痛觉过敏，被视为改变的响应特性 Spinomedullary（VC/C1-2）神经元和下颌肌肉活动。我们提出了嘌呤能（P2）受体和神经胶质细胞激活在TMJ启动中起关键作用，并在A中维持痛风刺激和性依赖性方式。该项目的长期目标是确定是否干扰神经元和神经胶质上的特定P2受体是治疗靶标管理人类的TMJ伤害感和TMD疼痛。定量感觉测试（QST）协议的开发是为了评估对TMJ响应神经元的治疗效果。汇合线使用电生理，行为，分子和解剖方法的证据三个问题：1）是短暂的低级TMJ炎症，足以引起持续的变化 TMJ响应性TG和VC/C1-2神经元的特性，下颌肌肉活动和下颌运动； 2）嘌呤能受体在TMJ启动中的作用是什么？ 3）神经胶质细胞在维持TMJ伤害感受？与以前的研究不同，该模型使用一次接触在男性和雌性大鼠和夫妻对识别的TMJ响应神经元的反应侮辱表型。 AIM 1在TMJ引发条件下建立QST协议，并确定启动对TG神经元，VC/C1-2神经元特性的影响，对MMEMG活性和下巴的影响移动。 AIM 2确定密切相关的P2受体的表达和蛋白质水平具有TG和VC/C1-2神经元以及这些受体在神经活动中的作用，下颌肌肉活性和下巴运动。 AIM 3确定P2受体的表达和蛋白质水平与VC/C1-2神经元的TG和小胶质细胞中的卫星神经胶质有关以及神经胶质细胞的作用 TMJ痛觉过敏中的激活。神经元 - 胶体交流是持续的关键特征在其他模型中，炎症性痛觉过敏，但在TMJ伤害感受下仍然定义很差。什么时候结合神经记录和下颌肌肉反射，抑制P2受体密切相关使用神经元或神经胶质，小胶质细胞抑制炎性体形成和胶质特异性的阻断药理和干扰RNA方法的分泌产品将增强了解持续性TMJ痛觉过敏的神经机制。