咬合干扰通过增强前扣带回兴奋性突触传递介导慢性咀嚼肌疼痛的机制研究

Occlusal interference induced chronic masticatory muscle pain (CMMP) is intractable and severely threatening the physical and mental welling-being of patients. The existing domestic and foreign investigations on mechanisms of occlusal interference induced CMMP mainly focus on the subcortical neural structures. The role of cortex involved in this condition has not been clarified. Studies have shown synaptic plasticity in anterior cingulate cortex (ACC) mediates chronic pain state. Glutamate receptors play key roles in excitatory synaptic transmission and plasticity in ACC. In pilot studies, we have shown 14 d occlusal interference enhances excitatory synaptic transmission in ACC in rats, and inhibiting glutamate receptor reverses this effect. This study will further investigate whether occlusal interference induces CMMP through enhancing excitatory synaptic transmission in ACC. The established rat model of occlusal interference will be used to observe the effects of different durations of occlusal interference on the synaptic density, glutamate receptor expression and synaptic strength in ACC, investigate the influences of up- or down-regulating excitatory synaptic strength in ACC on masticatory muscle pain threshold, and analyze the reverse or blocking action of inhibiting or silencing glutamate receptor in ACC on occlusal interference induced CMMP. This study will clarify the mechanism of synaptic plasticity in ACC underlying occlusal interference induced CMMP, demonstrate the role of glutamate receptor in ACC in this pathological condition and aid the development of novel clinical strategy against CMMP.

咬合干扰致慢性咀嚼肌疼痛难以治愈，严重影响患者身心健康。目前国内外相关机制研究多涉及大脑皮质以下神经结构，尚未阐明大脑皮质在该病理过程中的作用。研究表明前扣带回突触可塑性是介导慢性疼痛的重要皮质机制；谷氨酸受体在前扣带回兴奋性突触传递和可塑性中起关键作用。申请人通过预实验发现，14天咬合干扰可增强大鼠前扣带回兴奋性突触传递；抑制谷氨酸受体可逆转该效应。本项目拟进一步研究咬合干扰是否通过增强前扣带回兴奋性突触传递介导慢性咀嚼肌疼痛：利用已建立的咬合干扰大鼠模型，观察不同时间咬合干扰对前扣带回突触密度、谷氨酸受体表达和传递强度的影响，研究上调及下调前扣带回兴奋性突触传递对咀嚼肌疼痛阈值的影响，分析抑制或沉默前扣带回谷氨酸受体对咬合干扰致慢性咀嚼肌疼痛的逆转或阻断效果。本项目将阐明咬合干扰致慢性咀嚼肌疼痛的前扣带回突触可塑性机制，揭示前扣带回谷氨酸受体在该病理过程中的作用，为临床治疗提供新思路。

大脑皮质在咬合干扰致慢性咀嚼肌疼痛中的作用尚未阐明。研究表明谷氨酸受体介导的前扣带回突触可塑性变化是慢性疼痛重要的皮质机制。本研究基于实验性咬合干扰动物模型，结合神经电生理、分子生物学、动物行为学等方法，探索咬合干扰致慢性咀嚼肌疼痛的前扣带回突触机制。研究发现：（1）咬合干扰14d大鼠前扣带回突触后结构蛋白PSD95及NMDA受体亚单位NR2B表达升高；（2）咬合干扰14d及21d大鼠丘脑-前扣带回突触传递显著增强；（3）正常大鼠前扣带回突触存在一定可塑性，而咬合干扰14d大鼠前扣带回突触可塑性受到抑制；（4）抑制前扣带回AMPA受体可以下调对照组及咬合干扰大鼠前扣带回突触传递；（5）抑制前扣带回AMPA受体可提高大鼠咀嚼肌机械反应阈值；（6）抑制前扣带回NR2B可以逆转咬合干扰致大鼠前扣带回突触传递增强，但不影响正常大鼠前扣带回突触传递；（7）抑制前扣带回NR2B可以缓解咬合干扰大鼠咀嚼肌痛敏，但不影响正常大鼠口颌面痛觉感受。本研究揭示了前扣带回突触可塑性变化参与咬合干扰致慢性咀嚼肌疼痛的机制，证明抑制前扣带回NR2B可以特异性缓解咬合干扰致慢性咀嚼肌疼痛，可以为临床治疗慢性咀嚼肌疼痛提供新思路。

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