Mechanisms of persistent temporomandibular pain

描述(申请人提供)：痛性颞下颌关节紊乱病(TMJO)累及肌肉和关节等深层组织。这些疾病的病因和病理仍不清楚。该项目致力于建立颅颌区深部疼痛的动物模型，并致力于研究三叉神经脑干感觉核团和周围结构在持续性炎症性疼痛条件下的功能。我们已经证明，咬肌炎症激活了三叉神经脊束核(VSP)、中间亚核/尾侧过渡区(Vi/Vc)以及与上颈背角相邻的较尾侧层状亚核(Vc/Ci，2)中的不同区域。此外，Vi/Vc过渡区在处理与深部组织损伤相关的口面部输入中起着重要作用。鉴于我们以前的发现和在神经元可塑性和持续性疼痛方面的最新进展，我们建议在下一个授权期通过进一步确定炎症后三叉神经处理口腔深部输入的细胞和分子机制来扩大我们的研究范围，重点放在神经元-胶质细胞的相互作用上。我们的主要假设是：1)口面部深部组织损伤通过激活胶质细胞诱导VSP的Via/c过渡区的神经元可塑性；2)Via/c胶质细胞的激活和炎性细胞因子的释放通过与神经元谷氨酸受体的相互作用影响或促进神经元的可塑性，在炎症性痛觉过敏的发生中起关键作用。这些假说将在组织损伤和可塑性的大鼠模型中通过免疫组织化学、免疫沉淀、Western印迹、行为测试和神经药理学方法的组合进行测试。目的1验证咬肌炎症后VSP通路/c区神经胶质细胞活化，并通过释放炎性细胞因子影响神经元功能的假说。目的2将确定初级传入输入是否在口面部炎症后神经胶质细胞的激活中起作用。目的3验证Via/c胶质细胞激活和相关细胞因子释放通过与神经元谷氨酸受体相互作用促进神经元可塑性的假说，并在炎性痛觉过敏的发展中发挥关键作用。这些研究将阐明神经胶质细胞-细胞因子-神经元相互作用在口面部痛觉过敏发生中的意义，并进一步确定三叉神经移行区在口面部深部损伤反应中的重要性。这些发现将促进我们对与TMJD相关的持续性疼痛机制的理解，并有助于设计新的治疗方法。

DESCRIPTION (provided by applicant): Painful temporomandibular joint disorders (TMJO) involve deep tissues including muscle and joint. The etiology and pathology of these disorders remain unclear. This project has been dedicated to developing animal models of deep pain in the craniomandibular region and pursuing studies of the function of the trigeminal brainstem sensory nuclei arid surrounding structures in persistent inflammatory pain conditions. We have demonstrated that masseter inflammation activated distinct regions in the spinal trigeminal nucleus (Vsp), the subnucleus interpolaris/caudalis transition zone (Vi/Vc) and the more caudal laminated subnucleus caudalis contiguous with the upper cervical dorsal horn (Vc/Ci,2). Further, the Vi/Vc transition zone plays an important role in the processing of orofacial inputs related to deep tissue injury. In light of our previous findings and recent developments on neuronal plasticity and persistent pain, we propose to extend our studies by further identifying the cellular and molecular mechanisms of the trigeminal processing of deep orofacial input after inflammation in the next grant period with an emphasis on neuronal-glial interactions. Our major hypotheses are that 1) orofacial deep tissue injury induces neuronal plasticity in the ViA/c transition zone of the Vsp through activation of glia and 2) ViA/c glial activation and inflammatory cytokine release affect or facilitate neuronal plasticity through interactions with neuronal glutamate receptors and play a critical role in the development of inflammatory hyperalgesia. These hypotheses will be tested in rat models of tissue injury and plasticity by a combination of approaches involving immunohistochemistry, immunoprecipitation, Western blot, behavior testing and the neuropharmacological method. Aim 1 will test the hypothesis that glial cells are activated in the ViA/c of Vsp after masseter inflammation and affect neuronal function through release of inflammatory cytokines. Aim 2 will determine whether primary afferent input plays a role in glial activation after orofacial inflammation. Aim 3 will test the hypothesis that ViA/c glial activation and associated cytokine release facilitate neuron plasticity through interaction with neuronal glutamate receptors and play a critical role in the development of inflammatory hyperalgesia. These studies will elucidate the significance of glial-cytokine-neuronal interactions in the development of orofacial hyperalgesia and further establish the importance of the trigeminal transition zone in response to orofacial deep injury. The findings will advance our understanding of the mechanisms of persistent pain associated with TMJD and facilitate the designing of new therapeutic approaches.