Mechanisms of persistent temporomandibular pain

描述（由申请人提供）：疼痛性颞下颌关节疾病（TMJO）涉及深层组织，包括肌肉和关节。这些疾病的病因和病理尚不清楚。本项目致力于开发颅下颌骨深度疼痛动物模型，研究三叉脑干感觉核及其周围结构在持续性炎症性疼痛中的功能。我们已经证明，咬肌炎症激活了三叉脊髓核（Vsp）、内插亚核/尾侧过渡区（Vi/Vc）和与颈上背角相邻的更尾端层状尾侧亚核的不同区域（Vc/Ci,2）。此外，Vi/Vc过渡区在与深部组织损伤相关的口面输入处理中起重要作用。根据我们之前的研究结果和最近在神经元可塑性和持续性疼痛方面的进展，我们建议在下一个资助期进一步确定炎症后三叉神经处理深口面输入的细胞和分子机制，重点研究神经元-神经胶质的相互作用。我们的主要假设是：1)口面部深层组织损伤通过神经胶质的激活诱导Vsp的ViA/c过渡区神经元的可塑性；2)ViA/c神经胶质的激活和炎症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，并在炎性痛觉过敏的发生中发挥关键作用。这些假设将在大鼠组织损伤和可塑性模型中进行验证，方法包括免疫组织化学、免疫沉淀、免疫印迹、行为测试和神经药理学方法。Aim 1将验证咬肌炎症后Vsp ViA/c中胶质细胞被激活，并通过释放炎症细胞因子影响神经元功能的假设。目的2将确定初级传入输入是否在口面部炎症后的神经胶质激活中起作用。Aim 3将验证ViA/c胶质的激活和相关细胞因子的释放通过与神经元谷氨酸受体的相互作用促进神经元的可塑性，并在炎症性痛觉过敏的发生中发挥关键作用。这些研究将阐明神经胶质-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过渡区在口面部深度损伤反应中的重要性。这些发现将促进我们对颞下颌关节痛相关持续性疼痛机制的理解，并促进新的治疗方法的设计。

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.