Target Genes of Inflammatory Temporomandibular Pain

描述（由申请人提供）：慢性疼痛是一种常见的临床综合征，由于对慢性疼痛的细胞机制知之甚少，缺乏特异性和有效的治疗药物。来自实验动物模型的临床观察和药理学数据表明，不同病因引起的慢性疼痛状态，包括口面部疼痛，具有不同的生化和药理学特征，提示不同疼痛状态的特定机制。大量实验数据表明，感觉神经元和脊髓相关部分中特定基因表达的改变可能在神经可塑性中发挥特殊作用，从而导致特定的疼痛状态。我们推测，三叉神经节、尾侧亚核和上颈脊髓中特定基因及其相关通路的表达变化可能与颞下颌关节深部炎症后慢性口面部疼痛状态的发生有关。为了验证这一假设，我们计划使用Affymetrix基因芯片检测三叉神经节（包含感觉神经元）和相关的尾侧亚核/脊髓节段的基因表达谱，这些基因表达谱在有或没有深层颞下颌关节炎症的雄性大鼠中。我们将确定那些在炎症后具有特定调控的基因，这些基因也与慢性疼痛的时间发展有关。被识别的基因或被识别的基因与其他基因之间的相互作用所强调的潜在途径将使用计算机辅助数据挖掘进行研究。基因芯片分析中选择性基因的表达将通过实时PCR、原位杂交和Western blots等替代技术进行验证。选择性基因对慢性疼痛发展的潜在贡献将在未来的研究中通过药理学和分子生物学方法来确定。这项研究的结果应该提供三叉-脊髓复合体对口面部深层组织炎症的基因组反应的全局视图。在这种情况下识别特异性调控的基因和途径将为进一步研究颞下颌关节感染后慢性疼痛状态的分子机制提供一个集中的目标基因库。

DESCRIPTION (provided by applicant): Chronic pain is a common clinical syndrome lacking specific and effective therapeutic agents due to the fact that cellular mechanisms of chronic pain are poorly understood. Clinical observations and pharmacological data from experimental animal models have indicated that chronic pain states, including that of orofacial pain, derived from different etiologies have distinct biochemical and pharmacological characteristics, suggesting specific mechanisms for different pain states. A large body of experimental data indicates that altered expression of selected genes in sensory neurons and associated segments of spinal cord may play a special role in neuroplasticity contributing to a specific pain state. We hypothesize that changes in expression of specific genes and their related pathways in trigeminal ganglia, subnucleus caudalis and upper cervical spinal cord may be responsible for the development of chronic orofacial pain states after deep temporomandibular joint inflammation. To test this hypothesis, we plan to use Affymetrix gene chips to examine the gene expression profiles in trigeminal ganglia (containing sensory neurons) and the associated subnucleus caudalis/spinal cord segments of male rats with or without deep temporomandibular joint inflammation. We will identify those genes with specific regulation post inflammation that are also associated with the temporal development of chronic pain. Potential pathways underlined by interactions of identified genes or between identified genes and other genes will be studied using computer assisted data mining. Expression of selective genes from the gene chip analysis will be validated with alternative techniques including real-time PCR, in situ hybridization and Western blots. The potential contribution of selective genes to chronic pain development will be determined by pharmacological, and molecular biology approaches in future studies. The outcome of this study should provide a global view of genomic responses in the trigeminal-spinal complex to orofacial deep-tissue inflammation. Identification of specifically regulated genes and pathways under this condition will provide a focused target gene pool for further investigations of molecular mechanisms underlying chronic pain states post temporomandibular joint infection.