Defining Target Contribution To Orofacial Pain By Antisense Oligonucleotides

描述（由申请人提供）：慢性口面疼痛是一种常见的临床综合征，由于对慢性口面疼痛的细胞机制知之甚少，因此缺乏特异性和有效的治疗药物。基于体外生物化学研究和非口面神经损伤诱导的慢性疼痛模型的数据，我们假设三叉神经损伤导致三叉神经节和相关脑干和上颈脊髓中钙通道α-2-δ-1亚基（Cava 2d 1）和血小板反应蛋白-4（TSP 4）的表达改变，其通过促进突触发生在神经病理性疼痛的发展中发挥功能性作用。在本竞争性修订版中，我们计划测试纳米颗粒封装的针对Cava 2d 1和TSP 4 mRNA的反义寡核苷酸在逆转Cava 2d 1和/或TSP诱导损伤和阻断口面神经性疼痛发展方面是否分别比游离反义寡核苷酸更有效。此外，我们计划使用电生理记录技术来确定是否损伤诱导的这些蛋白质的表达在改变脊髓突触传递中发挥重要作用。这些研究的完成将使我们能够扩大原始提案的范围，并扩大原始项目的目标，以加快科学研究的克里思，确定新的目标和途径，开发用于口面疼痛管理的新药物。 公共卫生相关性：神经损伤引起的慢性口面神经痛（orofacial neuropathic pain，ONS）是一种常见的临床综合征，由于其细胞机制尚不清楚，缺乏特异有效的治疗药物。来自体外生物化学研究和非口面神经损伤疼痛模型的现有数据支持三叉神经损伤可能导致三叉神经节和相关脑干和上颈脊髓中钙通道α-2-δ-1亚基（Cava 2d 1）和血小板反应蛋白-4（TSP 4）的表达改变，其通过新机制在口面疼痛发展中发挥功能性作用。在这个探索性的建议中，我们计划测试三叉神经损伤是否会导致Cava 2d 1和TSP 4的表达改变，这有助于口面神经性疼痛模型中神经性疼痛的发生和/或维持。我们建议在母提案中使用生化和行为药理学方法来检验这一假设。在这项修订建议中，我们计划扩大原来建议的范围，加入两项新目标。一种是使用新的纳米技术来递送具有治疗潜力的药物，以阻断损伤引起的口面部疼痛和靶向基因调控。第二个是使用电生理学记录来观察损伤引起的变化是否会导致脊髓中突触神经传递的改变，从而导致口面疼痛。这项研究的完成将使我们能够扩大母提案的范围，加快这一研究领域的科学研究克里思，并发现慢性疼痛疾病的新药靶点。

DESCRIPTION (provided by applicant): Chronic orofacial pain is a common clinical syndrome lacking specific and effective therapeutic agents due to the fact that cellular mechanisms of chronic orofacial pain are poorly understood. Based on data from in vitro biochemical studies and non-orofacial, nerve injury-induced chronic pain models, we hypothesize that trigeminal nerve injury leads to altered expression of the calcium channel alpha-2-delta-1 subunit (Cava2d1) and thrombospondin-4 (TSP4) in trigeminal ganglia and associated brainstem and upper cervical spinal cord that plays a functional role in the development of neuropathic pain by promoting synaptogenesis. In this Competitive Revision, we plan to test if nanoparticle encapsulated antisense oligonucleotides against the Cava2d1 and TSP4 mRNA better efficacy than free antisense oligonucleotides in reversing Cava2d1 and/or TSP induction by injury and blocking orofacial neuropathic pain development, respectively. In addition, we plan to use electrophysiology recording techniques to define if injury-induced expression of these proteins play an important role in altering spinal synaptic transmission. Completion of these studies will allow us to expand the scope of the original proposal and to expand the goals of the original project to accelerate the tempo of scientific research in identifying new targets and pathways for the development of new medications for orofacial pain management. PUBLIC HEALTH RELEVANCE: Chronic orofacial pain derived from nerve injury, or orofacial neuropathic pain, is a common clinical syndrome lacking specific and effective therapeutic agents due to the fact that its cellular mechanisms are poorly understood. Existing data from in vitro biochemical studies and non-orofacial nerve injury pain models support that trigeminal nerve injury may lead to altered expression of the calcium channel alpha-2-delta-1 subunit (Cava2d1) and thrombospondin-4 (TSP4) in trigeminal ganglia and associated brainstem and upper cervical spinal cord that plays a functional role in orofacial pain development through a novel mechanism. In this exploratory proposal, we plan to test if trigeminal nerve injury causes altered expression of the Cava2d1 and TSP4 that contributes to the genesis and/or maintenance of neuropathic pain in an orofacial neuropathic pain model. We proposed to test this hypothesis using biochemical and behavioral pharmacology approaches in the parent proposal. In this revision proposal, we plan to expand the scope of the original proposal to include two new aims. One is to use novel nanotechnology in delivering agents with therapeutic potential to block injury-induced orofacial pain and target gene regulation. Second one is to use electrophysiology recording to see if injury-induced changes cause alterations in synaptic neurotransmission in the spinal cord that leads to orofacial pain. Completion of this study will allow us to expand the scope of the parent proposal and accelerate the tempo of scientific research in this under investigated field and the discovery of new drug targets for chronic pain disorders.