A novel pathway mediating the development of chronic orofacial neuropathic pain

介导慢性口面部神经病理性疼痛发展的新途径

基本信息

批准号：
8617090
负责人：
ZHIGANG David LUO
金额：
$ 72.28万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-07 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8617090
关键词：
Acute Adrenergic Agonists Afferent Neurons Aftercare Anatomic Sites Automobile Driving Behavioral Brain Stem Calcium Channel Calcium Signaling Cervical spinal cord structure Chronic Clinical Complex Confocal Microscopy Cytophotometry Data Development Electron Microscopy Ganglia Goals Hypersensitivity Injury Knockout Mice Ligands Measurement Mediating Mediator of activation protein Modeling Mus Nerve Neurons Nociception Orofacial Pain Pain Pathway interactions Patients Peripheral Peripheral nerve injury Pharmaceutical Preparations Physiological Play Posterior Horn Cells Process Protein Subunits Rattus Regulation Role Sampling Sensory Serotonin Receptors 5-HT-3 Site Slice Spinal Spinal Cord Spinal nerve structure Structure of trigeminal ganglion Synapses Synaptic Transmission Syndrome Tactile Tertiary Protein Structure Testing Therapeutic Agents Time Trigeminal System Trigeminal nerve structure Viral Viral Vector allodynia base channel blockers chronic constriction injury chronic pain craniofacial digital gabapentin interdisciplinary approach nerve injury neuronal excitability novel orofacial overexpression painful neuropathy prevent programs public health relevance receptor research study synaptogenesis thrombospondin 4 voltage

项目摘要

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 our preliminary data from a trigeminal nerve injury model and in non-orofacial pain models, we hypothesize that trigeminal nerve injury induced thrombospondin-4 (TSP4) expression in trigeminal ganglia (TG) and associated brainstem/upper cervical spinal cord (Vc/C2) that causes sensory neuron hyperexcitability, and abnormal synaptogenesis in the trigeminal complex in the spinal cord. These changes underlie the transition from trigeminal nerve injury to chronic pain development. In this proposal, we plan to identify the critical domain(s) of TSP4 in mediating behavioral hypersensitivity and spinal neuron hyperexcitability. Viral driven TSP4 expression in TG or Vc/C2, respectively, will be used to identify the site of the TSP4's action in chronic pain processing. We will perform confocal and electron microscopy to determine the extent of abnormal synaptogenesis in the nerve injury models. In addition, the influence of descending modulatory pathways and voltage-gated-calcium channels on TSP4-mediated behavioral hypersensitivity and dorsal horn neuron hyperexcitability will be studies using respective drugs. The influence of TSP4 on sensory neuron excitability, calcium channel activities, and intracellular calcium signaling will be studied in isolated neurons or intact TG from nerve injury models, or after TSP4 treatment. To determine if TSP4 induces behavioral hypersensitivity and dorsal horn neuron hyperexcitability through its interactions with its receptor, the calcium channel alpha-2-delta-1 subunit (Cava2d1), in a sensory neuron specific manner, Cava2d1 conditional knockout mice with selective deletion of Cava2d1 in subpopulation of sensory neurons will be used for these studies. The final goal of the proposed studies is to identify the peripheral and/or central mechanisms underlying TSP4-mediated transition to chronic pain states after trigeminal nerve injury.

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，缺乏特定且有效的治疗剂，因为人们对慢性口面部疼痛的细胞机制知之甚少。根据我们的初步数据，来自三叉神经损伤模型和非口交疼痛模型，我们假设三叉神经损伤诱导的三叉神经节神经节（TG）和相关的脑干/上宫颈脊髓（VC/C2）的脑干神经节（VC/C2）的构型造成感觉神经性神经性神经均匀性和均匀性和均匀性的均匀性和均匀性，并导致了造成的脑干神经节（TSP4）的表达脊髓中的复合物。这些变化是从三叉神经损伤到慢性疼痛发展的过渡。在此提案中，我们计划在介导行为超敏反应和脊髓神经元过敏性中识别TSP4的关键域。 TG或VC/C2中的病毒驱动TSP4表达将用于识别TSP4在慢性疼痛处理中作用的位点。我们将执行共聚焦和电子显微镜，以确定神经损伤模型中突触异常的程度。此外，下降调节途径和电压门控钙通道对TSP4介导的行为超敏反应和背角神经元过敏性的影响将是使用各自的药物进行研究。 TSP4对孤立的神经元或神经损伤模型的完整TG或TSP4处理后，将研究TSP4对感觉神经元兴奋性，钙通道活性和细胞内钙信号的影响。 To determine if TSP4 induces behavioral hypersensitivity and dorsal horn neuron hyperexcitability through its interactions with its receptor, the calcium channel alpha-2-delta-1 subunit (Cava2d1), in a sensory neuron specific manner, Cava2d1 conditional knockout mice with selective deletion of Cava2d1 in subpopulation of sensory neurons will be used for these studies.拟议的研究的最终目标是确定TSP4介导的三叉神经损伤后TSP4介导的向慢性疼痛状态过渡的外围和/或中心机制。