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：
8705625
负责人：
ZHIGANG David LUO
金额：
$ 12.38万
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/8705625
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 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（申请人提供）：慢性口面部疼痛是一种常见的临床综合征，由于人们对慢性口面部疼痛的细胞机制知之甚少，缺乏特异性和有效的治疗药物。根据我们在三叉神经损伤模型和非口面疼痛模型中的初步数据，我们假设三叉神经损伤诱导三叉神经节（TG）和相关脑干/上颈脊髓（Vc/ C2) 导致感觉神经元过度兴奋，以及脊髓三叉神经复合体突触发生异常。这些变化是从三叉神经损伤向慢性疼痛发展转变的基础。在本提案中，我们计划确定 TSP4 在介导行为超敏反应和脊髓神经元过度兴奋中的关键域。病毒驱动的 TSP4 在 TG 或 Vc/C2 中的表达将分别用于识别 TSP4 在慢性疼痛处理中的作用位点。我们将进行共聚焦和电子显微镜来确定神经损伤模型中异常突触发生的程度。此外，将使用相应的药物研究下行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度兴奋的影响。 TSP4 对感觉神经元兴奋性、钙通道活性和细胞内钙信号传导的影响将在来自神经损伤模型的分离神经元或完整 TG 中或在 TSP4 治疗后进行研究。为了确定 TSP4 是否通过其受体、钙通道 α-2-δ-1 亚基 (Cava2d1) 相互作用，以感觉神经元特异性方式诱导行为超敏反应和背角神经元过度兴奋，选择性删除 Cava2d1 的 Cava2d1 条件敲除小鼠感觉神经元亚群将用于这些研究。拟议研究的最终目标是确定三叉神经损伤后 TSP4 介导的慢性疼痛状态转变的周围和/或中枢机制。