SELECTIVE BLOCKADE OF TTX-R SODIUM CHANNELS FOR PAIN

选择性阻断 TTX-R 钠通道以缓解疼痛

• 批准号: 6188129
• 负责人: JOSEPHINE LAI
• 金额: $ 22.49万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-08 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6188129
• 关键词: antisense nucleic acid; behavior test; disease /disorder model; dorsal root; gene expression; hyperalgesia; immunocytochemistry; in situ hybridization; ion channel blocker; laboratory rat; nerve injury; neurofilament; neuropathology; neuropharmacology; pain; protein localization; sodium channel; spinal ganglion; tetrodotoxin

DESCRIPTION: (adapted from applicant's abstract) Pain associated with nerve injury (i.e., neuropathic pain) has been hypothesized to be related to increased afferent discharge associated with ectopic foci occurring in the injured nerve. One mechanism which may induce abnormal spontaneous afferent activity is the expression of a TTX-resistant sodium channel (called PN3 or SNS) which has recently been cloned and localized selectively to cells in the dorsal root ganglia (DRG). The applicant proposes to test the hypothesis that a) expression of PN3/SNS is a primary event that underlies the consequences of nerve-injury, including tactile allodynia and hyperalgesia, and b) that strategies aimed at interfering with expression or function of PN3/SNS may lead to a breakthrough for the treatment of neuropathic pain. This hypothesis will be tested by four specific aims: 1) localization of the PN3/SNS protein in the DRG as well as in the injured nerve fibers, using immunocytochemistry; 2) measuring the temporal expression of PN3/SNS (at transcriptional and translational levels) after peripheral nerve injury and correlation with behavioral consequences of onset and offset of nerve injury; 3) characterizing the time-response, reversibility, dose-effects, uptake and specificity of PN3/SNS antisense oligodeoxynucleotides (ODN) on the expression of PN3/SNS protein; and 4) determining the effects of pre- or post-treatment with antisense ODN on the behavioral consequences of nerve-injury and whether such changes in behavior correlate with changes in PN3/SNS protein. These studies may have great practical significance towards the development of an effective therapy for neuropathic pain with few, or no, side effects.

描述：（改编自申请人的摘要）与神经损伤相关的疼痛（即神经性疼痛）已被假设与受伤神经中发生的异位病灶相关的传入放电增加有关。一种可能诱导异常自发传入活动的机制是 TTX 抗性钠通道（称为 PN3 或 SNS）的表达，该通道最近已被克隆并选择性定位于背根神经节 (DRG) 的细胞。申请人提议检验以下假设：a) PN3/SNS 的表达是神经损伤后果的主要事件，包括触觉异常性疼痛和痛觉过敏，以及 b) 旨在干扰 PN3/SNS 表达或功能的策略可能会为神经性疼痛的治疗带来突破。这一假设将通过四个具体目标进行检验：1）使用免疫细胞化学在 DRG 以及受损神经纤维中定位 PN3/SNS 蛋白； 2) 测量周围神经损伤后 PN3/SNS 的时间表达（在转录和翻译水平）以及与神经损伤发生和消失的行为后果的相关性； 3)表征PN3/SNS反义寡脱氧核苷酸(ODN)对PN3/SNS蛋白表达的时间反应、可逆性、剂量效应、摄取和特异性； 4)确定反义ODN治疗前或治疗后对神经损伤行为后果的影响，以及这种行为变化是否与PN3/SNS蛋白的变化相关。这些研究对于开发一种副作用很少或没有副作用的神经性疼痛的有效疗法可能具有重大的实际意义。