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(即神经病理性疼痛)被假设与损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，该通道最近被克隆并选择性定位于背根神经节(DRG)细胞。申请人建议检验这样的假设：a)PN3/SNS的表达是神经损伤(包括触觉过敏和痛觉过敏)后果的主要事件，以及b)旨在干扰PN3/SNS的表达或功能的策略可能导致神经病理性疼痛的治疗突破。这一假说将通过四个特定的目标来验证：1)用免疫细胞化学方法定位PN3/SNS蛋白在DRG和损伤神经纤维中的位置；2)测量周围神经损伤后PN3/SNS在转录和翻译水平的表达及其与神经损伤开始和消失的行为后果的相关性；3)表征PN3/SNS反义寡核苷酸(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)观察反义ODN治疗前后对神经损伤行为后果的影响，以及这种行为改变是否与PN3/SNS蛋白的变化有关。这些研究可能对开发一种副作用很少或没有副作用的神经病理性疼痛的有效治疗方法具有重要的现实意义。