SELECTIVE BLOCKADE OF TTX-R SODIUM CHANNELS FOR PAIN

描述：（改编自申请人摘要）与神经损伤相关的疼痛（即神经性疼痛）已被假设与传入放电增加有关，并与损伤神经发生异位灶相关。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）的细胞。申请人提出验证以下假设：a) PN3/SNS的表达是导致神经损伤后果的主要事件，包括触觉异常性痛和痛觉过敏；b)旨在干扰PN3/SNS的表达或功能的策略可能导致神经性疼痛治疗的突破。这一假设将通过四个特定目标进行验证：1)利用免疫细胞化学方法定位PN3/SNS蛋白在DRG和受损神经纤维中的位置；2)测定周围神经损伤后PN3/SNS的时间表达（转录和翻译水平）及其与神经损伤发生和补偿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蛋白表达的时效、可逆性、剂量效应、摄取和特异性；4)确定反义ODN治疗前后对神经损伤行为后果的影响，以及这种行为变化是否与PN3/SNS蛋白的变化相关。这些研究可能对开发一种副作用少或无副作用的有效治疗神经性疼痛的方法具有重要的现实意义。

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.