SELECTIVE BLOCKADE OF TTX-R SODIUM CHANNELS FOR PAIN

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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.