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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS038771-03
Application #
6394151
Study Section
Special Emphasis Panel (ZRG1-BDCN-6 (08))
Program Officer
Kitt, Cheryl A
Project Start
1999-06-08
Project End
2002-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
3
Fiscal Year
2001
Total Cost
$231,613
Indirect Cost
Name
University of Arizona
Department
Pharmacology
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Gold, Michael S; Weinreich, Daniel; Kim, Chang-Sook et al. (2003) Redistribution of Na(V)1.8 in uninjured axons enables neuropathic pain. J Neurosci 23:158-66
Lai, Josephine; Gold, Michael S; Kim, Chang Sook et al. (2002) Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8. Pain 95:143-52