Block of peripheral nerve sodium channels selectively inhibits features of neuropathic pain in rats

Richard M. Brochu, Ivy E. Dick, Jason W. Tarpley, Erin McGowan, David Gunner, James Herrington, Pengcheng P. Shao, Dong Ok, Chunshi Li, William H. Parsons, Gary L. Stump, Christopher P. Regan, Joseph J. Lynch, Kathryn A. Lyons, Owen B. McManus, Samantha Clark, Zahid Ali, Gregory J. Kaczorowski, William J. Martin, Birgit T. Priest

Research output: Contribution to journalArticle

Abstract

Several sodium channel blockers are used clinically to treat neuropathic pain. However, many patients fail to achieve adequate pain relief from these highly brain-penetrant drugs because of dose-limiting central nervous system side effects. Here, we describe the functional properties of trans-N-{[2′-(aminosulfonyl)biphenyl-4-yl]methyl}-N-methyl-N′-[4- (trifluoromethoxy) benzyl]cyclopentane-1,2-dicarboxamide (CDA54), a peripherally acting sodium channel blocker. In whole-cell electrophysiological assays, CDA54 blocked the inactivated states of hNav1.7 and hNav1.8, two channels of the peripheral nervous system implicated in nociceptive transmission, with affinities of 0.25 and 0.18 μM, respectively. CDA54 displayed similar affinities for the tetrodotoxin-resistant Na+ current in small-diameter mouse dorsal root ganglion neurons. Peripheral nerve injury causes spontaneous electrical activity in normally silent sensory neurons. CDA54 inhibited these injury-induced spontaneous action potentials at concentrations 10-fold lower than those required to block normal A- and C-fiber conduction. Consistent with the selective inhibition of injury-induced firing, CDA54 (10 mg/kg p.o.) significantly reduced behavioral signs of neuropathic pain in two nerve injury models, whereas the same dose of CDA54 did not affect acute nociception or motor coordination. In anesthetized dogs, CDA54, at plasma concentrations of 6.7 μM, had no effect on cardiac electrophysiological parameters including conduction. Thus, the peripheral nerve sodium channel blocker CDA54 selectively inhibits sensory nerve signaling associated with neuropathic pain.

Original languageEnglish (US)
Pages (from-to)823-832
Number of pages10
JournalMolecular Pharmacology
Volume69
Issue number3
DOIs
StatePublished - Mar 2006
Externally publishedYes

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ASJC Scopus subject areas

  • Pharmacology

Cite this

Brochu, R. M., Dick, I. E., Tarpley, J. W., McGowan, E., Gunner, D., Herrington, J., Shao, P. P., Ok, D., Li, C., Parsons, W. H., Stump, G. L., Regan, C. P., Lynch, J. J., Lyons, K. A., McManus, O. B., Clark, S., Ali, Z., Kaczorowski, G. J., Martin, W. J., & Priest, B. T. (2006). Block of peripheral nerve sodium channels selectively inhibits features of neuropathic pain in rats. Molecular Pharmacology, 69(3), 823-832. https://doi.org/10.1124/mol.105.018127