μO-conotoxin MrVIB selectively blocks NaV1.8 sensory neuron specific sodium channels and chronic pain behavior without motor deficits

J. Ekberg, A. Jayamanne, C. W. Vaughan, S. Aslan, Linda Thomas, J. Mould, Roger Drinkwater, M. D. Baker, B. Abrahamsen, J. N. Wood, David J. Adams, M. J. Christie*, Richard J. Lewis

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

150 Citations (Scopus)

Abstract

The tetrodotoxin-resistant voltage-gated sodium channel (VGSC) Na V1.8 is expressed predominantly by damage-sensing primary afferent nerves and is important for the development and maintenance of persistent pain states. Here we demonstrate that μO-conotoxin MrVIB from Conus marmoreus displays substantial selectivity for NaV1.9 and inhibits pain behavior in models of persistent pain. In rat sensory neurons, submicromolar concentrations of MrVIB blocked tetrodotoxin-resistant current characteristic of NaV1.8 but not NaV1.9 or tetrodotoxin-sensitive VGSC currents. MrVIB blocked human NaV1.8 expressed in Xenopus oocytes with selectivity at least 10-fold greater than other VGSCs. In neuropathic and chronic inflammatory pain models, allodynia and hyperalgesia were both reduced by intrathecal infusion of MrVIB (0.03-3 nmol), whereas motor side effects occurred only at 30-fold higher doses. In contrast, the nonselective VGSC blocker lignocaine displayed no selectivity for allodynia and hyperalgesia versus motor side effects. The actions of MrVIB reveal that VGSC antagonists displaying selectivity toward NaV1.8 can alleviate chronic pain behavior with a greater therapeutic index than nonselective antagonists.

Original languageEnglish
Pages (from-to)17030-17035
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number45
DOIs
Publication statusPublished - 7 Nov 2006
Externally publishedYes

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