μO-conotoxin MrVIB selectively blocks Nav1.8 sensory neuron specific sodium channels and chronic pain behavior without motor deficits

doi:10.1073/pnas.0601819103

μO-conotoxin MrVIB selectively blocks Na_v1.8 sensory neuron specific sodium channels and chronic pain behavior without motor deficits

*Institute for Molecular Bioscience and
^†School of Biomedical Sciences, University of Queensland, QLD 4072, Australia;
^‡Pain Management Research Institute and Kolling Institute, Northern Clinical School, University of Sydney at Royal North Shore Hospital, St Leonards, NSW 2065, Australia; and
^¶Molecular Nociception Group, Department of Biology, University College of London, Gower Street, London WC1E 6BT, United Kingdom

Edited by William A. Catterall, University of Washington School of Medicine, Seattle, WA, and approved September 1, 2006 (received for review March 6, 2006)

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 Na_v1.8 and inhibits pain behavior in models of persistent pain. In rat sensory neurons, submicromolar concentrations of MrVIB blocked tetrodotoxin-resistant current characteristic of Na_v1.8 but not Na_v1.9 or tetrodotoxin-sensitive VGSC currents. MrVIB blocked human Na_v1.8 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 Na_v1.8 can alleviate chronic pain behavior with a greater therapeutic index than nonselective antagonists.

Footnotes

^‖To whom correspondence may be addressed. E-mail: macc{at}med.usyd.edu.au or r.lewis{at}imb.uq.edu.au
Author contributions: J.E. and A.J. contributed equally to this work; J.E., C.W.V., R.D., M.D.B., J.N.W., D.J.A., M.J.C., and R.J.L. designed research; J.E., A.J., S.A., L.T., J.M., R.D., M.D.B., and B.A. performed research; L.T., R.D., and R.J.L. contributed new reagents/analytic tools; J.E., A.J., S.A., J.M., B.A., J.N.W., D.J.A., M.J.C., and R.J.L. analyzed data; and J.E., A.J., C.W.V., M.D.B., J.N.W., D.J.A., M.J.C., and R.J.L. wrote the paper.
↵ ^§Present address: Xenome Ltd., 120 Meiers Road, Indooroopilly, QLD 4068, Australia.
The authors declare no conflict of interest.
This article is a PNAS direct submission.
Abbreviations:

CFA,

complete Freund's adjuvant;

C.I.,

confidence interval;

DRG,

dorsal root ganglion;

PNL,

partial ligation of the sciatic nerve;

PWL,

paw withdrawal latency;

PWT,

paw withdrawal threshold;

TTX-R,

tetrodotoxin-resistant;

TTX-S,

tetrodotoxin-sensitive;

VGSC,

voltage-gated sodium channel.
Freely available online through the PNAS open access option.