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

Abstract

The tetrodotoxin-resistant voltage-gated sodium channel (VGSC) Na(v)1.8 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 muO-conotoxin MrVIB from Conus marmoreus displays substantial selectivity for Na(v)1.8 and inhibits pain behavior in models of persistent pain. In rat sensory neurons, submicromolar concentrations of MrVIB blocked tetrodotoxin-resistant current characteristic of Na(v)1.8 but not Na(v)1.9 or tetrodotoxin-sensitive VGSC currents. MrVIB blocked human Na(v)1.8 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(v)1.8 can alleviate chronic pain behavior with a greater therapeutic index than nonselective antagonists.

• Authors: J Ekberg, A Jayamanne, C W Vaughan, S Aslan, L Thomas, J Mould, R Drinkwater, M D Baker, B Abrahamsen, J N Wood, D J Adams, M J Christie, R J Lewis
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 103 Issue 45 Pg. 17030-5 (Nov 07 2006) ISSN: 0027-8424 [Print] United States
• PMID: 17077153 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Conotoxins
• NAV1.8 Voltage-Gated Sodium Channel
• Nerve Tissue Proteins
• Recombinant Proteins
• SCN10A protein, human
• Scn10a protein, rat
• Sodium Channel Blockers
• Sodium Channels
• muO-conotoxin MrVIB
• Tetrodotoxin

Topics

• Animals
• Chronic Disease
• Conotoxins (administration & dosage, pharmacology)
• Female
• Ganglia, Spinal (drug effects, metabolism)
• In Vitro Techniques
• Male
• NAV1.8 Voltage-Gated Sodium Channel
• Nerve Tissue Proteins (antagonists & inhibitors, genetics, metabolism)
• Neurons (drug effects, metabolism)
• Oocytes (drug effects, metabolism)
• Pain (drug therapy, physiopathology)
• Rats
• Rats, Sprague-Dawley
• Recombinant Proteins (antagonists & inhibitors, genetics, metabolism)
• Sodium Channel Blockers (administration & dosage, pharmacology)
• Sodium Channels (drug effects, genetics, metabolism)
• Tetrodotoxin (pharmacology)
• Xenopus laevis