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

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Ekberg J, Jayamanne A, Vaughan CW, Aslan S, Thomas L, Mould J, Drinkwater R, Baker MD, Abrahamsen B, Wood JN, Adams DJ, Christie MJ, Lewis RJ

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

Proc Natl Acad Sci U S A. 2006 Nov 7;103(45):17030-5. Epub 2006 Oct 31.

PubMed ID

17077153 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Lidocaine	Sodium channel protein type 10 subunit alpha	Protein	Humans	Yes	Inhibitor	Details