title: 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.affiliation: Institute for Molecular Bioscience and School of Biomedical Sciences, University of Queensland, QLD 4072, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Ekberg
authors.forename: A
authors.initials: A
authors.lastname: Jayamanne
authors.forename: C W
authors.initials: CW
authors.lastname: Vaughan
authors.forename: S
authors.initials: S
authors.lastname: Aslan
authors.forename: L
authors.initials: L
authors.lastname: Thomas
authors.forename: J
authors.initials: J
authors.lastname: Mould
authors.forename: R
authors.initials: R
authors.lastname: Drinkwater
authors.forename: M D
authors.initials: MD
authors.lastname: Baker
authors.forename: B
authors.initials: B
authors.lastname: Abrahamsen
authors.forename: J N
authors.initials: JN
authors.lastname: Wood
authors.forename: D J
authors.initials: DJ
authors.lastname: Adams
authors.forename: M J
authors.initials: MJ
authors.lastname: Christie
authors.forename: R J
authors.initials: RJ
authors.lastname: Lewis
mesh_terms: D000818:Animals; D002908:Chronic Disease; D020916:Conotoxins / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology; D014982:Xenopus laevis
chemical_list: D020916:Conotoxins; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; C568317:SCN10A protein, human; C568319:Scn10a protein, rat; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C094741:muO-conotoxin MrVIB; D013779:Tetrodotoxin