title: Synthetic muO-conotoxin MrVIB blocks TTX-resistant sodium channel NaV1.8 and has a long-lasting analgesic activity.
abstract: MuO-conotoxin MrVIB is a blocker of voltage-gated sodium channels, including TTX-sensitive and -resistant subtypes. A comprehensive characterization of this peptide has been hampered by the lack of sufficient synthetic material. Here, we describe the successful chemical synthesis and oxidative folding of MrVIB that has made an investigation of the pharmacological properties and therapeutic potential of the peptide feasible. We show for the first time that synthetic MrVIB blocks rat NaV1.8 sodium channels and has potent and long-lasting local anesthetic effects when tested in two pain assays in rats. Furthermore, MrVIB can block propagation of action potentials in A- and C-fibers in sciatic nerve as well as skeletal muscle in isolated preparations from rat. Our work provides the first example of analgesia produced by a conotoxin that blocks sodium channels. The emerging diversity of antinociceptive mechanisms targeted by different classes of conotoxins is discussed.
authors.affiliation: Department of Biology, The University of Utah, Salt Lake City, Utah 84112, USA. bulaj@biology.utah.edu
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Bulaj
authors.forename: Min-Min
authors.initials: MM
authors.lastname: Zhang
authors.forename: Brad R
authors.initials: BR
authors.lastname: Green
authors.forename: Brian
authors.initials: B
authors.lastname: Fiedler
authors.forename: Richard T
authors.initials: RT
authors.lastname: Layer
authors.forename: Sue
authors.initials: S
authors.lastname: Wei
authors.forename: Jacob S
authors.initials: JS
authors.lastname: Nielsen
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Low
authors.forename: Brian D
authors.initials: BD
authors.lastname: Klein
authors.forename: John D
authors.initials: JD
authors.lastname: Wagstaff
authors.forename: Linda
authors.initials: L
authors.lastname: Chicoine
authors.forename: T Patrick
authors.initials: TP
authors.lastname: Harty
authors.forename: Heinrich
authors.initials: H
authors.lastname: Terlau
authors.forename: Doju
authors.initials: D
authors.lastname: Yoshikami
authors.forename: Baldomero M
authors.initials: BM
authors.lastname: Olivera
mesh_terms: D000595:Amino Acid Sequence; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D020916:Conotoxins / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008969:Molecular Sequence Data; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels; D013779:Tetrodotoxin / Q000494:pharmacology*
chemical_list: D000700:Analgesics; D020916:Conotoxins; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568319:Scn10a protein, rat; D015222:Sodium Channels; D013779:Tetrodotoxin