title: A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat.
abstract: Activation of tetrodotoxin-resistant sodium channels contributes to action potential electrogenesis in neurons. Antisense oligonucleotide studies directed against Na(v)1.8 have shown that this channel contributes to experimental inflammatory and neuropathic pain. We report here the discovery of A-803467, a sodium channel blocker that potently blocks tetrodotoxin-resistant currents (IC(50) = 140 nM) and the generation of spontaneous and electrically evoked action potentials in vitro in rat dorsal root ganglion neurons. In recombinant cell lines, A-803467 potently blocked human Na(v)1.8 (IC(50) = 8 nM) and was >100-fold selective vs. human Na(v)1.2, Na(v)1.3, Na(v)1.5, and Na(v)1.7 (IC(50) values >or=1 microM). A-803467 (20 mg/kg, i.v.) blocked mechanically evoked firing of wide dynamic range neurons in the rat spinal dorsal horn. A-803467 also dose-dependently reduced mechanical allodynia in a variety of rat pain models including: spinal nerve ligation (ED(50) = 47 mg/kg, i.p.), sciatic nerve injury (ED(50) = 85 mg/kg, i.p.), capsaicin-induced secondary mechanical allodynia (ED(50) approximately 100 mg/kg, i.p.), and thermal hyperalgesia after intraplantar complete Freund's adjuvant injection (ED(50) = 41 mg/kg, i.p.). A-803467 was inactive against formalin-induced nociception and acute thermal and postoperative pain. These data demonstrate that acute and selective pharmacological blockade of Na(v)1.8 sodium channels in vivo produces significant antinociception in animal models of neuropathic and inflammatory pain.
authors.affiliation: Neuroscience Research, Abbott Laboratories, Abbott Park, IL 60064, USA. michael.jarvis@abbott.com
authors.forename: Michael F
authors.initials: MF
authors.lastname: Jarvis
authors.forename: Prisca
authors.initials: P
authors.lastname: Honore
authors.forename: Char-Chang
authors.initials: CC
authors.lastname: Shieh
authors.forename: Mark
authors.initials: M
authors.lastname: Chapman
authors.forename: Shailen
authors.initials: S
authors.lastname: Joshi
authors.forename: Xu-Feng
authors.initials: XF
authors.lastname: Zhang
authors.forename: Michael
authors.initials: M
authors.lastname: Kort
authors.forename: William
authors.initials: W
authors.lastname: Carroll
authors.forename: Brian
authors.initials: B
authors.lastname: Marron
authors.forename: Robert
authors.initials: R
authors.lastname: Atkinson
authors.forename: James
authors.initials: J
authors.lastname: Thomas
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
authors.forename: Michael
authors.initials: M
authors.lastname: Krambis
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Steve
authors.initials: S
authors.lastname: McGaraughty
authors.forename: Katharine
authors.initials: K
authors.lastname: Chu
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Roeloffs
authors.forename: Chengmin
authors.initials: C
authors.lastname: Zhong
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Mikusa
authors.forename: Gricelda
authors.initials: G
authors.lastname: Hernandez
authors.forename: Donna
authors.initials: D
authors.lastname: Gauvin
authors.forename: Carrie
authors.initials: C
authors.lastname: Wade
authors.forename: Chang
authors.initials: C
authors.lastname: Zhu
authors.forename: Madhavi
authors.initials: M
authors.lastname: Pai
authors.forename: Marc
authors.initials: M
authors.lastname: Scanio
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.forename: Irene
authors.initials: I
authors.lastname: Drizin
authors.forename: Robert
authors.initials: R
authors.lastname: Gregg
authors.forename: Mark
authors.initials: M
authors.lastname: Matulenko
authors.forename: Ahmed
authors.initials: A
authors.lastname: Hakeem
authors.forename: Michael
authors.initials: M
authors.lastname: Gross
authors.forename: Matthew
authors.initials: M
authors.lastname: Johnson
authors.forename: Kennan
authors.initials: K
authors.lastname: Marsh
authors.forename: P Kay
authors.initials: PK
authors.lastname: Wagoner
authors.forename: James P
authors.initials: JP
authors.lastname: Sullivan
authors.forename: Connie R
authors.initials: CR
authors.lastname: Faltynek
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Krafte
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000700:Analgesics / Q000494:pharmacology; D000814:Aniline Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D005071:Evoked Potentials / Q000187:drug effects; D005663:Furans / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007249:Inflammation; D007700:Kinetics; D008297:Male; D020422:Mononeuropathies / Q000628:therapy*; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors*; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D010146:Pain / Q000139:chemically induced / Q000473:pathology*; D059408:Pain Management; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D015222:Sodium Channels / Q000378:metabolism*
chemical_list: C520740:A 803467; D000700:Analgesics; D000814:Aniline Compounds; D005663:Furans; 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; D002211:Capsaicin