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A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat

Proceedings of the National Academy of Sciences - PNAS, 2007-05, Vol.104 (20), p.8520-8525 [Peer Reviewed Journal]

2007 by The National Academy of Sciences of the USA 2007 ;ISSN: 0027-8424 ;EISSN: 1091-6490 ;DOI: 10.1073/pnas.0611364104 ;PMID: 17483457

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Title:
A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat
Author: Jarvis, Michael F ; Honore, Prisca ; Shieh, Char-Chang ; Chapman, Mark ; Joshi, Shailen ; Zhang, Xu-Feng ; Kort, Michael ; Carroll, William ; Marron, Brian ; Atkinson, Robert ; Thomas, James ; Liu, Dong ; Krambis, Michael ; Liu, Yi ; McGaraughty, Steve ; Chu, Katharine ; Roeloffs, Rosemarie ; Zhong, Chengmin ; Mikusa, Joseph P ; Hernandez, Gricelda ; Gauvin, Donna ; Wade, Carrie ; Zhu, Chang ; Pai, Madhavi ; Scanio, Marc ; Shi, Lei ; Drizin, Irene ; Gregg, Robert ; Matulenko, Mark ; Hakeem, Ahmed ; Gross, Michael ; Johnson, Matthew ; Marsh, Kennan ; Wagoner, P. Kay ; Sullivan, James P ; Faltynek, Connie R ; Krafte, Douglas S
Subjects: Action Potentials - drug effects ; Analgesics - pharmacology ; Aniline Compounds - administration & dosage ; Aniline Compounds - chemistry ; Aniline Compounds - pharmacokinetics ; Aniline Compounds - pharmacology ; Animals ; Biological Sciences ; Capsaicin - pharmacology ; Evoked Potentials - drug effects ; Furans - administration & dosage ; Furans - chemistry ; Furans - pharmacokinetics ; Furans - pharmacology ; Ganglia, Spinal - cytology ; Ganglia, Spinal - drug effects ; Humans ; Inflammation ; Kinetics ; Male ; Mononeuropathies - therapy ; NAV1.8 Voltage-Gated Sodium Channel ; Nerve Tissue Proteins - antagonists & inhibitors ; Neurons - cytology ; Neurons - drug effects ; Pain - chemically induced ; Pain - pathology ; Pain Management ; Rats ; Rats, Sprague-Dawley ; Recombinant Proteins - metabolism ; Sodium Channel Blockers - administration & dosage ; Sodium Channel Blockers - chemistry ; Sodium Channel Blockers - pharmacokinetics ; Sodium Channel Blockers - pharmacology ; Sodium Channels - metabolism
Is Part Of: Proceedings of the National Academy of Sciences - PNAS, 2007-05, Vol.104 (20), p.8520-8525
Description: Activation of tetrodotoxin-resistant sodium channels contributes to action potential electrogenesis in neurons. Antisense oligonucleotide studies directed against Nav1.8 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 (IC₅₀ = 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 Nav1.8 (IC₅₀ = 8 nM) and was >100-fold selective vs. human Nav1.2, Nav1.3, Nav1.5, and Nav1.7 (IC₅₀ values >=1 μM). 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 (ED₅₀ = 47 mg/kg, i.p.), sciatic nerve injury (ED₅₀ = 85 mg/kg, i.p.), capsaicin-induced secondary mechanical allodynia (ED₅₀ [almost equal to] 100 mg/kg, i.p.), and thermal hyperalgesia after intraplantar complete Freund's adjuvant injection (ED₅₀ = 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 Nav1.8 sodium channels in vivo produces significant antinociception in animal models of neuropathic and inflammatory pain.
Publisher: United States: National Academy of Sciences
Language: English
Identifier: ISSN: 0027-8424
EISSN: 1091-6490
DOI: 10.1073/pnas.0611364104
PMID: 17483457
Source: Geneva Foundation Free Medical Journals at publisher websites
MEDLINE
PubMed Central

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A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat

2007 by The National Academy of Sciences of the USA 2007 ;ISSN: 0027-8424 ;EISSN: 1091-6490 ;DOI: 10.1073/pnas.0611364104 ;PMID: 17483457

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