A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat.
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.
Jarvis
Michael F
MF
Neuroscience Research, Abbott Laboratories, Abbott Park, IL 60064, USA. michael.jarvis@abbott.com
Honore
Prisca
P
Shieh
Char-Chang
CC
Chapman
Mark
M
Joshi
Shailen
S
Zhang
Xu-Feng
XF
Kort
Michael
M
Carroll
William
W
Marron
Brian
B
Atkinson
Robert
R
Thomas
James
J
Liu
Dong
D
Krambis
Michael
M
Liu
Yi
Y
McGaraughty
Steve
S
Chu
Katharine
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Roeloffs
Rosemarie
R
Zhong
Chengmin
C
Mikusa
Joseph P
JP
Hernandez
Gricelda
G
Gauvin
Donna
D
Wade
Carrie
C
Zhu
Chang
C
Pai
Madhavi
M
Scanio
Marc
M
Shi
Lei
L
Drizin
Irene
I
Gregg
Robert
R
Matulenko
Mark
M
Hakeem
Ahmed
A
Gross
Michael
M
Johnson
Matthew
M
Marsh
Kennan
K
Wagoner
P Kay
PK
Sullivan
James P
JP
Faltynek
Connie R
CR
Krafte
Douglas S
DS
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*
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