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6028988 
Journal Article 
A-803467, a potent and selective Na^sub v^1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat 
Chapman, M; Char-Chang, S; Honore, P; Jarvis, MF; et al. 
2007 
1 
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
EISSN: 1091-6490 
104 
20 
8520 
Activation of tetrodotoxin-resistant sodium channels contributes to action potential electrogenesis in neurons. Antisense oligonucleotide studies directed against Na...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... = 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...1 .8 (IC... = 8 nM) and was >100-fold selective vs. human Na...1 .2, Na...1 .3, Na...1 .5, and Na...1 .7 (IC... values ≥ 1 ...M). 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... = 47 mg/kg, i.p.), sciatic nerve injury (ED... = 85 mg/kg, i.p.), capsaicin-induced secondary mechanical allodynia (ED... 100 mg/kg, i.p.), and thermal hyperalgesia after intraplantar complete Freund's adjuvant injection (ED... = 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...1 .8 sodium channels in vivo produces significant antinociception in animal models of neuropathic and inflammatory pain. (ProQuest-CSA LLC: ... denotes formulae/symbols omitted.) 
Sciences: Comprehensive Works; Inflammatory diseases; Rodents; Neurons; Genetic recombination