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

Michael F Jarvis, Prisca Honore, Char-Chang Shieh, Mark Chapman, Shailen Joshi, Xu-Feng Zhang, Michael Kort, William Carroll, Brian Marron, Robert Atkinson, James Thomas, Dong Liu, Michael Krambis, Yi Liu, Steve McGaraughty, Katharine Chu, Rosemarie Roeloffs, Chengmin Zhong, Joseph P Mikusa, Gricelda Hernandez, Donna Gauvin, Carrie Wade, Chang Zhu, Madhavi Pai, Marc Scanio, Lei Shi, Irene Drizin, Robert Gregg, Mark Matulenko, Ahmed Hakeem, Michael Gross, Matthew Johnson, Kennan Marsh, P Kay Wagoner, James P Sullivan, Connie R Faltynek, Douglas S Krafte

文献索引：Proc. Natl. Acad. Sci. U. S. A. 104 , 8520-5, (2007)

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摘要

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.