Journal Article

A-803467, a Potent and Selective${\\rm Na}_{{\\rm v}}1.8$Sodium Channel Blocker, Attenuates Neuropathic and Inflammatory Pain in the Rat

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

2007

Overview

Activation of tetrodotoxin-resistant sodium channels contributes to action potential electrogenesis in neurons. Antisense oligonucleotide studies directed against${\\rm Na}_{{\\rm v}}1.8$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 (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${\\rm Na}_{{\\rm v}}1.8$(IC₅₀ = 8 nM) and was > 100-fold selective vs. human${\\rm Na}_{{\\rm v}}1.2$,${\\rm Na}_{{\\rm v}}1.3$,${\\rm Na}_{{\\rm v}}1.5$, and${\\rm Na}_{{\\rm v}}1.7$(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 ≈ 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${\\rm Na}_{{\\rm v}}1.8$sodium channels in vivo produces significant antinociception in animal models of neuropathic and inflammatory pain.

• Publisher: National Academy of Sciences
• Subject: Action potentials / Analgesics / Electric current / Electric potential / Hyperalgesia / Inhibitory concentration 50 / Neurons / Pain / Sodium channel blockers / Sodium channels