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

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.
Proceedings of the National Academy of Sciences of the United States of America 2007 v.104 no.20 pp. 8520-8525
action potentials, adjuvants, animal models, ganglia, humans, inhibitory concentration 50, nerve tissue, neurons, nociception, oligonucleotides, pain, rats, sodium channels
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.