A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat
| Autor: | Char Chang Shieh, P. Kay Wagoner, Robert J. Gregg, Connie R. Faltynek, James P. Sullivan, Steve McGaraughty, James Thomas, Joseph P. Mikusa, Xu Feng Zhang, Prisca Honore, William A. Carroll, Carrie Wade, Matthew D. Johnson, Dong Liu, Marc J. C. Scanio, Donna M. Gauvin, Michael J. Krambis, Madhavi Pai, Ahmed A. Hakeem, Yi Liu, Brian E. Marron, Chengmin Zhong, Chang Zhu, Irene Drizin, Lei Shi, Michael E. Kort, Mark A. Matulenko, Kennan C. Marsh, Mark L. Chapman, Michael F. Jarvis, Rosemarie Roeloffs, Katharine L. Chu, Robert N. Atkinson, Gricelda Hernandez, Shailen K. Joshi, Douglas S. Krafte, Michael L. Gross |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2007 |
| Předmět: |
Male
Action Potentials Pain Nerve Tissue Proteins Pharmacology Sodium Channels Rats Sprague-Dawley NAV1.8 Voltage-Gated Sodium Channel Sodium channel blocker Dorsal root ganglion Ganglia Spinal medicine Animals Humans Pain Management Furans Evoked Potentials Neurons Inflammation Analgesics Multidisciplinary Aniline Compounds Chemistry Sodium channel Mononeuropathies Sciatic nerve injury Biological Sciences medicine.disease Recombinant Proteins Rats Kinetics Nociception Allodynia medicine.anatomical_structure Hyperalgesia Neuropathic pain Commentary medicine.symptom Capsaicin Sodium Channel Blockers |
| Popis: | 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 ≥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 (ED 50 = 47 mg/kg, i.p.), sciatic nerve injury (ED 50 = 85 mg/kg, i.p.), capsaicin-induced secondary mechanical allodynia (ED 50 ≈ 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|