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

@article{citeulike:1676093, abstract = {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 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 (ED50 = 47 mg/kg, i.p.), sciatic nerve injury (ED50 = 85 mg/kg, i.p.), capsaicin-induced secondary mechanical allodynia (ED50 approx 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. 10.1073/pnas.0611364104}, author = {Jarvis, Michael F. and Honore, Prisca and Shieh, Char-Chang and Chapman, Mark and Joshi, Shailen and Zhang, Xu-Feng and Kort, Michael and Carroll, William and Marron, Brian and Atkinson, Robert and Thomas, James and Liu, Dong and Krambis, Michael and Liu, Yi and Mcgaraughty, Steve and Chu, Katharine and Roeloffs, Rosemarie and Zhong, Chengmin and Mikusa, Joseph P. and Hernandez, Gricelda and Gauvin, Donna and Wade, Carrie and Zhu, Chang and Pai, Madhavi and Scanio, Marc and Shi, Lei and Drizin, Irene and Gregg, Robert and Matulenko, Mark and Hakeem, Ahmed and Gross, Michael and Johnson, Matthew and Marsh, Kennan and Wagoner, Kay P. and Sullivan, James P. and Faltynek, Connie R. and Krafte, Douglas S. }, citeulike-article-id = {1676093}, doi = {10.1073/pnas.0611364104}, journal = {Proceedings of the National Academy of Sciences}, keywords = {pain, pn3}, month = {May}, number = {20}, pages = {8520--8525}, posted-at = {2007-09-19 14:59:23}, priority = {3}, title = {A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat}, url = {http://dx.doi.org/10.1073/pnas.0611364104}, volume = {104}, year = {2007} }

TY - JOUR ID - citeulike:1676093 L3 - citeulike-article-id:1676093 TI - A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat JF - Proceedings of the National Academy of Sciences VL - 104 IS - 20 SP - 8520 EP - 8525 N2 - 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 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 (ED50 = 47 mg/kg, i.p.), sciatic nerve injury (ED50 = 85 mg/kg, i.p.), capsaicin-induced secondary mechanical allodynia (ED50 approx 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. 10.1073/pnas.0611364104 KW - pain KW - pn3 AU - Jarvis, Michael AU - Honore, Prisca AU - Shieh, Char-Chang AU - Chapman, Mark AU - Joshi, Shailen AU - Zhang, Xu-Feng AU - Kort, Michael AU - Carroll, William AU - Marron, Brian AU - Atkinson, Robert AU - Thomas, James AU - Liu, Dong AU - Krambis, Michael AU - Liu, Yi AU - Mcgaraughty, Steve AU - Chu, Katharine AU - Roeloffs, Rosemarie AU - Zhong, Chengmin AU - Mikusa, Joseph AU - Hernandez, Gricelda AU - Gauvin, Donna AU - Wade, Carrie AU - Zhu, Chang AU - Pai, Madhavi AU - Scanio, Marc AU - Shi, Lei AU - Drizin, Irene AU - Gregg, Robert AU - Matulenko, Mark AU - Hakeem, Ahmed AU - Gross, Michael AU - Johnson, Matthew AU - Marsh, Kennan AU - Wagoner, Kay AU - Sullivan, James AU - Faltynek, Connie AU - Krafte, Douglas PY - 2007/05/15/ UR - http://dx.doi.org/10.1073/pnas.0611364104 ER -