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*, and
- Douglas S. Krafte‡,§
- *Neuroscience Research, Abbott Laboratories, Abbott Park, IL 60064; and
- ‡Icagen, Inc., Durham, NC 27703
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Edited by William A. Catterall, University of Washington School of Medicine, Seattle, WA, and approved March 25, 2007 (received for review December 20, 2006)
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 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 Nav1.8 sodium channels in vivo produces significant antinociception in animal models of neuropathic and inflammatory pain.
Footnotes
- †To whom correspondence may be addressed at: Abbott Laboratories, R-4PM, AP9A/3,100 Abbott Park Road, Abbott Park, IL 60064. E-mail: michael.jarvis{at}abbott.com
- §To whom correspondence may be addressed at: Icagen, Inc., P.O. Box 14487, Research Triangle Park, NC 27709. E-mail: dkrafte{at}icagen.com
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Author contributions: M.F.J., P.H., C.-C.S., M. Kort, W.C., B.M., R.K.W., J.P.S., C.R.F., and D.S.K. designed research; P.H., C.-C.S., M.C., S.J., X.-F.Z., R.A., J.T., D.L., M. Krambis, Y.L., S.M., K.C., R.R., C. Zhong, J.P.M., G.H., D.G., C.W., C. Zhu, M.P., M.S., L.S., I.D., R.G., M.M., A.H., M.G., M.J., and K.M. performed research; M. Kort, W.C., B.M., R.A., J.T., M.S., I.D., R.G., L.S., M.M., A.H., M.G., and M.J. contributed new reagents/analytic tools; M.F.J., P.H., C.-C.S., M.C., S.J., S.M., K.M., P.K.W., J.P.S., C.R.F., and D.S.K. analyzed data; and M.F.J., P.H., and D.S.K. wrote the paper.
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Conflict of interest statement: All authors are employees of either Abbott Laboratories or Icagen, Inc.
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This article is a PNAS Direct Submission.
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See Commentary on page 8205.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0611364104/DC1.
- Abbreviations:
- CARR,
- carrageenan;
- CFA,
- complete Freund's adjuvant;
- DRG,
- dorsal root ganglion;
- TTX,
- tetrodotoxin;
- TTX-R,
- TTX-resistant;
- WDR,
- wide dynamic range.
- © 2007 by The National Academy of Sciences of the USA
