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The tetrodotoxin-resistant Na+ channel Nav1.8 reduces the potency of local anesthetics in blocking C-fiber nociceptors

  • Katrin Kistner
  • Katharina Zimmermann
  • Corina Ehnert
  • Peter W. Reeh
  • Andreas LefflerEmail author
Sensory Physiology

Abstract

The generation of action potentials in nociceptive neurons is accomplished by the tetrodotoxin-resistant (TTXr) Na+ channel Nav1.8. Following nerve injury, a redistribution of Nav1.8 from dorsal root ganglion (DRG) neurons into peripheral axons contributes to hyperexcitability and possibly to neuropathic pain. Nav1.8 has been reported to display a lower sensitivity to block by Na+ channel blockers as compared to TTX-sensitive (TTXs) Nav subunits. Furthermore, the antinociceptive efficacy of lidocaine is increased in Nav1.8-knockout mice. Here, we asked if Nav1.8 expression can reduce the susceptibility of sensory neurons to block by lidocaine. Employing wild-type and Nav1.8-knockout mice, we examined C-fibers in the skin-nerve preparation and Na+ currents in DRG neurons by patch-clamp recordings. Deletion of Nav1.8 resulted in an enhanced tonic block of Na+ currents in DRG neurons held at −80 mV but not at −140 mV. Accordingly, lower concentrations of lidocaine were required for a conduction block of C-fibers from Nav1.8-knockout as compared to wild-type mice. The efficacy of lidocaine on neurons lacking Nav1.8 was further increased by cold temperatures, due to a synergistic hyperpolarizing shift of the slow inactivation of TTXs Na+ channels by lidocaine and cooling. Finally, the ∼90% reduction of TTXr Na+ currents in injured neurons from mice with a peripheral nerve injury was accompanied with an enhanced tonic block by lidocaine. In conclusion, our data demonstrate that the expression of Nav1.8 in sensory neurons can confine the antinociceptive efficacy of lidocaine and other Na+ channel blockers employed for pain treatment.

Keywords

Sodium channel Tetrodotoxin Sensory neuron Pain Lidocaine Neuropathic pain 

Abbreviations

Nav1.8

SNS

Nav1.9

NaN or SNS2

TTX

Tetrodotoxin

ITTX-Slow

Slowly inactivating TTX-resistant current

ITTX-Per

Persistent TTX-resistant current

Iintact

Total current in intact neurons

Iinjured

Total current in injured neurons

SNI

Spared nerve injury

DRG

Dorsal root ganglion

Notes

Acknowledgments

We thank John Wood (University College London) for providing the Nav.1.8-knockout mice and Iwona Izydorczyk for excellent technical assistance. We also thank Gerd Geisslinger (pharmazentrum frankfurt/ZAFES) for support and helpful discussions. This work was supported by a local grant of the Medical Faculty of the University of Erlangen-Nuremberg (ELAN NO. 56810013) and by BMBF 01EM0511 (Deutscher Forschungsverbund Neuropathischer Schmerz).

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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Katrin Kistner
    • 2
  • Katharina Zimmermann
    • 2
  • Corina Ehnert
    • 3
  • Peter W. Reeh
    • 2
  • Andreas Leffler
    • 1
    Email author
  1. 1.Department of AnesthesiologyFriedrich-Alexander-UniversityErlangen-NurembergGermany
  2. 2.Department of Physiology and PathophysiologyFriedrich-Alexander-UniversityErlangen-NurembergGermany
  3. 3.pharmazentrum frankfurt/ZAFES, Institute of Clinical PharmacologyJohann Wolfgang Goethe-UniversityFrankfurt am MainGermany

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