Get access

Preconditioning Depolarizing Ramp Currents Enhance the Effect of Sodium Channel Blockers in Primary Sensory Afferents

Authors

  • Nisha Vastani PhD,

    1. Institute of Anesthesiology, University Hospital of Zurich, Zurich, Switzerland
    Search for more papers by this author
  • Burkhardt Seifert Prof.,

    1. Division of Biostatistics, Institute of Social and Preventive Medicine, University of Zurich, Zurich, Switzerland
    Search for more papers by this author
  • Donat R. Spahn Prof.,

    1. Institute of Anesthesiology, University Hospital of Zurich, Zurich, Switzerland
    2. Swiss Pain Research Consortium, Institute of Anesthesiology, University Hospital of Zurich, Zurich, Switzerland
    Search for more papers by this author
  • Konrad Maurer MD

    Corresponding author
    1. Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland
    2. Clinical Trials Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland
    3. Swiss Pain Research Consortium, Institute of Anesthesiology, University Hospital of Zurich, Zurich, Switzerland
    • Institute of Anesthesiology, University Hospital of Zurich, Zurich, Switzerland
    Search for more papers by this author

  • Conflict of Interest: NV: none. BS: none. Prof. Spahn was the chairman of the ABC Faculty and is a member of the ABC Trauma Faculty, which both are managed by Thomson Physicians World GmbH, and sponsored by an unrestricted educational grant from Novo Nordisk A/S, and CSL Behring GmbH. In the past three years, Prof. Spahn has received honoraria or travel support for consulting or lecturing from the following companies: Abbott AG; AstraZeneca AG; Bayer (Schweiz) AG; Baxter S.p.A.; B. Braun Melsungen AG; Boehringer Ingelheim (Schweiz) GmbH; Bristol-Myers-Squibb; CSL Behring GmbH; Curacyte AG; Ethicon Biosurgery; Fresenius SE; Galenica AG, (including Vifor SA, Villars-sur-Glâne, Switzerland); GlaxoSmithKline GmbH & Co. KG; Janssen-Cilag AG, Baar, Switzerland; Janssen-Cilag EMEA, Beerse, Belgium; Merck Sharp & Dohme-Chibret AG, Opfikon-Glattbrugg; Novo Nordisk A/S; Octapharma AG; Organon AG; Oxygen Biotherapeutics; Term Innovations GmbH; Roche Pharma (Schweiz) AG; and Schering-Plough International, Inc., Dr. Maurer has received travel support for consulting or lecturing from the following companies: Pfizer AG; Bristol-Myers Squibb SA; Mundipharma Medical Company; Janssen-Cilag AG; UCB; Medtronic; B. Braun Medical AG; Grünenthal Pharma Schweiz; and St. Jude Medical AG.
  • For more information on author guidelines, an explanation of our peer review process, and conflict of interest informed consent policies, please go to http://www.wiley.com/bw/submit.asp?ref=1094-7159&site=1
  • Source(s) of financial support: This study was funded by the Swiss Foundation for Anesthesia Research (SFAR), by the Swiss National Science Foundation (Grant No. SPUM 33CM30_124117), and by the Institute of Anesthesiology, University Hospital Zurich, Switzerland.

Address correspondence to: Konrad Maurer, MD, Pain Research Unit, Institute of Anesthesiology, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland. Email: konrad.maurer@usz.ch

Abstract

Objectives

The conformational state of voltage-gated sodium channels is an important determinant for the efficacy of both local anesthesia and electrical neuromodulation techniques. This study investigated the role of subthreshold preconditioning ramp currents on axonal nerve excitability parameters in the presence of sodium channel blockers in myelinated A and unmyelinated C fibers.

Materials and Methods

A- and C-fiber compound action potentials were recorded extracellularly in vitro in saphenous nerve from adult rats. Nerve fibers were stimulated with a supramaximal current pulse either alone or after a 300-msec conditioning polarizing ramp current (between −10% and +100% of the original threshold current) in the presence and absence of lidocaine and tetrodotoxin (TTX). A computerized threshold tracking program (QTRAC©, Institute of Neurology, University College London, London, UK) was used to determine the membrane thresholds.

Results

Preconditioning ramp currents of weak strengths increased membrane excitability. Stronger preconditioning ramp currents enhanced the potency of lidocaine and TTX to increase excitability thresholds. In A and C fibers stimulated with ramp currents of 110% (A fibers) and 40% (C fibers), lidocaine (80 μM) induced a 168 ± 15% (p < 0.001) and 302 ± 23% (p < 0.001) increase in threshold, respectively (no ramp current: 135 ± 9% and 124 ± 4%, respectively). TTX (16 nM) induced an increase in threshold of 455 ± 45% (p < 0.001) and 214 ± 22% (p = 0.005), respectively (no ramp current: 205 ± 12% and 128 ± 6%, respectively).

Conclusions

Slow preconditioning ramp stimuli inactivate sodium currents. In the presence of sodium channel blockers, stronger ramp stimuli cause an increase in threshold, which is larger than that caused by the sodium channel blocker alone. Therefore, we conclude that small depolarizing ramp currents could be used to increase excitability threshold in the presence of low concentrations of local anesthetics. These additive effects might represent a target to address with peripheral nerve stimulation in order to suppress afferent pain signaling.

Ancillary