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.
Preconditioning Depolarizing Ramp Currents Enhance the Effect of Sodium Channel Blockers in Primary Sensory Afferents
Article first published online: 19 FEB 2013
© 2013 International Neuromodulation Society
Neuromodulation: Technology at the Neural Interface
Volume 16, Issue 4, pages 336–344, July/August 2013
How to Cite
Vastani, N., Seifert, B., Spahn, D. R. and Maurer, K. (2013), Preconditioning Depolarizing Ramp Currents Enhance the Effect of Sodium Channel Blockers in Primary Sensory Afferents. Neuromodulation: Technology at the Neural Interface, 16: 336–344. doi: 10.1111/ner.12031
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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.
- Issue published online: 5 AUG 2013
- Article first published online: 19 FEB 2013
- Manuscript Accepted: 3 JAN 2013
- Manuscript Revised: 14 DEC 2012
- Manuscript Received: 13 APR 2012
- Swiss Foundation for Anesthesia Research (SFAR)
- Swiss National Science Foundation, Berne, Switzerland. Grant Numbers: 33CM30_124117, 406440-131268
- Institute of Anesthesiology, University Hospital Zurich, Switzerland
- Basic science;
- local anesthetics;
- peripheral nerve stimulation;
- sensory neurons;
- threshold tracking
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.
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).
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.