The differential effects of two sodium channel modulators on the conductive properties of C-fibers in pig skin in vivo

Otilia Obreja, Michael Hirth, Brian Turnquist, Roman Rukwied, Matthias Ringkamp, Martin Schmelz

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Axonal sodium channels are attractive targets for chronic pain treatment, and recent evidence suggests that specific targeting of the slow inactivation of sodium channels (NaV) might exert analgesic effects. Using a human-like animal model, the pig, we compared changes in the conductive properties of different C-fiber classes on acute administration of lidocaine (nonselective NaV blocker) and lacosamide (selective enhancer of NaV slow inactivation). Methods: Single-fiber extracellular recordings from saphenous nerves were performed. We classified C-fibers according to mechanical responsiveness and amount of activity-dependent slowing (ADS) of conduction velocity. Lidocaine (4 mM; 100 μL), lacosamide (4 mM; 100 μL), or saline was injected intradermally at the stimulation site, and changes of fibers' conductive properties were assessed. Results: Conduction latencies evoked by lidocaine were more prominent in mechanosensitive (5.5%± 2.1%) than in mechano-insensitive nociceptors (2.5% ± 1%), whereas lacosamide increased conduction latencies to a greater extent in the mechano-insensitive (3% ± 1%) than in mechanosensitive C-nociceptors (2% ± 0.9%). Lidocaine, but not lacosamide, increased electrical thresholds in all mechanosensitive, but not in the mechano-insensitive, C-fibers. Lacosamide blocked conduction and, in addition, reduced ADS in mechano-insensitive nociceptors significantly more than in mechanosensitive nociceptors (ΔADS: 2.4% ± 0.5% vs 1.6% ± 0.5%), whereas lidocaine had opposite effects. Saline had no significant effect on the conductive properties of C-fibers. Conclusion: Local application of test compounds in pig skin allows for functional assessment of steady-state and use-dependent modulation of sodium channels in nociceptive and nonnociceptive C-fibers. Increased analgesic specificity might derive from selective enhancement of slow inactivation of sodium channels.

Original languageEnglish (US)
Pages (from-to)560-571
Number of pages12
JournalAnesthesia and analgesia
Volume115
Issue number3
DOIs
StatePublished - Sep 1 2012

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

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