title: The differential effects of two sodium channel modulators on the conductive properties of C-fibers in pig skin in vivo.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Anesthesiology and Operative Intensive Care, Heidelberg University, Mannheim, Germany. otilia.obreja@medma.uni-heidelberg.de
authors.forename: Otilia
authors.initials: O
authors.lastname: Obreja
authors.forename: Michael
authors.initials: M
authors.lastname: Hirth
authors.forename: Brian
authors.initials: B
authors.lastname: Turnquist
authors.forename: Roman
authors.initials: R
authors.lastname: Rukwied
authors.forename: Matthias
authors.initials: M
authors.lastname: Ringkamp
authors.forename: Martin
authors.initials: M
authors.lastname: Schmelz
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D004558:Electric Stimulation; D005260:Female; D000078334:Lacosamide; D008012:Lidocaine / Q000494:pharmacology; D008297:Male; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects* / Q000502:physiology; D009431:Neural Conduction / Q000187:drug effects* / Q000502:physiology; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology; D011930:Reaction Time / Q000187:drug effects; D012867:Skin / Q000294:innervation; D015222:Sodium Channels / Q000187:drug effects*; D013552:Swine
chemical_list: D000081:Acetamides; D000700:Analgesics; D015222:Sodium Channels; D000078334:Lacosamide; D008012:Lidocaine