title: Preconditioning depolarizing ramp currents enhance the effect of sodium channel blockers in primary sensory afferents.
abstract: OBJECTIVE
  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.
  
  
  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.
authors: Institute of Anesthesiology, University Hospital of Zurich, Zurich, Switzerland.
authors: Nisha
authors: N
authors: Vastani
authors: Burkhardt
authors: B
authors: Seifert
authors: Donat R
authors: DR
authors: Spahn
authors: Konrad
authors: K
authors: Maurer
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000344:Afferent Pathways / Q000187:drug effects* / Q000502:physiology*; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D004558:Electric Stimulation / Q000379:methods*; D008012:Lidocaine / Q000494:pharmacology; D008297:Male; D009412:Nerve Fibers / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012684:Sensory Thresholds / Q000187:drug effects / Q000502:physiology; D012867:Skin / Q000294:innervation; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D013779:Tetrodotoxin / Q000494:pharmacology*
chemical_list: D000779:Anesthetics, Local; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; D008012:Lidocaine
keywords: Basic science; local anesthetics; peripheral nerve stimulation; sensory neurons; threshold tracking