title: Lidocaine reduces the transition to slow inactivation in Na(v)1.7 voltage-gated sodium channels.
abstract: OBJECTIVE
  The primary use of local anaesthetics is to prevent or relieve pain by reversibly preventing action potential propagation through the inhibition of voltage-gated sodium channels. The tetrodotoxin-sensitive voltage-gated sodium channel subtype Na(v)1.7, abundantly expressed in pain-sensing neurons, plays a crucial role in perception and transmission of painful stimuli and in inherited chronic pain syndromes. Understanding the interaction of lidocaine with Na(v)1.7 channels could provide valuable insight into the drug's action in alleviating pain in distinct patient populations. The aim of this study was to determine how lidocaine interacts with multiple inactivated conformations of Na(v)1.7 channels.
  
  
  METHODS
  We investigated the interactions of lidocaine with wild-type Na(v)1.7 channels and a paroxysmal extreme pain disorder mutation (I1461T) that destabilizes fast inactivation. Whole cell patch clamp recordings were used to examine the activity of channels expressed in human embryonic kidney 293 cells.
  
  
  RESULTS
  Depolarizing pulses that increased slow inactivation of Na(v)1.7 channels also reduced lidocaine inhibition. Lidocaine enhanced recovery of Na(v)1.7 channels from prolonged depolarizing pulses by decreasing slow inactivation. A paroxysmal extreme pain disorder mutation that destabilizes fast inactivation of Na(v)1.7 channels decreased lidocaine inhibition.
  
  
  CONCLUSIONS
  Lidocaine decreased the transition of Na(v)1.7 channels to the slow inactivated state. The fast inactivation gate (domain III-IV linker) is important for potentiating the interaction of lidocaine with the Na(v)1.7 channel.
authors.affiliation: Department of Pharmacology and Toxicology, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Sheets
authors.forename: Brian W
authors.initials: BW
authors.lastname: Jarecki
authors.forename: Theodore R
authors.initials: TR
authors.lastname: Cummins
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000779:Anesthetics, Local / Q000494:pharmacology*; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D008012:Lidocaine / Q000494:pharmacology*; D009154:Mutation; D062556:NAV1.7 Voltage-Gated Sodium Channel; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010146:Pain / Q000235:genetics / Q000378:metabolism; D018408:Patch-Clamp Techniques / Q000379:methods; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D000779:Anesthetics, Local; D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D015222:Sodium Channels; D013779:Tetrodotoxin; D008012:Lidocaine