title: The opioid methadone induces a local anaesthetic-like inhibition of the cardiac Na⁺ channel, Na(v)1.5.
abstract: OBJECTIVE
  Treatment with methadone is associated with severe cardiac arrhythmias, a side effect that seems to result from an inhibition of cardiac hERG K⁺ channels. However, several other opioids are inhibitors of voltage-gated Na⁺ channels. Considering the common assumption that an inhibition of the cardiac Na⁺ channel Na(v)1.5, is the primary mechanism for local anaesthetic (LA)-induced cardiotoxicity, we hypothesized that methadone has LA-like properties leading to a modulation of Na(v)1.5 channels.
  
  
  METHODS
  The whole-cell patch clamp technique was applied to investigate the effects of methadone on wild-type and mutant human Na(v)1.5 channels expressed in HEK293 cells. A homology model of human Na(v)1.5 channels was used to perform automated ligand-docking studies.
  
  
  RESULTS
  Methadone inhibited Na(v)1.5 channels in a state-dependent manner, that is, tonic block was stronger with inactivated channels than with resting channels and a use-dependent block at 10 Hz. Methadone induced a concentration-dependent shift of the voltage dependency of both fast and slow inactivation towards more hyperpolarized potentials, and impaired recovery from fast and slow inactivation. The LA-insensitive mutants N406K and F1760A exhibited reduced tonic and use-dependent block by methadone, and docking predictions positioned methadone in a cavity that was delimited by the residue F1760. Dextromethadone and levomethadone induced discrete stereo-selective effects on Na(v)1.5 channels.
  
  
  CONCLUSIONS
  Methadone interacted with the LA-binding site to inhibit Na(v)1.5 channels. Our data suggest that these channels are a hitherto unrecognized molecular component contributing to cardiac arrhythmias induced by methadone.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Schulze
authors.forename: C
authors.initials: C
authors.lastname: Stoetzer
authors.forename: A O
authors.initials: AO
authors.lastname: O'Reilly
authors.forename: E
authors.initials: E
authors.lastname: Eberhardt
authors.forename: N
authors.initials: N
authors.lastname: Foadi
authors.forename: J
authors.initials: J
authors.lastname: Ahrens
authors.forename: F
authors.initials: F
authors.lastname: Wegner
authors.forename: A
authors.initials: A
authors.lastname: Lampert
authors.forename: J
authors.initials: J
authors.lastname: de la Roche
authors.forename: A
authors.initials: A
authors.lastname: Leffler
mesh_terms: D000779:Anesthetics, Local / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008691:Methadone / Q000737:chemistry / Q000494:pharmacology*; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000187:drug effects* / Q000378:metabolism; D009294:Narcotics / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D000779:Anesthetics, Local; D018076:DNA, Complementary; D008024:Ligands; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009294:Narcotics; C568320:SCN5A protein, human; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D008691:Methadone
keywords: Nav1.5; cardiac toxicity; local anaesthetic; methadone; sodium channel