title: Methadone is a local anaesthetic-like inhibitor of neuronal Na+ channels and blocks excitability of mouse peripheral nerves.
abstract: BACKGROUND
  Opioids enhance and prolong analgesia when applied as adjuvants to local anaesthetics (LAs). A possible molecular mechanism for this property is a direct inhibition of voltage-gated Na(+) channels which was reported for some opioids. Methadone is an effective adjuvant to LA and was recently reported to inhibit cardiac Na(+) channels. Here, we explore and compare LA properties of methadone and bupivacaine on neuronal Na(+) channels, excitability of peripheral nerves, and cell viability.
  
  
  METHODS
  Effects of methadone were explored on compound action potentials (CAP) of isolated mouse saphenous nerves. Patch clamp recordings were performed on Na(+) channels in ND7/23 cells, the α-subunits Nav1.2, Nav1.3, Nav1.7, and Nav1.8, and the hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2). Cytotoxicity was determined using flow cytometry.
  
  
  RESULTS
  Methadone (IC50 86-119 µM) is a state-dependent and unselective blocker on Nav1.2, Nav1.3, Nav1.7, and Nav1.8 with a potency comparable with that of bupivacaine (IC50 177 µM). Both bupivacaine and methadone also inhibit C- and A-fibre CAPs in saphenous nerves in a concentration-dependent manner. Tonic block of Nav1.7 revealed a discrete stereo-selectivity with a higher potency for levomethadone than for dextromethadone. Methadone is also a weak blocker of HCN2 channels. Both methadone and bupivacaine induce a pronounced cytotoxicity at concentrations required for LA effects.
  
  
  CONCLUSIONS
  Methadone induces typical LA effects by inhibiting Na(+) channels with a potency similar to that of bupivacaine. This hitherto unknown property of methadone might contribute to its high efficacy when applied as an adjuvant to LA.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany stoetzer.carsten@mh-hannover.de.
authors.forename: C
authors.initials: C
authors.lastname: Stoetzer
authors.affiliation: Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Kistner
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Stüber
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Wirths
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Schulze
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Doll
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Foadi
authors.affiliation: Department of Neurology, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Wegner
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Ahrens
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Leffler
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000701:Analgesics, Opioid / Q000494:pharmacology; D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D002045:Bupivacaine / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005434:Flow Cytometry / Q000379:methods; D006801:Humans; D008691:Methadone / Q000494:pharmacology*; D051379:Mice; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques / Q000379:methods; D010525:Peripheral Nerves / Q000187:drug effects*; D015222:Sodium Channels / Q000187:drug effects*
chemical_list: D000701:Analgesics, Opioid; D000779:Anesthetics, Local; D015222:Sodium Channels; D008691:Methadone; D002045:Bupivacaine
keywords: bupivacaine; local anaesthetic; methadone; nerve block; sodium channel