title: Concomitant facilitation of GABAA receptors and KV7 channels by the non-opioid analgesic flupirtine.
abstract: OBJECTIVE
  Flupirtine is a non-opioid analgesic that has been in clinical use for more than 20 years. It is characterized as a selective neuronal potassium channel opener (SNEPCO). Nevertheless, its mechanisms of action remain controversial and are the purpose of this study.
  
  
  METHODS
  Effects of flupirtine on native and recombinant voltage- and ligand-gated ion channels were explored in patch-clamp experiments using the following experimental systems: recombinant K(IR)3 and K(V)7 channels and α3β4 nicotinic acetylcholine receptors expressed in tsA 201 cells; native voltage-gated Na(+), Ca(2+), inward rectifier K(+), K(V)7 K(+), and TRPV1 channels, as well as GABA(A), glycine, and ionotropic glutamate receptors expressed in rat dorsal root ganglion, dorsal horn and hippocampal neurons.
  
  
  RESULTS
  Therapeutic flupirtine concentrations (≤10 µM) did not affect voltage-gated Na(+) or Ca(2+) channels, inward rectifier K(+) channels, nicotinic acetylcholine receptors, glycine or ionotropic glutamate receptors. Flupirtine shifted the gating of K(V)7 K(+) channels to more negative potentials and the gating of GABA(A) receptors to lower GABA concentrations. These latter effects were more pronounced in dorsal root ganglion and dorsal horn neurons than in hippocampal neurons. In dorsal root ganglion and dorsal horn neurons, the facilitatory effect of therapeutic flupirtine concentrations on K(V)7 channels and GABA(A) receptors was comparable, whereas in hippocampal neurons the effects on K(V)7 channels were more pronounced.
  
  
  CONCLUSIONS
  These results indicate that flupirtine exerts its analgesic action by acting on both GABA(A) receptors and K(V)7 channels.
authors.affiliation: Center for Physiology and Pharmacology, Department of Neurophysiology and Neuropharmacology, Medical University of Vienna, Austria.
authors.forename: Felicia
authors.initials: F
authors.lastname: Klinger
authors.forename: Petra
authors.initials: P
authors.lastname: Geier
authors.forename: Mario M
authors.initials: MM
authors.lastname: Dorostkar
authors.forename: Giri K
authors.initials: GK
authors.lastname: Chandaka
authors.forename: Arsalan
authors.initials: A
authors.lastname: Yousuf
authors.forename: Isabella
authors.initials: I
authors.lastname: Salzer
authors.forename: Helmut
authors.initials: H
authors.lastname: Kubista
authors.forename: Stefan
authors.initials: S
authors.lastname: Boehm
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000166:cytology; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D051656:KCNQ Potassium Channels / Q000502:physiology*; D020671:Posterior Horn Cells / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology*; D017783:Superior Cervical Ganglion / Q000166:cytology
chemical_list: D000631:Aminopyridines; D018712:Analgesics, Non-Narcotic; D051656:KCNQ Potassium Channels; D011963:Receptors, GABA-A; C034161:flupirtine