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Concomitant facilitation of GABA A receptors and K V7 channels by the non-opioid analgesic flupirtine

Journal Article


Abstract


  • BACKGROUND AND PURPOSE 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. EXPERIMENTAL APPROACH 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 IR3 and K V7 channels and α3β4 nicotinic acetylcholine receptors expressed in tsA 201 cells; native voltage-gated Na +, Ca 2+, inward rectifier K +, K V7 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. KEY 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 V7 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 V7 channels and GABA A receptors was comparable, whereas in hippocampal neurons the effects on K V7 channels were more pronounced. CONCLUSIONS AND IMPLICATIONS These results indicate that flupirtine exerts its analgesic action by acting on both GABA A receptors and K V7 channels. © 2012 The British Pharmacological Society.

Publication Date


  • 2012

Citation


  • Klinger, F., Geier, P., Dorostkar, M. M., Chandaka, G. K., Yousuf, A., Salzer, I., . . . Boehm, S. (2012). Concomitant facilitation of GABA A receptors and K V7 channels by the non-opioid analgesic flupirtine. British Journal of Pharmacology, 166(5), 1631-1642. doi:10.1111/j.1476-5381.2011.01821.x

Scopus Eid


  • 2-s2.0-84862738335

Start Page


  • 1631

End Page


  • 1642

Volume


  • 166

Issue


  • 5

Abstract


  • BACKGROUND AND PURPOSE 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. EXPERIMENTAL APPROACH 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 IR3 and K V7 channels and α3β4 nicotinic acetylcholine receptors expressed in tsA 201 cells; native voltage-gated Na +, Ca 2+, inward rectifier K +, K V7 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. KEY 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 V7 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 V7 channels and GABA A receptors was comparable, whereas in hippocampal neurons the effects on K V7 channels were more pronounced. CONCLUSIONS AND IMPLICATIONS These results indicate that flupirtine exerts its analgesic action by acting on both GABA A receptors and K V7 channels. © 2012 The British Pharmacological Society.

Publication Date


  • 2012

Citation


  • Klinger, F., Geier, P., Dorostkar, M. M., Chandaka, G. K., Yousuf, A., Salzer, I., . . . Boehm, S. (2012). Concomitant facilitation of GABA A receptors and K V7 channels by the non-opioid analgesic flupirtine. British Journal of Pharmacology, 166(5), 1631-1642. doi:10.1111/j.1476-5381.2011.01821.x

Scopus Eid


  • 2-s2.0-84862738335

Start Page


  • 1631

End Page


  • 1642

Volume


  • 166

Issue


  • 5