Concomitant facilitation of GABA_A receptors and K_V7 channels by the non‐opioid analgesic flupirtine

Abstract

BACKGROUND AND PURPOSEFlupirtine 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 APPROACHEffects of flupirtine on native and recombinant voltage-and ligand-gated ion channels were explored in patch-clamp experiments using the following experimental systems: recombinant KIR3 and KV7 channels and a3b4 nicotinic acetylcholine receptors expressed in tsA 201 cells; native voltage-gated Na, and TRPV1 channels, as well as GABAA, glycine, and ionotropic glutamate receptors expressed in rat dorsal root ganglion, dorsal horn and hippocampal neurons. KEY RESULTSTherapeutic flupirtine concentrations (Յ10 mM) 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 KV7 K + channels to more negative potentials and the gating of GABAA 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 KV7 channels and GABAA receptors was comparable, whereas in hippocampal neurons the effects on KV7 channels were more pronounced. CONCLUSIONS AND IMPLICATIONSThese results indicate that flupirtine exerts its analgesic action by acting on both GABAA receptors and KV7 channels. AbbreviationsBMI, bicuculline methiodide; CNQX, cyano-2,3-dihydroxy-7-nitroquinoxaline; DRG, dorsal root ganglion; NBQX, 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide; SCG, superior cervical ganglion; SNEPCO, selective neuronal potassium channel opener

G-protein–gated Inwardly Rectifying Potassium Channels Modulate Respiratory Depression by Opioids

“…Flupirtine also indirectly antagonizes NMDA receptors 23 , activates GABA A receptors 25 and activates other inward rectifier potassium channels 25 , which can modulate preBötC activity 26 . To determine whether flupirtine depresses rhythmic breathing by selectively acting on GIRK channels, we applied it to the preBötC ( Fig.…”

“…Although correlation maps cannot exclude that flupirtine may diffuse beyond the preBötC and may activate GIRK channels in other populations of neurons, it indicated that there was a region of the brainstem with a higher sensitivity to flupirtine that also expresses NK-1R. Flupirtine also indirectly antagonizes NMDA receptors 23 , and activates GABA A receptors 25 and other inward rectifier potassium channels 25 , which may explain why it decreased diaphragm muscle amplitude. To determine whether the effects of flupirtine were due to its action on GIRK channels only, we used mice lacking functional GIRK channels.…”

Metabolic activation and analgesic effect of flupirtine in healthy subjects, influence of the polymorphic NAT2, UGT1A1 and GSTP1

“…The drug acts centrally on GABA(A) receptors and the selective neuronal Kv7 potassium channel [1][2][3], thus offering a mechanism-based therapy for pain relief and normalization of muscle tension [4,5]. In patients with acute and chronic pain, flupirtine is clinically as efficient as weak opioids and NSAIDs [4][5][6][7].…”

Flupirtine effectively prevents development of acute neonatal seizures in an animal model of global hypoxia

“…Evidence from clinical and basic science research studies suggests that KCNQ potassium channels play a very important role in controlling excitation in early-life [33, 35, 36, 39]. Flupirtine, a KCNQ channel opener [12, 23, 28, 42], has been used clinically as an analgesic in Europe for over two decades with a good safety record. Our earlier study demonstrated that flupirtine is more efficacious than diazepam and phenobarbital for the treatment of chemoconvulsant-induced neonatal seizures [37].…”