δ Subunit‐containing GABA_A receptors are preferred targets for the centrally acting analgesic flupirtine

Abstract

Background and PurposeThe Kv7 channel activator flupirtine is a clinical analgesic characterized as ‘selective neuronal potassium channel opener’. Flupirtine was found to exert comparable actions at GABAA receptors and Kv7 channels in neurons of pain pathways, but not in hippocampus.Experimental ApproachExpression patterns of GABAA receptors were explored in immunoblots of rat dorsal root ganglia, dorsal horns and hippocampi using antibodies for 10 different subunits. Effects of flupirtine on recombinant and native GABAA receptors were investigated in patch clamp experiments and compared with the actions on Kv7 channels.Key ResultsImmunoblots pointed towards α2, α3, β3 and γ2 subunits as targets, but in all γ2-containing receptors the effects of flupirtine were alike: leftward shift of GABA concentration-response curves and diminished maximal amplitudes. After replacement of γ2S by δ, flupirtine increased maximal amplitudes. Currents through α1β2δ receptors were more enhanced than those through Kv7 channels. In hippocampal neurons, flupirtine prolonged inhibitory postsynaptic currents, left miniature inhibitory postsynaptic currents (mIPSCs) unaltered and increased bicuculline-sensitive tonic currents; penicillin abolished mIPSCs, but not tonic currents; concentration-response curves for GABA-induced currents were shifted to the left by flupirtine without changes in maximal amplitudes; in the presence of penicillin, maximal amplitudes were increased; GABA-induced currents in the presence of penicillin were more sensitive towards flupirtine than K+ currents. In dorsal horn neurons, currents evoked by the δ-preferring agonist THIP (gaboxadol) were more sensitive towards flupirtine than K+ currents.Conclusions and ImplicationsFlupirtine prefers δ-containing GABAA receptors over γ-containing ones and over Kv7 channels.

Breaking barriers to novel analgesic drug development

“…Positive allosteric modulators of GABAA chloride channels could have potential as pain relievers 231,232 , but generally also produce strong sedation. It was recently found that flupirtine acts to enhance GABA-mediated currents at concentrations comparable to those enhancing Kv7 activity 233 . Because GABAA channels are highly diverse in terms of subunit structure (being pentameric combinations of 19 different potential subunits) with different combinations in different neurons and sub-cellular regions, which is still very incompletely understood, it may be possible to find agents with selectivity for specific subunit combinations that enhance pain-relief properties relative to sedation 234 .…”

Suppression of KCNQ/M Potassium Channel in Dorsal Root Ganglia Neurons Contributes to the Development of Osteoarthritic Pain

“…In this study, we also found flupirtine significantly reduced the mechanical allodynia and thermal hyperalgesia in the MIA-induced osteoarthritic model. However, flupirtine could also shift the gating of GA-BAA receptors to lower GABA concentrations except activating KCNQ/M channel [20]. To further confirm the specific action of flupirtine on osteoarthritic pain through the activation of KCNQ/M channel function, we used the blocker XE991 to test whether the effect of flupirtine could be reversed.…”

Anticonvulsant effect of flupirtine in an animal model of neonatal hypoxic-ischemic encephalopathy

“…However, it is not approved for any indications in the USA. Flupirtine has been shown to affect the function of KCNQ potassium channels (Klinger et al, 2012;Martire et al, 2004;Wladyka and Kunze, 2006), the G protein-coupled inwardly rectifying potassium (GIRK) channels (Jakob and Krieglstein,1997;Kornhuber et al, 1999;Montandon et al, 2016;Sattler et al, 2008) (but see (Klinger et al, 2012)), and GABA A receptors (Klinger et al, 2012(Klinger et al, , 2015. KCNQ channels are voltage gated, depolarization activated potassium channels.…”