BJP British Journal of Pharmacology / Subunitcontaining GABAA receptors are preferred targets for the centrally acting analgesic flupirtine

Background and Purpose The 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 Approach Expression 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 Results Immunoblots pointed towards 2, 3, 3 and 2 subunits as targets, but in all 2containing receptors the effects of flupirtine were alike: leftward shift of GABA concentrationresponse curves and diminished maximal amplitudes. After replacement of 2S by , flupirtine increased maximal amplitudes. Currents through 12 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 bicucullinesensitive tonic currents; penicillin abolished mIPSCs, but not tonic currents; concentrationresponse curves for GABAinduced currents were shifted to the left by flupirtine without changes in maximal amplitudes; in the presence of penicillin, maximal amplitudes were increased; GABAinduced currents in the presence of penicillin were more sensitive towards flupirtine than K+ currents. In dorsal horn neurons, currents evoked by the preferring agonist THIP (gaboxadol) were more sensitive towards flupirtine than K+ currents. Conclusions and Implications Flupirtine prefers containing GABAA receptors over containing ones and over Kv7 channels.(VLID)484634