δ Subunit‐containing GABA(A) receptors are preferred targets for the centrally acting analgesic flupirtine

BACKGROUND AND PURPOSE: The K(v)7 channel activator flupirtine is a clinical analgesic characterized as ‘selective neuronal potassium channel opener’. Flupirtine was found to exert comparable actions at GABA(A) receptors and K(v)7 channels in neurons of pain pathways, but not in hippocampus. EXPERIMENTAL APPROACH: Expression patterns of GABA(A) 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 GABA(A) receptors were investigated in patch clamp experiments and compared with the actions on K(v)7 channels. KEY RESULTS: Immunoblots 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 K(v)7 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 IMPLICATIONS: Flupirtine prefers δ‐containing GABA(A) receptors over γ‐containing ones and over K(v)7 channels.