The non-opioid analgesic flupirtine is a modulator of GABAA receptors involved in pain sensation
BMC Pharmacology volume 8, Article number: A14 (2008)
Flupirtine is a centrally acting, non-opioid analgesic with muscle relaxant and neuroprotective properties. Although routinely used in the clinic, its mechanism of action remained poorly understood; it had been suggested to antagonize NMDA receptors and to activate G protein-coupled inward rectifier (GIRK) and KCNQ K+ channels. Since spinal GABAA receptors are involved in pain sensation, we investigated the effects of flupirtine on this and other transmitter-gated ion channels.
Materials and methods
Perforated patch clamp recordings were obtained in primary cultures of rat hippocampal, sympathetic and dorsal root ganglion (DRG) neurons.
Flupirtine (30 μM) enhanced currents evoked by GABA (10 μM) in all neurons investigated, but this effect was significantly larger in DRG than hippocampal or sympathetic neurons. In DRG neurons, flupirtine behaved as uncompetitive antagonist: it lowered EC50 values for GABA-induced currents 5.3-fold and depressed maximal amplitudes by 34%. In hippocampal neurons, EC50 values were reduced 3.1-fold; maxima remained unchanged. Flupirtine concentration-dependently enhanced currents evoked by 3 μM GABA up to 8-fold in DRG (EC50: 21 μM) and 2-fold in hippocampal neurons (EC50: 13 μM). In hippocampal, but not DRG, neurons, flupirtine (100 μM) alone elicited inward currents that were not additive to those evoked by pentobarbital, abolished by bicuculline, but not altered by flumazenil. Flupirtine (10 μM) failed to affect currents through NMDA, AMPA/kainate, glycine or nicotinic receptors in hippocampal and sympathetic neurons, respectively; it also failed to affect currents through GIRK1/2 channels, but concentration-dependently activated currents through KCNQ channels; this effect was more pronounced in sympathetic than DRG or hippocampal neurons.
These results reveal flupirtine as subtype-selecting allosteric modulator of GABAA receptors; its analgetic action may thus results from a combined action on GABAA receptors and KCNQ channels in pain pathways.
Supported by the Austrian Science Fund FWF (W1205).
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Popovici, F., Dorostkar, M. & Boehm, S. The non-opioid analgesic flupirtine is a modulator of GABAA receptors involved in pain sensation. BMC Pharmacol 8 (Suppl 1), A14 (2008). https://doi.org/10.1186/1471-2210-8-S1-A14