The anticonvulsant retigabine is a subtype selective modulator of GABAA receptors.

OBJECTIVE: Within its range of therapeutic plasma concentrations, the anticonvulsant retigabine (ezogabine) is believed to selectively act on Kv7 channels. Here, the contribution of specific γ-aminobutyric acid (GABA)A receptor subtypes to the antiseizure effects of retigabine was investigated. METHODS: Using patch-clamp recordings, seizure-like activity, tonic currents, and GABA-induced currents in hippocampal neurons were tested for their sensitivity toward retigabine, as were recombinant GABAA receptors expressed in tsA 201 cells. RESULTS: Retigabine reduced seizure-like activity elicited by low Mg(2+) in a concentration-dependent manner with half maximal inhibition at 1 µm. Seizure-like activity triggered by blocking either Kv7 channels or GABAA receptors was equally reduced by retigabine, but when these channels/receptors were blocked simultaneously, the inhibition was lost. Retigabine (10 µm) enhanced bicuculline-sensitive tonic currents in hippocampal neurons, but failed to affect GABA-evoked currents. However, when receptors involved in phasic GABAergic inhibition were blocked by penicillin, retigabine did enhance GABA-evoked currents. In tsA 201 cells expressing various combinations of GABAA receptor subunits, 10 µm retigabine enhanced currents through α1ß2δ, α4ß2δ, α4ß3δ, and α6ß2δ receptors, but left currents through α1ß2γ2S, α4ß3γ2S, α5ß3γ2S, and α6ß2γ2S receptors unaltered. With αß receptors, retigabine diminished currents through α1ß2 and α4ß3, but increased currents through α6ß2 receptors. The enhancement of currents through α1ß2δ receptors by retigabine was concentration dependent and became significant at 1 µm. SIGNIFICANCE: These results demonstrate that retigabine is a subtype selective modulator of GABAA receptors with preference for extrasynaptic δ-containing receptors; this property may contribute to its broad antiepileptic effectiveness and explain its lack of effect on absence seizures.

Control of sensory neuron excitability by serotonin involves 5HT2C receptors and Ca(2+)-activated chloride channels.

Serotonin (5HT) is a constituent of the so-called "inflammatory soup" that sensitizes nociceptors during inflammation. Nevertheless, receptors and signaling mechanisms that mediate an excitation of dorsal root ganglion (DRG) neurons by 5HT remained controversial. Therefore, capsaicin-sensitive nociceptive neurons dissociated from rat DRGs were used to investigate effects of 5HT on membrane excitability and currents through ligand- as well as voltage-gated ion channels. In 58% of the neurons tested, 5HT increased action potential firing, an effect that was abolished by the 5HT2 receptor antagonist ritanserin, but not by the 5HT3 antagonist tropisetron. Unlike other algogenic mediators, such as PGE2 and bradykinin, 5HT did not affect currents through TTX-resistant Na(+) channels or Kv7 K(+) channels. In all neurons investigated, 5HT potentiated capsaicin-evoked currents through TRPV1 channels, an effect that was attenuated by antagonists at 5HT2A (4 F 4 PP), 5HT2B (SB 204741), as well as 5HT2C (RS 102221) receptors. 5HT triggered slowly arising inward Cl(-) currents in 53% of the neurons. This effect was antagonized by the 5HT2C receptor blocker only, and the current was prevented by an inhibitor of Ca(2+)-activated chloride channels (CaCC). The 5HT-induced increase in action potential firing was also abolished by this CaCC blocker and by the TRPV1 inhibitor capsazepine. Amongst the subtype selective 5HT2 antagonists, only RS 102221 (5HT2C-selectively) counteracted the rise in action potential firing elicited by 5HT. These results show that 5HT excites DRG neurons mainly via 5HT2C receptors which concomitantly mediate a sensitization of TRPV1 channels and an opening of CaCCs.