Differential modulatory actions of the volatile convulsant flurothyl and its anesthetic isomer at inhibitory ligand-gated ion channels

A challenge for theories of general anesthesia is the existence of compound s predicted to be anesthetics but which, instead, do not produce anesthesia and often elicit other behavioral effects such as convulsions. This study focused on flurothyl' (bis[2,2,2-trifluoroethyl] ether), a potent volatile convulsant, and its anesthetic isomer, 'iso-flurothyl' (1,1,1,3,3,3-hexaflu oro-2-mrthoxypropane). The effects of flurothyl and iso-flurothyl were stud ied using the whole-cell patch-clamp technique on agonist-activated chlorid e currents in human GABA(A), glycine, and GABA(c) rho(1) receptors expresse d in HEK 293 cells. GABA(A) and glycine receptors are promising molecular t argets for the actions of inhaled ether general anesthetics. Flurothyl acte d as a non-competitive antagonist at GABA(A) alpha(2)beta(1) and alpha(2)be ta(1)gamma(2s) receptors, but had no effect at glycine alpha(1) receptors. Flurothyl had biphasic actions on GABA responses at GABA(A) rho(1) receptor s. In contrast, iso-flurothyl enhanced ('potentiated') submaximal agonist r esponses at GABA(A) and glycine receptors, but had no effect on GABA respon ses at GABA(c) rho(1) receptors. Point mutations in GABA(A) and glycine rec eptor subunits, which have been previously shown to abolish potentiation of agonist responses by the ether anesthetics enflurane and isoflurane, also ablated potentiation of agonist responses by iso-flurothyl. These same muta tions in the GABA(A) receptor had only modest effects on the inhibitory act ions of flurothyl. GABA(A) receptors with mutations conferring insensitivit y to antagonism by picrotoxin were still inhibited by flurothyl, suggesting that picrotoxin and flurothyl antagonize GABA responses by distinct sites or mechanisms of action. In summary, antagonism of GABA(A) receptors is lik ely to account for the convulsant effects of flurothyl, while the general a nesthetic actions of iso-flurothyl, like those of other ether anesthetics, may be related to positive modulation of GABA(A) and/or glycine receptors. (C) 2000 Published by Elsevier Science Ltd. All rights reserved.