Abstract
A challenge for theories of general anesthesia is the existence of compounds 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-hexafluoro-2-methoxypropane). The effects of flurothyl and iso-flurothyl were studied using the whole-cell patch-clamp technique on agonist-activated chloride currents in human GABA(A), glycine, and GABA(C) rho(1) receptors expressed in HEK 293 cells. GABA(A) and glycine receptors are promising molecular targets for the actions of inhaled ether general anesthetics. Flurothyl acted as a non-competitive antagonist at GABA(A) alpha(2)beta(1) and alpha(2)beta(1)gamma(2s) receptors, but had no effect at glycine alpha(1) receptors. Flurothyl had biphasic actions on GABA responses at GABA(C) rho(1) receptors. In contrast, iso-flurothyl enhanced ('potentiated') submaximal agonist responses at GABA(A) and glycine receptors, but had no effect on GABA responses at GABA(C) rho(1) receptors. Point mutations in GABA(A) and glycine receptor 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 mutations in the GABA(A) receptor had only modest effects on the inhibitory actions of flurothyl. GABA(A) receptors with mutations conferring insensitivity 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 likely to account for the convulsant effects of flurothyl, while the general anesthetic actions of iso-flurothyl, like those of other ether anesthetics, may be related to positive modulation of GABA(A) and/or glycine receptors.