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Introduction: Tolerance is observed for a variety of central nervous system depressants including ethanol, which is an anesthetic, but has not been convincingly demonstrated for a potent halogenated volatile anesthetic. Failure to demonstrate tolerance to these agents may be the result of inadequate exposure to anesthetic. In this study, we exposed Xenopus laevis tadpoles to surgical anesthetic concentrations of isoflurane for 1 wk., Methods: Xenopus laevis tadpoles were produced by in vitro fertilization, and exposed to isoflurane (0.59%, 0.98%, 1.52%) or oxygen for 1 wk starting from the time of fertilization., Results: Changes in anesthetic EC(50) were small and not in a consistent direction. Control animals had an anesthetic EC(50) of 0.594% +/- 0.003% isoflurane. Tadpoles exposed to 1.52% isoflurane had a lower EC(50) than controls (by 16%), whereas tadpoles raised under 0.59% and 0.98% isoflurane had higher EC(50)s than control (by 4.7% and 7.4%, respectively)., Conclusion: We provide the first description of week-long exposures of vertebrates to surgical anesthetic concentrations of isoflurane, and the first report of such exposures in developing vertebrates. Tolerance to isoflurane does not occur in developing Xenopus laevis tadpoles. Taken together with studies in other organisms, the development of tolerance to ethanol but not isoflurane suggests that mechanisms shared by these drugs probably do not account for the development of tolerance.

Background: We tested the hypothesis that two metabolites that are elevated in ketosis (beta-hydroxybutyric acid, and acetone) modulate ion channels in a manner similar to anesthetics and produce anesthesia in animals., Methods: alpha1beta2gamma2sgamma-aminobutyric acid type A (GABA(A)), alpha1 glycine, NR1/NR2A N-methyl-d-aspartate, and two pore domain TRESK channels were expressed in Xenopus laevis oocytes and studied using two-electrode voltage clamping. The effect of beta hydroxybutyric acid and acetone on channel function was measured. The anesthetic effects of these drugs were measured in X. laevis tadpoles., Results: Both beta hydroxybutyric acid and acetone enhanced glycine receptor function in the concentration range that is obtained in ketoacidosis in humans. Beta hydroxybutyric acid also enhanced GABA(A) receptor function at these concentrations. Both acetone and beta-hydroxybutyric acid anesthetized tadpoles, with an EC50 for acetone of 264 +/- 2 mM (mean +/- se) and for beta-hydroxybutyric acid of 151 +/- 11 mM at pH 7.0. Acetone enhanced GABA(A) receptors at concentrations of 50 mM and above. Inhibition of TRESK channel function was seen with 100 mM acetone or larger concentration. N-methyl-D-aspartate receptor function was inhibited at concentrations of acetone of 200 mM and larger., Conclusions: Beta hydroxybutyric acid and acetone are anesthetics. Both ketone bodies enhance inhibitory glycine receptors at concentrations observed clinically in ketoacidosis. In addition, beta-hydroxybutyric acid enhances GABA(A) receptor function at these concentrations. Subanesthetic concentrations of these drugs may contribute to the lethargy and impairment of consciousness seen in ketoacidosis.