• Bo Han, Hilary S McCarren, Dan O'Neill, and Max B Kelz.
• From the Department of Anesthesiology and Critical Care (B.H.), Department of Pharmacology (H.S.M.), University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania; Department of Anesthesiology, Weill Cornell Medical College, New York, New York (D.O.); and Department of Anesthesiology and Critical Care, Center for Sleep and Circadian Neurobiology, Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania (M.B.K.).
• Anesthesiology. 2014 Nov 1; 121 (5): 999-1009.

BackgroundNumerous studies demonstrate that anesthetic-induced unconsciousness is accompanied by activation of hypothalamic sleep-promoting neurons, which occurs through both pre- and postsynaptic mechanisms. However, the correlation between drug exposure, neuronal activation, and onset of hypnosis remains incompletely understood. Moreover, the degree to which anesthetics activate both endogenous populations of γ-aminobutyric acid (GABA)ergic sleep-promoting neurons within the ventrolateral preoptic (VLPO) and median preoptic nuclei remains unknown.MethodsMice were exposed to oxygen, hypnotic doses of isoflurane or halothane, or 1,2-dichlorohexafluorocyclobutane (F6), a nonimmobilizer. Hypothalamic brain slices prepared from anesthetic-naive mice were also exposed to oxygen, volatile anesthetics, or F6 ex vivo, both in the presence and absence of tetrodotoxin. Double-label immunohistochemistry was performed to quantify the number of c-Fos-immunoreactive nuclei in the GABAergic subpopulation of neurons in the VLPO and the median preoptic areas to test the hypothesis that volatile anesthetics, but not nonimmobilizers, activate sleep-promoting neurons in both nuclei.ResultsIn vivo exposure to isoflurane and halothane doubled the fraction of active, c-Fos-expressing GABAergic neurons in the VLPO, whereas F6 failed to affect VLPO c-Fos expression. Both in the presence and absence of tetrodotoxin, isoflurane dose-dependently increased c-Fos expression in GABAergic neurons ex vivo, whereas F6 failed to alter expression. In GABAergic neurons of the median preoptic area, c-Fos expression increased with isoflurane and F6, but not with halothane exposure.ConclusionsAnesthetic unconsciousness is not accompanied by global activation of all putative sleep-promoting neurons. However, within the VLPO hypnotic doses of volatile anesthetics, but not nonimmobilizers, activate putative sleep-promoting neurons, correlating with the appearance of the hypnotic state.

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