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doi: 10.1097/ALN.0000000000000383
Perioperative Medicine: Basic Science

Distinctive Recruitment of Endogenous Sleep-promoting Neurons by Volatile Anesthetics and a Nonimmobilizer

Han, Bo M.D., Ph.D.; McCarren, Hilary S. Ph.D.; O’Neill, Dan M.D.; Kelz, Max B. M.D., Ph.D.

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Background: Numerous 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.
Methods: Mice 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.
Results: In 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.
Conclusions: Anesthetic 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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