An essential role for orexins in emergence from general anesthesia

Abstract

The neural mechanisms through which the state of anesthesia arises and dissipates remain unknown. One common belief is that emergence from anesthesia is the inverse process of induction, brought about by elimination of anesthetic drugs from their CNS site(s) of action. Anesthetic-induced unconsciousness may result from specific interactions of anesthetics with the neural circuits regulating sleep and wakefulness. Orexinergic agonists and antagonists have the potential to alter the stability of the anesthetized state. In this report, we refine the role of the endogenous orexin system in impacting emergence from, but not entry into the anesthetized state, and in doing so, we distinguish mechanisms of induction from those of emergence. We demonstrate that isoflurane and sevoflurane, two commonly used general anesthetics, inhibit c-Fos expression in orexinergic but not adjacent melaninconcentrating hormone (MCH) neurons; suggesting that wakeactive orexinergic neurons are inhibited by these anesthetics. Genetic ablation of orexinergic neurons, which causes acquired murine narcolepsy, delays emergence from anesthesia, without changing anesthetic induction. Pharmacologic studies with a selective orexin-1 receptor antagonist confirm a specific orexin effect on anesthetic emergence without an associated change in induction. We conclude that there are important differences in the neural substrates mediating induction and emergence. These findings support the concept that emergence depends, in part, on recruitment and stabilization of wake-active regions of brain.anesthetic hypnosis ͉ arousal ͉ narcolepsy ͉ NREM sleep circuits ͉ volatile anesthetics

Dementia and sensitivity to anesthetics

“…Traditionally, this has been considered a pharmacokinetic phenomenon, but more recent data support the hypothesis that emergence from anesthesia is under distinct neurobiological control. [22][23][24] These findings bear on the present question. Even if we assume no difference in anesthetic sensitivity between demented and non-demented patients at the beginning of the anesthetic effect, there may nonetheless be significant differences at its end.…”

“…Cela a été traditionnellement considéré comme étant un phénomène pharmacocinétique, mais des données plus récentes étayent l'hypothèse que l'émergence de l'anesthésie relève d'un contrôle neurobiologique distinct. [22][23][24] Ces constatations sont pertinentes pour la question présente. Même si nous supposons qu'il n'y a pas de différence de sensibilité aux anesthésiques entre les patients atteints de démence et les patients indemnes de MA au commencement de l'effet des anesthésiques, il pourrait néanmoins y avoir des différences significatives quand cet effet prend fin.…”

Sepsis and the orexin system

“…administration of OXs reduced intravenous anesthesia time while OX1 receptor antagonist prolonged it [31,32]. Similarly, Kelts et al [33] reported that genetic ablation of OXergic neurons (OX/ataxin-3 mice) and selective OX1 receptor antagonists delayed emergence from volatile anesthesia such as sevoflurane and isoflurane. Based on these observations, sepsis-induced OXergic depression may reduce anesthesia requirement.…”

Lesion of cholinergic neurons in nucleus basalis enhances response to general anesthetics

“…Despite advances made on the molecular action of various general anesthetics, such as their action on K + channels, GABA A , nicotinic and glutamate receptors (Franks, 2008), brain structures underlying general anesthesia remain unclear. Anesthetic-induced loss of consciousness was enhanced if arousal related brain structures were ablated or inactivated (Devor and Zalkind, 2001;Nelson et al, 2002;Flint et al, 2010;Franks, 2008;Kelz et al, 2008;Lu et al, 2008;Luo and Leung, 2009), and sleep deprivation increased the potency of propofol and isoflurane (Tung et al, 2002).…”