An essential role for orexins in emergence from general anesthesia

Max B. Kelz, Yi Sun, Jingqiu Chen, Cheng Meng Qing, Jason T. Moore, Sigrid C. Veasey, Shelley Dixon, Marcus Thornton, Hiromasa Funato, Masashi Yanagisawa

Research output: Contribution to journalArticlepeer-review

251 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1309-1314
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number4
StatePublished - Jan 29 2008


  • Anesthetic hypnosis
  • Arousal
  • NREM sleep circuits
  • Narcolepsy
  • Volatile anesthetics

ASJC Scopus subject areas

  • General


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