title: 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 melanin-concentrating hormone (MCH) neurons; suggesting that wake-active 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.
authors.affiliation: Department of Anesthesiology and Critical Care, Mahoney Institute for Neurological Sciences, Center for Sleep and Respiratory Neurobiology, University of Pennsylvania, Philadelphia, PA 19104, USA. kelzma@uphs.upenn.edu
authors.forename: Max B
authors.initials: MB
authors.lastname: Kelz
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
authors.forename: Jingqiu
authors.initials: J
authors.lastname: Chen
authors.forename: Qing
authors.initials: Q
authors.lastname: Cheng Meng
authors.forename: Jason T
authors.initials: JT
authors.lastname: Moore
authors.forename: Sigrid C
authors.initials: SC
authors.lastname: Veasey
authors.forename: Shelley
authors.initials: S
authors.lastname: Dixon
authors.forename: Marcus
authors.initials: M
authors.lastname: Thornton
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Funato
authors.forename: Masashi
authors.initials: M
authors.lastname: Yanagisawa
mesh_terms: D000768:Anesthesia, General / Q000009:adverse effects; D018685:Anesthetics, Inhalation; D000818:Animals; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D007530:Isoflurane; D008297:Male; D008738:Methyl Ethers; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009479:Neuropeptides / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000068797:Orexins; D021381:Protein Transport; D016760:Proto-Oncogene Proteins c-fos / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000077149:Sevoflurane; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D018685:Anesthetics, Inhalation; D047908:Intracellular Signaling Peptides and Proteins; D008738:Methyl Ethers; D009479:Neuropeptides; D000068797:Orexins; D016760:Proto-Oncogene Proteins c-fos; D000077149:Sevoflurane; D007530:Isoflurane