Cited by 341Sleep and Wakefulness ResearchAnesthesia and Sedative AgentsNeuroscience of respiration and sleep

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An essential role for orexins in emergence from general anesthesia

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Kelz, Max B., Sun, Yi, Chen, Jingqiu, Cheng Meng, Qing, Moore, Jason T., Veasey, Sigrid C., Dixon, Shelley, Thornton, Marcus, Funato, Hiromasa, Yanagisawa, Masashi·2008·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0707146105PMC PMC2234134

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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.

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Authors: Kelz, M. B., Sun, Y., Chen, J., Cheng Meng, Q., Moore, J. T., Veasey, S. C., Dixon, S., Thornton, M., Funato, H., & Yanagisawa, M.
Affiliations: University of Pennsylvania (US)
*Department of Anesthesiology and Critical Care,
Howard Hughes Medical Institute (US)
ORCID: Kelz, Max B.
Sun, Yi
Chen, Jingqiu
Veasey, Sigrid C.
Funato, Hiromasa
Yanagisawa, Masashi
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2008-01-29
Volume: 105
Issue: 4
Pages: 1309-1314
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.0707146105
PMC: PMC2234134
OpenAlex: W2135826809
Cited by: 341
References: 36
Citations by year: 2026: 12 · 2025: 15 · 2024: 21 · 2023: 17 · 2022: 14 · 2021: 30 · 2020: 25 · 2019: 18 · 2018: 19 · 2017: 12 · 2016: 13 · 2015: 14 · 2014: 22 · 2013: 11 · 2012: 19
FWCI: 13.09
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Foundation for Anesthesia Education and Research
University of Pennsylvania
National Institutes of Health
National Institute of General Medical Sciences (K08GM077357)
Topics: Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
Health Sciences › Medicine › Anesthesiology and Pain Medicine › Anesthesia and Sedative Agents
Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroscience of respiration and sleep
Keywords: orexin, emergence from anesthesia, general anesthesia, anesthesia induction, isoflurane, sevoflurane, Fos expression, orexinergic neurons, melanin-concentrating hormone neurons, orexin-1 receptor antagonist, sleep-wake regulation, loss of consciousness
MeSH terms: Orexins, Sevoflurane, Anesthesia, General, Animals, Female, Isoflurane, Male, Methyl Ethers, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Neuropeptides, Signal Transduction, Proto-Oncogene Proteins c-fos, Anesthetics, Inhalation, Protein Transport, Intracellular Signaling Peptides and Proteins, Mice

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An essential role for orexins in emergence from general anesthesia

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