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An essential role for orexins in emergence from general anesthesia
Open accessAbstract
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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“using c-Fos as a proxy for antecedent activity, neurons within many of these nuclei have been identified to be inhibited during general anesthesia [98, 100, 101, 114].”
From The Biology of General Anesthesia from Paramecium to Primate (2019) · cites this paper as [114]
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The Neurobiology of Anesthetic Emergence
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Reitz, S. L., Wasilczuk, A. Z., Beh, G. H., Proekt, A., & Kelz, M. B. (2020) · Current Biology · doi:10.1016/j.cub.2020.10.050 · Cited by 48
Self-citationα2-Adrenergic Stimulation of the Ventrolateral Preoptic Nucleus Destabilizes the Anesthetic State
McCarren, H. S., Chalifoux, M. R., Han, B., Moore, J. T., Meng, Q. C., Baron-Hionis, N., Sedigh-Sarvestani, M., Contreras, D., Beck, S. G., & Kelz, M. B. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.1135-14.2014 · Cited by 45
Self-citationA stochastic basis for neural inertia in emergence from general anaesthesia
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Yang, C., Zhang, L., Hao, H., Ran, M., Li, J., & Dong, H. (2019) · Neuropeptides · doi:10.1016/j.npep.2019.03.004 · Cited by 43
Asymmetric neural dynamics characterize loss and recovery of consciousness
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Robust alternative to the righting reflex to assess arousal in rodents
Gao, S., & Calderon, D. P. (2020) · Scientific Reports · doi:10.1038/s41598-020-77162-3 · Cited by 41
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Metadata
- 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)
- 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
- 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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