Role of endogenous sleep-wake and analgesic systems in anesthesia

Lu, Jun; Nelson, Laura E.; Franks, Nick; Maze, Mervyn; Chamberlin, Nancy L.; Saper, Clifford B.

doi:10.1002/cne.21685

Cited by 230Sleep and Wakefulness ResearchAnesthesia and Sedative AgentsNeuroscience of respiration and sleep

Role of endogenous sleep-wake and analgesic systems in anesthesia

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Lu, Jun, Nelson, Laura E., Franks, Nick, Maze, Mervyn, Chamberlin, Nancy L., Saper, Clifford B.·2008·Journal of Comparative Neurology

DOI 10.1002/cne.21685PMC PMC4924624

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Abstract

Classical anesthetics of the γ‐aminobutyric acid type A receptor (GABA A )‐enhancing class (e.g., pentobarbital, chloral hydrate, muscimol, and ethanol) produce analgesia and unconsciousness (sedation). Dissociative anesthetics that antagonize the N‐methyl‐D‐aspartate (NMDA) receptor (e.g., ketamine, MK‐801, dextromethorphan, and phencyclidine) produce analgesia but do not induce complete loss of consciousness. To understand the mechanisms underlying loss of consciousness and analgesia induced by general anesthetics, we examined the patterns of expression of c‐Fos protein in the brain and correlated these with physiological effects of systemically administering GABAergic agents and ketamine at dosages used clinically for anesthesia in rats. We found that GABAergic agents produced predominantly delta activity in the electroencephalogram (EEG) and sedation. In contrast, anesthetic doses of ketamine induced sedation, followed by active arousal behaviors, and produced a faster EEG in the theta range. Consistent with its behavioral effects, ketamine induced Fos expression in cholinergic, monoaminergic, and orexinergic arousal systems and completely suppressed Fos immunoreactivity in the sleep‐promoting ventrolateral preoptic nucleus (VLPO). In contrast, GABAergic agents suppressed Fos in the same arousal‐promoting systems but increased the number of Fos‐immunoreactive neurons in the VLPO compared with waking control animals. All anesthetics tested induced Fos in the spinally projecting noradrenergic A5–7 groups. 6‐hydroxydopamine lesions of the A5–7 groups or ibotenic acid lesions of the ventrolateral periaqueductal gray matter (vlPAG) attenuated antinociceptive responses to noxious thermal stimulation (tail‐flick test) by both types of anesthetics. We hypothesize that neural substrates of sleep‐wake behavior are engaged by low‐dose sedative anesthetics and that the mesopontine descending noradrenergic cell groups contribute to the analgesic effects of both NMDA receptor antagonists and GABA A receptor‐enhancing anesthetics. J. Comp. Neurol. 508:648–662, 2008. © 2008 Wiley‐Liss, Inc.

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VLPO metabolic activation, measured by c-Fos, is associated with various sedative-hypnotic drugs.
“identified the metabolic activation of VLPO—as determined by c-Fos expression, a marker of antecedent cellular activity—in association with a variety of sedative-hypnotic drugs [98–100].”
From The Biology of General Anesthesia from Paramecium to Primate (2019) · cites this paper as [100]
Except for ketamine, systemic hypnotic doses of every general anesthetic examined recruit sleep-promoting VLPO neurons.
“with the exception of ketamine, systemic delivery of hypnotic doses of every general anesthetic examined recruits sleep-promoting neurons in the VLPO [98–102]”
From The Biology of General Anesthesia from Paramecium to Primate (2019) · cites this paper as [100]
Using c-Fos as a proxy, neurons in many wake-promoting nuclei are inhibited during general anesthesia.
“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 [100]

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“Proposals about where exactly this might occur include the locus coeruleus, tuberomammillary nucleus, medial thalamus, lateral hypothalamus, and preoptic area (Correa-Sales et al., 1992; Alkire et al., 2008; Franks, 2008; Lu et al., 2008; Brown et al., 2010; Moore et al., 2012; Zecharia et al., 2012; Scharf and Kelz,…”
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Authors: Lu, J., Nelson, L. E., Franks, N., Maze, M., Chamberlin, N. L., & Saper, C. B.
Affiliations: Beth Israel Deaconess Medical Center (US)
Chelsea and Westminster Hospital (GB)
Corresponding author: Lu, Jun
ORCID: Lu, Jun
Maze, Mervyn
Saper, Clifford B.
Venue: Journal of Comparative Neurology
Publisher: Wiley
Published: 2008-03-28
Volume: 508
Issue: 4
Pages: 648-662
ISSN: 0021-9967 (ISSN-L)
1096-9861
DOI: 10.1002/cne.21685
PMC: PMC4924624
OpenAlex: W2062443617
Cited by: 230
References: 82
Citations by year: 2026: 2 · 2025: 8 · 2024: 13 · 2023: 13 · 2022: 9 · 2021: 14 · 2020: 17 · 2019: 11 · 2018: 22 · 2017: 11 · 2016: 14 · 2015: 11 · 2014: 14 · 2013: 14 · 2012: 10
FWCI: 8.10
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: The Journal of Comparative Neurology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Johns Hopkins University
National Heart, Lung, and Blood Institute (HL 60292, P50HL060292)
National Institute of Neurological Disorders and Stroke (NS 33987, NS051609, R01NS033987, R01NS051609)
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: general anesthesia, anesthetic analgesia, loss of consciousness, GABA-A receptor agonists, ketamine, NMDA receptor antagonists, Fos expression, sleep-wake regulation, ventrolateral preoptic nucleus, ventrolateral periaqueductal gray, orexin, arousal system, cholinergic system, monoaminergic systems, antinociception, 6-hydroxydopamine lesion, ibotenic acid lesions
MeSH terms: Analgesics, Anesthesia, Animals, Electroencephalography, Male, Sleep, Sleep Stages, Wakefulness, Rats, Sprague-Dawley, Rats

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Role of endogenous sleep-wake and analgesic systems in anesthesia

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