Hypnotic Hypersensitivity to Volatile Anesthetics and Dexmedetomidine in Dopamine β-Hydroxylase Knockout Mice
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Background: Multiple lines of evidence suggest that the adrenergic system can modulate sensitivity to anesthetic-induced immobility and anesthetic-induced hypnosis as well. However, several considerations prevent the conclusion that the endogenous adrenergic ligands norepinephrine and epinephrine alter anesthetic sensitivity. Methods: Using dopamine β-hydroxylase knockout (Dbh) mice genetically engineered to lack the adrenergic ligands and their siblings with normal adrenergic levels, we test the contribution of the adrenergic ligands upon volatile anesthetic induction and emergence. Moreover, we investigate the effects of intravenous dexmedetomidine in adrenergic-deficient mice and their siblings using both righting reflex and processed electroencephalographic measures of anesthetic hypnosis. Results: We demonstrate that the loss of norepinephrine and epinephrine and not other neuromodulators co-packaged in adrenergic neurons is sufficient to cause hypersensitivity to induction of volatile anesthesia. However, the most profound effect of adrenergic deficiency is retarding emergence from anesthesia, which takes two to three times as long in Dbh mice for sevoflurane, isoflurane, and halothane. Having shown that Dbh mice are hypersensitive to volatile anesthetics, we further demonstrate that their hypnotic hypersensitivity persists at multiple doses of dexmedetomidine. Dbh mice exhibit up to 67% shorter latencies to loss of righting reflex and up to 545% longer durations of dexmedetomidine-induced general anesthesia. Central rescue of adrenergic signaling restores control-like dexmedetomidine sensitivity. A novel continuous electroencephalographic analysis illustrates that the longer duration of dexmedetomidine-induced hypnosis is not due to a motor confound, but occurs because of impaired anesthetic emergence. Conclusions: Adrenergic signaling is essential for normal emergence from general anesthesia. Dexmedetomidine-induced general anesthesia does not depend on inhibition of adrenergic neurotransmission.
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Impairing adrenergic signaling from locus coeruleus increases volatile anesthetic potency, facilitating entry into and impairing exit from hypnosis.
“Impairing adrenergic signaling from this nucleus increases the potency of volatile anesthetics—facilitating entry into and impairing exit from hypnotic states [120].”
From The Biology of General Anesthesia from Paramecium to Primate (2019) · cites this paper as [120]
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- Authors
- Hu, F. Y., Hanna, G. M., Han, W., Mardini, F., Thomas, S. A., Wyner, A. J., & Kelz, M. B.
- Affiliations
- University of Pennsylvania (US)
- Massachusetts General Hospital (US)
- Graduate Student, Departments of Applied Mathematics and Computational Science, School of Arts and Sciences.
- Research Specialist, Department of Anesthesiology and Critical Care.
- Associate Professor.
- Venue
- Anesthesiology
- Published
- 2012-11-01
- Volume
- 117
- Issue
- 5
- Pages
- 1006-1017
- ISSN
- 0003-3022 (ISSN-L)
- PMC
- PMC3628827
- OpenAlex
- W2051384070
- Cited by
- 58
- References
- 52
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 3 · 2023: 6 · 2022: 3 · 2021: 3 · 2020: 1 · 2019: 6 · 2018: 5 · 2017: 2 · 2016: 4 · 2015: 4 · 2014: 5 · 2013: 5 · 2012: 2
- FWCI
- 6.83
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Anesthesiology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (K08GM077357, GM077357, GM088156, R01GM088156)
- Topics
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Anesthesia and Sedative Agents
- Life Sciences › Neuroscience › Developmental Neuroscience › Anesthesia and Neurotoxicity Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Keywords
- norepinephrine, epinephrine, dexmedetomidine, emergence from anesthesia, sevoflurane, isoflurane, halothane, righting reflex, adrenergic signaling
- MeSH terms
- Animals, Dopamine beta-Hydroxylase, Drug Hypersensitivity, Female, Hypnotics and Sedatives, Male, Mice, Inbred C57BL, Volatilization, Mice, Knockout, Anesthetics, Inhalation, Dexmedetomidine, Mice, Mice, 129 Strain
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