Authors: Zhao X et al.
Journal: Anesthesiology, December 9, 2025. DOI: 10.1097/ALN.0000000000005826
Summary
This preclinical mechanistic study investigated how acute stress alters anesthetic efficacy and emergence from isoflurane anesthesia, with a focus on sex-specific effects and underlying brainstem circuitry. Recognizing that preoperative stress contributes to variability in anesthetic depth and recovery, the authors aimed to define the neural pathways responsible for these effects.
Using a mouse model, acute stress was induced by brief restraint prior to isoflurane anesthesia. Anesthetic depth and emergence were assessed via loss and recovery of righting reflex and supported by electroencephalographic analysis. Acute stress significantly reduced anesthetic depth and markedly accelerated emergence in male mice, whereas females showed no comparable changes, highlighting a clear sex-specific response.
Neuronal mapping revealed increased activation of locus coeruleus norepinephrine (LCNE) neurons during anesthesia following stress in males. Disruption of LCNE activity through pharmacologic lesioning or chemogenetic inhibition eliminated stress-induced effects on anesthesia. Circuit tracing identified downstream projections from LCNE neurons to GABAergic neurons in the dorsal raphe nucleus (DRN). Targeted inhibition of the LCNE→DRNGABA circuit abolished stress-related acceleration of emergence. Further mechanistic validation showed that α1-adrenergic receptors within DRNGABA neurons were required for this modulation, as pharmacologic blockade or gene knockdown normalized anesthetic responses.
These findings define a sex-specific stress–arousal circuit that weakens isoflurane anesthesia and promotes faster emergence through noradrenergic signaling in males. The study provides a neural framework linking emotional stress to anesthetic variability and highlights biologic sex as a critical modifier of anesthetic state control.
Key Points
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Acute stress reduces anesthetic depth and accelerates emergence from isoflurane in male but not female mice.
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Stress increases activity of locus coeruleus norepinephrine neurons during anesthesia in males.
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The LCNE → DRNGABA circuit is essential for stress-induced modulation of anesthesia.
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α1-adrenergic receptors in DRNGABA neurons mediate this effect.
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Disruption of this circuit abolishes stress-related changes in anesthetic efficacy.
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Findings provide mechanistic insight into sex-specific variability in anesthetic emergence.
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