Authors: Zhao, Xianghe et al.
Anesthesiology November 2025 | DOI: 10.1097/ALN.0000000000005826
This preclinical study explored how acute stress influences anesthetic depth and emergence from isoflurane anesthesia, focusing on sex-specific neural mechanisms. Using a mouse model exposed to 30 minutes of restraint stress, investigators assessed the onset and recovery of anesthesia through loss and return of righting reflexes and EEG spectral changes. Advanced neurobiological tools—including immunofluorescence, fiber photometry, optogenetics, chemogenetics, and receptor-targeted interventions—were employed to map the relevant brainstem circuits.
Results showed that acute stress significantly reduced isoflurane anesthesia depth and accelerated emergence in male mice (mean recovery 6.8 ± 1.8 min vs. 15.8 ± 3.2 min in controls, P = 0.0034), while female mice exhibited no such effect. Neural activation mapping demonstrated increased activity of locus coeruleus norepinephrine (LCNE) neurons after stress exposure. Inhibiting these LCNE neurons—either pharmacologically or via chemogenetics—abolished the accelerated emergence, confirming their key role.
Circuit tracing identified LCNE projections to GABAergic neurons in the dorsal raphe nucleus (DRN). Further inhibition of this LCNE→DRNGABA pathway, or disruption of α1-adrenergic receptors (α1-ARs) within DRN neurons, eliminated the stress-induced modulation of isoflurane anesthesia in males.
These findings reveal a sex-specific, adrenergically mediated circuit controlling anesthetic emergence under stress. The LCNE→DRNGABA pathway and DRN α1-AR signaling appear crucial for stress-related variability in anesthetic sensitivity, offering mechanistic insight into perioperative stress responses and anesthesia management.
What You Should Know
Acute stress accelerates emergence from isoflurane anesthesia in males via heightened locus coeruleus–raphe circuit activity, a mechanism absent in females. Understanding these sex-dependent neural pathways may improve perioperative strategies for stress modulation and anesthetic dosing.
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