Circadian–melatonin signaling in general anesthesia: molecular mechanisms and perioperative implications
5 affiliations
- 1Department of Anesthesiology, Ditmanson Medical Foundation Chia-Yi Christian Hospital
- 2School of Medicine, College of Medicine, Fu Jen Catholic University
- 3Division of Nephrology, Department of Internal Medicine, Cardinal-Tien Hospital, School of Medicine, College of Medicine, Fu Jen Catholic University
- 4Division of Nephrology, Department of Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation
- 5Division of Nephrology, Department of Internal Medicine, Fu Jen Catholic University Hospital
Abstract
Anesthesia and surgery are delivered to a temporally organized organism whose physiology is governed by the suprachiasmatic nucleus, peripheral molecular clocks, and pineal melatonin signaling. This review synthesizes mechanistic, preclinical, and clinical evidence on how anesthetic agents, surgical stress, and the perioperative environment interact with circadian and melatonergic signaling, and on whether that interaction can be targeted therapeutically. In rodent and cellular studies, volatile and intravenous anesthetics alter clock function in an agent- and phase-dependent manner; proposed mechanisms include GABAergic and glutamatergic modulation of entrainment, transcriptional and chromatin-level repression of CLOCK–BMAL1/PER–CRY signaling, and metabolic coupling through CaMK–CREB, AMPK, SIRT1, and GSK-3β. These mechanisms have not been confirmed in humans. In patients, these effects are inseparable from surgical injury, opioids, fasting, inflammation, and disrupted light–dark exposure, all of which suppress melatonin amplitude, delay its onset, and promote internal desynchrony. Melatonin signals through MT ₁ and MT ₂ receptors to produce chronobiotic, anxiolytic, and antinociceptive effects, whereas the mitochondrial, redox, and anti-inflammatory actions, described almost exclusively in animal and cellular models, require substantially higher exposures and have not been demonstrated in surgical patients; the two arms are pharmacologically distinct and should not be pooled. Clinically, preoperative anxiolysis with melatonin in adults is the most consistently supported indication, whereas evidence for postoperative sleep, analgesia, delirium prevention, and organ protection remains heterogeneous and of low certainty. Most trials have used fixed clock-time dosing without measuring internal circadian phase or achieved plasma exposure, so null results cannot distinguish an ineffective mechanism from an inadequate intervention. The circadian–melatonin axis remains a plausible perioperative target, but clinical translation requires phase-aware, exposure-informed, and adequately powered trials.
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BibTeX
@article{mui2026circadianmelatonin,
title = {{Circadian–melatonin signaling in general anesthesia: molecular mechanisms and perioperative implications}},
author = {Wui-Chiu Mui and Yi-Chou Hou and Yi-Cheng Liao and Kuo-Cheng Lu},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1960152},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1960152/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Circadian–melatonin signaling in general anesthesia: molecular mechanisms and perioperative implications
AU - Wui-Chiu Mui
AU - Yi-Chou Hou
AU - Yi-Cheng Liao
AU - Kuo-Cheng Lu
PY - 2026
DA - 2026/10/15
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1960152
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1960152/full
AB - Anesthesia and surgery are delivered to a temporally organized organism whose physiology is governed by the suprachiasmatic nucleus, peripheral molecular clocks, and pineal melatonin signaling. This review synthesizes mechanistic, preclinical, and clinical evidence on how anesthetic agents, surgical stress, and the perioperative environment interact with circadian and melatonergic signaling, and on whether that interaction can be targeted therapeutically. In rodent and cellular studies, volatile and intravenous anesthetics alter clock function in an agent- and phase-dependent manner; proposed mechanisms include GABAergic and glutamatergic modulation of entrainment, transcriptional and chromatin-level repression of CLOCK–BMAL1/PER–CRY signaling, and metabolic coupling through CaMK–CREB, AMPK, SIRT1, and GSK-3β. These mechanisms have not been confirmed in humans. In patients, these effects are inseparable from surgical injury, opioids, fasting, inflammation, and disrupted light–dark exposure, all of which suppress melatonin amplitude, delay its onset, and promote internal desynchrony. Melatonin signals through MT ₁ and MT ₂ receptors to produce chronobiotic, anxiolytic, and antinociceptive effects, whereas the mitochondrial, redox, and anti-inflammatory actions, described almost exclusively in animal and cellular models, require substantially higher exposures and have not been demonstrated in surgical patients; the two arms are pharmacologically distinct and should not be pooled. Clinically, preoperative anxiolysis with melatonin in adults is the most consistently supported indication, whereas evidence for postoperative sleep, analgesia, delirium prevention, and organ protection remains heterogeneous and of low certainty. Most trials have used fixed clock-time dosing without measuring internal circadian phase or achieved plasma exposure, so null results cannot distinguish an ineffective mechanism from an inadequate intervention. The circadian–melatonin axis remains a plausible perioperative target, but clinical translation requires phase-aware, exposure-informed, and adequately powered trials.
SN - 1663-9812
ER -