Esketamine accelerates emergence from isoflurane general anaesthesia by activating the paraventricular thalamus glutamatergic neurones in mice

Wen-Ying Duan; Kang Peng; Hui-Min Qin; Bai-Ming Li; Yun-Xin Xu; Dan-Jun Wang; Le Yu; Hui Wang; Ji Hu; Qing-Xiu Wang

doi:10.1016/j.bja.2023.10.038

Esketamine accelerates emergence from isoflurane general anaesthesia by activating the paraventricular thalamus glutamatergic neurones in mice

Br J Anaesth. 2024 Feb;132(2):334-342. doi: 10.1016/j.bja.2023.10.038. Epub 2023 Dec 2.

Authors

Wen-Ying Duan¹, Kang Peng², Hui-Min Qin³, Bai-Ming Li¹, Yun-Xin Xu¹, Dan-Jun Wang¹, Le Yu¹, Hui Wang¹, Ji Hu⁴, Qing-Xiu Wang⁵

Affiliations

¹ Department of Anesthesiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
² School of Life Science and Technology, ShanghaiTech University, Shanghai, China; Department of Rehabilitation Medicine, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China.
³ School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
⁴ School of Life Science and Technology, ShanghaiTech University, Shanghai, China. Electronic address: huji@shanghaitech.edu.cn.
⁵ Department of Anesthesiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China. Electronic address: qxw1123@126.com.

PMID: 38044237
DOI: 10.1016/j.bja.2023.10.038

Abstract

Background: Delayed emergence from general anaesthesia poses a significant perioperative safety hazard. Subanaesthetic doses of ketamine not only deepen anaesthesia but also accelerate recovery from isoflurane anaesthesia; however, the mechanisms underlying this phenomenon remain elusive. Esketamine exhibits a more potent receptor affinity and fewer adverse effects than ketamine and exhibits shorter recovery times after brief periods of anaesthesia. As the paraventricular thalamus (PVT) plays a pivotal role in regulating wakefulness, we studied its role in the emergence process during combined esketamine and isoflurane anaesthesia.

Methods: The righting reflex and cortical electroencephalography were used as measures of consciousness in mice during isoflurane anaesthesia with coadministration of esketamine. The expression of c-Fos was used to determine neuronal activity changes in PVT neurones after esketamine administration. The effect of esketamine combined with isoflurane anaesthesia on PVT glutamatergic (PVT^Glu) neuronal activity was monitored by fibre photometry, and chemogenetic technology was used to manipulate PVT^Glu neuronal activity.

Results: A low dose of esketamine (5 mg kg^-1) accelerated emergence from isoflurane general anaesthesia (474 [30] s vs 544 [39] s, P=0.001). Esketamine (5 mg kg^-1) increased PVT c-Fos expression (508 [198] vs 258 [87], P=0.009) and enhanced the population activity of PVT^Glu neurones (0.03 [1.7]% vs 6.9 [3.4]%, P=0.002) during isoflurane anaesthesia (1.9 [5.7]% vs -5.1 [5.3]%, P=0.016) and emergence (6.1 [6.2]% vs -1.1 [5.0]%, P=0.022). Chemogenetic suppression of PVT^Glu neurones abolished the arousal-promoting effects of esketamine (459 [33] s vs 596 [33] s, P<0.001).

Conclusions: Our results suggest that esketamine promotes recovery from isoflurane anaesthesia by activating PVT^Glu neurones. This mechanism could explain the rapid arousability exhibited upon treatment with a low dose of esketamine.

Keywords: consciousness; emergence; esketamine; paraventricular thalamus; righting reflex.

MeSH terms

Anesthesia, General
Anesthetics, Inhalation* / pharmacology
Animals
Isoflurane* / pharmacology
Ketamine* / pharmacology
Mice
Thalamus* / drug effects

Substances

Anesthetics, Inhalation
Esketamine
Isoflurane
Ketamine