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

Abstract

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. 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. 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). 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.