Esketamine accelerates emergence from isoflurane general anaesthesia by activating the paraventricular thalamus glutamatergic neurones in mice.
Abstract
<h4>Background</h4>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.<h4>Methods</h4>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<sup>Glu</sup>) neuronal activity was monitored by fibre photometry, and chemogenetic technology was used to manipulate PVT<sup>Glu</sup> neuronal activity.<h4>Results</h4>A low dose of esketamine (5 mg kg<sup>-1</sup>) accelerated emergence from isoflurane general anaesthesia (474 [30] s vs 544 [39] s, P=0.001). Esketamine (5 mg kg<sup>-1</sup>) increased PVT c-Fos expression (508 [198] vs 258 [87], P=0.009) and enhanced the population activity of PVT<sup>Glu</sup> 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<sup>Glu</sup> neurones abolished the arousal-promoting effects of esketamine (459 [33] s vs 596 [33] s, P<0.001).<h4>Conclusions</h4>Our results suggest that esketamine promotes recovery from isoflurane anaesthesia by activating PVT<sup>Glu</sup> neurones. This mechanism could explain the rapid arousability exhibited upon treatment with a low dose of esketamine.
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