Edinger-Westphal Neurons Contribute to Emergence from Desflurane and Sevoflurane Anesthesia in Mice

Abstract

Most general anesthetics have long been believed to work by exerting a wide range of inhibitory impacts on the central nervous system, yet accumulating evidence has highlighted their excitatory effects—particularly that multiple anesthetics activate a common neural target to induce anesthesia. However, it remains unclear whether three widely used volatile anesthetics (isoflurane, sevoflurane, desflurane) with similar pharmacokinetic and pharmacodynamic properties share a common brain region for their anesthetic effects, and most receptors mediating the excitatory effects of general anesthetics remain unidentified. To explore the shared excitatory neural targets of common volatile anesthetics, we combined c-Fos staining, targeted recombination in active populations (TRAP), fluorescence in situ hybridization (FISH) in adult male and female mice, and molecular docking prediction to characterize anesthetic-activated neurons, their cell types, and potential mediating receptors. We found that desflurane and sevoflurane, except isoflurane, significantly increased c-Fos expression in Edinger-Westphal (EW) neurons with high urocortin 1 (UCN1) expression. Chemogenetic inhibition of sevoflurane-activated EW neurons shortened the emergence time from desflurane anesthesia without significantly changing the induction time. Furthermore, growth hormone secretagogue receptor (GHSR) was substantially enriched in both sevoflurane- and desflurane-activated EW neurons, and local knockdown of GHSR in EW neurons accelerated recovery from both anesthetics. These findings suggest that UCN1 + EW neurons and GHSR contribute greatly to recovery from desflurane and sevoflurane anesthesia.