A Potential Mechanism of Sodium Channel Mediating the General Anesthesia Induced by Propofol. Xiao Jinglei,Chen Zhengguo,Yu Buwei Frontiers in cellular neuroscience General anesthesia has revolutionized healthcare over the past 200 years and continues to show advancements. However, many phenomena induced by general anesthetics including paradoxical excitation are still poorly understood. Voltage-gated sodium channels (Na ) were believed to be one of the proteins targeted during general anesthesia. Based on electrophysiological measurements before and after propofol treatments of different concentrations, we mathematically modified the Hodgkin-Huxley sodium channel formulations and constructed a thalamocortical model to investigate the potential roles of Na . The ion channels of individual neurons were modeled using the Hodgkin-Huxley type equations. The enhancement of propofol-induced GABAa current was simulated by increasing the maximal conductance and the time-constant of decay. Electroencephalogram (EEG) was evaluated as the post-synaptic potential from pyramidal (PY) cells. We found that a left shift in activation of Na was induced primarily by a low concentration of propofol (0.3-10 μM), while a left shift in inactivation of Na was induced by an increasing concentration (0.3-30 μM). Mathematical simulation indicated that a left shift of Na activation produced a Hopf bifurcation, leading to cell oscillations. Left shift of Na activation around a value of 5.5 mV in the thalamocortical models suppressed normal bursting of thalamocortical (TC) cells by triggering its chaotic oscillations. This led to irregular spiking of PY cells and an increased frequency in EEG readings. This observation suggests a mechanism leading to paradoxical excitation during general anesthesia. While a left shift in inactivation led to light hyperpolarization in individual cells, it inhibited the activity of the thalamocortical model after a certain depth of anesthesia. This finding implies that high doses of propofol inhibit the network partly by accelerating Na toward inactivation. Additionally, this result explains why the application of sodium channel blockers decreases the requirement for general anesthetics. Our study provides an insight into the roles that Na plays in the mechanism of general anesthesia. Since the activation and inactivation of Na are structurally independent, it should be possible to avoid side effects by state-dependent binding to the Na to achieve precision medicine in the future. 10.3389/fncel.2020.593050

Microglia modulate general anesthesia through P2Y receptor. Current biology : CB General anesthesia (GA) is an unconscious state produced by anesthetic drugs, which act on neurons to cause overall suppression of neuronal activity in the brain. Recent studies have revealed that GA also substantially enhances the dynamics of microglia, the primary brain immune cells, with increased process motility and territory surveillance. However, whether microglia are actively involved in GA modulation remains unknown. Here, we report a previously unrecognized role for microglia engaging in multiple GA processes. We found that microglial ablation reduced the sensitivity of mice to anesthetics and substantially shortened duration of loss of righting reflex (LORR) or unconsciousness induced by multiple anesthetics, thereby promoting earlier emergence from GA. Microglial repopulation restored the regular anesthetic recovery, and chemogenetic activation of microglia prolonged the duration of LORR. In addition, anesthesia-accompanying analgesia and hypothermia were also attenuated after microglial depletion. Single-cell RNA sequencing analyses showed that anesthesia prominently affected the transcriptional levels of chemotaxis and migration-related genes in microglia. By pharmacologically targeting different microglial motility pathways, we found that blocking P2Y receptor (P2YR) reduced the duration of LORR of mice. Moreover, genetic ablation of P2YR in microglia also promoted quicker recovery in mice from anesthesia, verifying the importance of microglial P2YR in anesthetic regulation. Our work presents the first evidence that microglia actively participate in multiple processes of GA through P2YR-mediated signaling and expands the non-immune roles of microglia in the brain. 10.1016/j.cub.2023.04.047

Esketamine accelerates emergence from isoflurane general anaesthesia by activating the paraventricular thalamus glutamatergic neurones in mice. British journal of anaesthesia 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) neuronal activity was monitored by fibre photometry, and chemogenetic technology was used to manipulate PVT neuronal activity. RESULTS:A low dose of esketamine (5 mg kg) accelerated emergence from isoflurane general anaesthesia (474 [30] s vs 544 [39] s, P=0.001). Esketamine (5 mg kg) increased PVT c-Fos expression (508 [198] vs 258 [87], P=0.009) and enhanced the population activity of PVT 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 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 neurones. This mechanism could explain the rapid arousability exhibited upon treatment with a low dose of esketamine. 10.1016/j.bja.2023.10.038

Dopamine D2-receptor Antagonist Droperidol Deepens Sevoflurane Anesthesia. Araki Ryuhei,Hayashi Kazuko,Sawa Teiji Anesthesiology BACKGROUND:Although midbrain dopaminergic pathways are known to contribute to arousal and emergence from anesthesia, few reports exist regarding the anesthetic effects of dopamine D2 receptor antagonism in humans. This study examined the effect of the D2 receptor antagonist droperidol on sevoflurane anesthesia by examining α and slow wave electroencephalogram oscillations. METHODS:Forty-five patients, age 20 to 60 yr, were enrolled. Frontal electroencephalograms were continuously collected for offline analysis via Bispectral Index monitoring. After induction of anesthesia, end-tidal sevoflurane concentration was deliberately maintained at 1%, and intravenous droperidol (0.05 mg/kg bolus) was administered. Electroencephalogram changes were examined in power spectrum and bicoherence, before and 10 min after droperidol injection, then compared using the Wilcoxon signed-ranks test and/or paired t test. RESULTS:Droperidol significantly augmented the α-bicoherence peak induced by sevoflurane from 30.3% (24.2%, 42.4%) to 50.8% (41.7%, 55.2%) (median [25th, 75th percentiles]; P < 0.0001), Hodges-Lehman median difference, 15.8% (11.3 to 21.4%) (95% CI). The frequency of the α-bicoherence peak was simultaneously shifted to the lower frequency; from 11.5 (11.0, 13.0) to 10.5 (10.0, 11.0) Hz (median [25th, 75th percentiles], P < 0.0001). Averaged bicoherence in the δ-θ area increased conspicuously from 17.2% (15.6 to 18.7%) to 25.1% (23.0 to 27.3%) (mean [95% CI]; P < 0.0001), difference, 8.0% (6.0 to 9.9%). CONCLUSIONS:Droperidol augments both α and δ-θ bicoherences while shifting the α-bicoherence peaks to lower frequencies, and enhances the effect of sevoflurane anesthesia on the electroencephalogram via γ-aminobutyric acid-mediated oscillatory network regulation. 10.1097/ALN.0000000000002046