The application of general anesthesia in clinical therapy has been an indispensable part of modern medicine for more than a century. However, due to the complexity of the brain and the extensive actions of general anesthetic drugs, neural mechanisms underlying general anesthesia have remained a mystery. 

Recently, Dr. DU Jiulin’s lab at the Institute of Neuroscience of the Chinese Academy of Sciences and Prof. YU Tian’s team at Zunyi Medical College used a larval zebrafish model to explore this mystery. Their research revealed that two commonly used intravenous anesthetic drugs, propofol and etomidate, suppress the excitability of locus coeruleus (LC) neurons via synergic mechanisms – thus inhibiting presynaptic excitatory inputs and inducing membrane hyperpolarization of these cells. 

This study, which was published in Cell Reports on September 18, shows that the locus coeruleus-norepinephrine (LC-NE) system plays a modulatory role in both the induction of and emergence from intravenous general anesthesia. 

The LC nucleus is a main site for synthesizing NE in the brain. Recent studies have shown that activation of the LC-NE system in mice facilitates behavioral arousal from inhalational isoflurane-induced anesthesia. In contrast, inhibition of this system causes hypersensitive induction to and delayed the recovery from anesthesia induced by inhalational anesthetics. 

However, understanding the role of intravenous anesthetics on the LC-NE system and the synaptic mechanisms involved remained rudimentary. 

To better understand the action of intravenous anesthetics, researchers first established an anesthesia zebrafish model via bath application of two intravenous anesthetic drugs, propofol and etomidate. The researchers determined the state of general anesthesia by examining the animal’s spontaneous locomotion as well as electrical activity of the brain and spinal nerves. 

They then found that local lesion of LC neurons via two-photon laser-based ablation or genetic depletion of NE synthesis accelerated the induction of general anesthesia and retarded emergence from general anesthesia. 

Mechanistically, in vivo whole-cell recording revealed that both of the anesthetics used in the study suppress LC neuronal activity through a cooperative mechanism: They inhibit presynaptic excitatory inputs and induce GABA_A receptor-mediated hyperpolarization of these neurons. 

These results show that the LC-NE system contributes to both the induction of and emergence from intravenous general anesthesia via a cooperative mechanism. The study also highlights the usefulness of the larval zebrafish model for studying neural mechanisms of general anesthesia. 

This study was supported by Shanghai Science and Technology Committee, Key Research Program of Frontier Sciences and Strategic Priority Research Program of Chinese Academy of Sciences, and Natural Science Foundation of China.

Figure: Propofol and Etomidate accelerate the induction into general anesthesia of zebrafish by suppress LC neuron's activities. (Image by DU Jiulin)