Sevoflurane depresses neurons in the medial parabrachial nucleus by potentiating postsynaptic GABA A receptors and background potassium channels

Despite persistent clinical use for over 170 years, the neuronal mechanisms by which general anesthetics produce hypnosis remain unclear. Previous studies suggest that anesthetics exert hypnotic effects by acting on endogenous arousal circuits. Recently, it has been shown that the medial parabrachial nucleus (MPB) is a novel wakepromoting component in the dorsolateral pons. However, it is not known whether and how the MPB contributes to anesthetic-induced hypnosis. Here, we investigated the action of sevoflurane, a widely used volatile anesthetic agent that best represents the drug class of halogenated ethers, on MPB neurons in mice. Using in vivo fiber photometry, we found that the population activities of MPB neurons were inhibited during sevoflurane-induced loss of consciousness. Using in vitro whole-cell patch-clamp recordings, we revealed that sevoflurane suppressed the firing rate of MPB neurons in concentration-dependent and reversible manners. At a concentration equal to MAC of hypnosis, sevoflurane potentiated synaptic GABA(A) receptors (GABA(A)-Rs), and the inhibitory effect of sevoflurane on the firing rate of MPB neurons was completely abolished by picrotoxin, which is a selective GABA(A)-R antagonist. At a concentration equivalent to MAC of immobility, sevoflurane directly hyperpolarized MPB neurons and induced a significant decrease in membrane input resistance by increasing a basal potassium conductance. Moreover, pharmacological blockade of GABA(A)-Rs in the MPB prolongs induction and shortens emergence under sevoflurane inhalation at MAC of hypnosis. These results indicate that sevoflurane inhibits MPB neurons through postsynaptic GABA(A)-Rs and background potassium channels, which contributes to sevofluraneinduced hypnosis.