These days, it is hard to imagine having a surgical procedure without anaesthetics. Yet some 170 years after their first use in medicine, the way in which these drugs exert their hypnotic effects remains a mystery. Writing in Current Biology, Moore et al. shed light on the question (J. T. Moore et al. Curr. Biol. http://dx.doi.org/10.1016/j.cub.2012.08.042; 2012).
Many biological molecules are sensitive to anaesthetics, among them membrane ion-channel proteins. To make matters more complex, there are dozens of anaesthetic agents, and yet they don't seem to share a single molecular target. An emerging theory is that these drugs inhibit the neural circuitry associated with wakefulness. Moore and colleagues asked whether they also affect sleep-promoting neurons.
The authors focused on the anaesthetic agent isoflurane and its effects on the ventrolateral preoptic nucleus (VLPO) — a key component of the arousal (wakefulness) neurocircuitry. Neurons of the VLPO are active during sleep and, in response to inhibitory neuromodulators such as GABA, they inhibit signalling by downstream arousal-promoting neurons. Moore et al. find that concentrations of isoflurane that induce sedation or anaesthetic hypnosis also activate VLPO neurons, just like sleep does. Moreover, damaging these neurons reduces the hypnotic effects of isoflurane.
Of the two neuronal subpopulations that form the VLPO, only one is thought to be involved in promoting sleep. By studying slices of mouse hypothalamus — the brain region in which VLPO neurons are found — Moore and colleagues show that isoflurane specifically activates the sleep-promoting subpopulation. Exactly how it does so is unknown, but the researchers' data indicate that a reduction in the conductance of potassium ions is involved.
The authors do not rule out a role for other sleep-promoting neuronal circuits in mediating the effects of anaesthetics. But their take-home message is that, to understand how anaesthetics act, studying sleep induction is probably just as useful as investigating the inhibition of wakefulness.
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Shadan, S. Sleep to oblivion. Nature 491, 46 (2012). https://doi.org/10.1038/491046a