Anesthetics activate brain's sleep switch. (You're Feeling Sleepy...).

Since the mid-19th century, surgeons and their grateful patients have made use of ether and other general anesthetics. Yet exactly how these compounds produce a painfree, unconscious state remains mysterious. Now, scientists chipping away at the anatomical details have discovered that two of today's most common general anesthetics produce their sedative effects by triggering the brain's sleep circuits.

Further research on the brain circuits affected by these anesthetics may lead to improved agents that generate an even more natural sleeplike state, say the biologists, who chronicle their research in an upcoming Nature Neuroscience.

"The notion that anesthetics might somehow be recruiting a natural pathway that promotes sleep, as opposed to mucking up a pathway that keeps you awake," hasn't been considered seriously before, says study coauthor Nick P. Franks of the Imperial College School of Medicine in London.

The new work represents the fruits of a long-overdue collaboration between sleep scientists and anesthesia investigators, says Neil L. Harrison of Cornell University medical school in New York City. While he and other scientists have shown over the past decade that anesthetics work via specific protein receptors on the surfaces of nerve cells, Harrison notes that Franks' study is one of the first to pinpoint precise nerve circuits influenced by the compounds.

Franks' team focused on a brain region called the hypothalamus. Previous research had indicated its importance in controlling the sleep-wake state. Several years ago, for example, Clifford Saper of Beth Israel Deaconess Medical Center in Boston and his colleagues showed that a portion of the hypothalamus known as the ventrolateral preoptic nucleus (VLPO) acts as a sleep switch. Its cells turn on during sleep, releasing a neurotransmitter called GABA, which turns off another hypothalamic site, the tuberomammillary nucleus (TMN). When active, the TMN promotes wakefulness.

Working with Saper, Franks' group used the activity of a gene called c-fos to monitor the brain-cell activity of rats treated with either of two general anesthetics, propofol or pentobarbital. The anesthetized rodents exhibited increased brain-cell activity in the VLPO and decreased activity in the TMN, the same pattern seen during deep, dreamless sleep.

Propofol and pentobarbital appear to work by binding to GABA receptors on nerve cells in the TMN and elsewhere in the brain. The VLPO region doesn't contain GABA receptors, however.

"We know VLPO is being excited, but we don't know how. We need to find that out," says Franks.

Ultimately, Franks would like to trace the neural circuitry behind consciousness. "Understanding what leads to loss of consciousness is what really appeals to me," he says.