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Itching for relief. More than 50 diseases can cause itchy misery.

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The Secret of the Itch

Not all itches go away with a simple scratch. Roughly 15% of people suffer relentless, long-term itch, often caused by diseases and medications; terminally ill cancer patients, for example, often experience such severe whole-body itch in response to morphine that many choose to live in pain rather than take the medication. Now, researchers have identified a hormone in mice that delivers itchy sensations to neurons in the spinal cord, which then relays the signal to the brain. The discovery could point to treatments for people who suffer from chronic itch caused by disease or medication.

Scientists have known for a long time that sensory neurons called TRPV1 cells can detect itchy substances on the skin, says Mark Hoon, a neuroscientist at National Institute of Dental and Craniofacial Research in Bethesda, Maryland. Because TRPV1 neurons also respond to hot and painful stimuli, however, it wasn't clear whether the neurons that respond to itch are unique, or if itch might simply be low-grade pain. That's made it difficult to develop treatments that target itch without affecting other sensory systems, Hoon says.

While analyzing molecules excreted by TRPV1 cells in search of anything that might be itch-specific, Hoon and his colleagues came across a small group of the neurons that produce natriuretic polypeptide b (Nppb), a hormone that regulates heart function and can also act as a neurotransmitter. "We wondered what those cells were doing," Hoon says. To find out, the team genetically modified mice to block production of Nppb in TRPV1 neurons, then injected the skin on their shoulders with a range of itch-inducing compounds, including histamine, an inflammatory molecule involved in immune responses, and the malaria drug chloroquine. Normally, these substances make mice scratch nonstop, but the knockout mice hardly scratched themselves at all after the injection, showing that Nppb was required to produce the sensation of itch, the authors report online today in Science. No other sensory systems appeared to be affected in the knockout mice, Hoon says.

Next, the researchers looked to the dorsal horn of the spinal cord, where signals from peripheral nerves are routed to the brain, and found the receptors for Nppb in a group of neurons that release a molecule called gastrin-releasing peptide, or GRP. GRP was previously thought to be the original molecular trigger for itch, Hoon says. Now, he says, it's clear that Nppb-releasing TRPV1 neurons, not GRP-releasing cells, are the first trigger in transmitting itch, presenting a new "Achilles heel" that could be investigated for treatment. "These cells weren't known before," Hoon says. "They weren't even envisaged."

New therapies for humans that safely block Nppb activity are still be a long way off, however. Although the Nppb-knockout mice lived a normal lifespan, when the researchers killed the receptor cells in the spinal cord, the mice died prematurely, suggesting that it could be dangerous to try humans, Hoon says.

The results of the study remain "very convincing, and important," says Glenn Giesler, a neuroscientist at the University of Minnesota in Twin Cities. A treatment that could disrupt itch signaling at the level of the spinal cord would be "a tremendous boon," he says. "At least they now have a new target."