There's nothing funny about an itch that drives you mad.

If the subject of itch seems frivolous compared to other medical matters, consider this: in regions where the drug chloroquine is used to treat malaria, patients often discontinue treatment rather than endure the excruciating itch that comes as a side effect. And case studies tell of itch sufferers who injure themselves in search of relief; in one well-documented case, a woman scratched through her skull and into her brain tissue in her sleep.

Still, the subject of itch was ignored in favor of pain studies for decades, says HHMI early career scientist Xinzhong Dong, a neuroscientist at the Johns Hopkins University School of Medicine. Attention to the field is increasing now, thanks in part to Dong's work unraveling the puzzling pathways that carry certain itch sensations from the skin to the brain.

In collaboration with HHMI investigator David Anderson, a neuroscientist at the California Institute of Technology, Dong identified a protein that functions as an itch receptor in a small subset of nerve cells. The scientists reported the research in the December 25, 2009, issue of Cell.

Allergic itch happens when cells in the immune system release the chemical histamine. It is easily treated with antihistamines, which lessen itch by binding to histamine receptors on the surface of sensory neurons. But allergic itch accounts for only one-third of all types of itch.

Other forms of itch—including the kind caused by chloroquine—don't work through histamine receptors, so antihistamines are ineffective. Lacking a better option, physicians usually treat nonallergic itch with steroids, which, if used for long, can have dangerous side effects, including eye disease, osteoporosis, and gastrointestinal illness. The search for alternative treatments has been complicated by the absence of a known receptor.

Nearly a decade ago, when Dong was a postdoc in Anderson's lab, he stumbled on a class of receptors called Mrgprs. A subset of these receptors was found almost exclusively on a class of sensory neurons thought to be involved in the sensing of pain.

Dong and Anderson first presumed that the Mrgprs, too, were related to pain. “At the time, we had no inkling of itch,” he says.

To determine the role of the receptors, the scientists engineered a line of what Anderson calls “super-knockout” mice lacking 12 genes coding for receptors in the Mrgpr family.

They expected the mice to be less sensitive to pain than normal mice, but the mice lacking the Mrgpr genes appeared suspiciously normal. “What was striking was that there was very little wrong with these mice,” recalls Anderson. They showed virtually no difference in their response to pain, compared with normal mice.

Years later, Dong was inspired by studies conducted by Zhou-Feng Chen, another former postdoc from Anderson's lab who is now at the Washington University School of Medicine, on how neurons deliver itch sensations to the brain. Dong returned to the Mrgpr-knockout mice with a new question: would they show any deficits in their itch responses?

Illustration: VSA Partners

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