When the receptor for capsaicin—the chemical 
that gives heat to chili peppers—is added to
itch-sensing neurons, exposure to the normally
painful capsaicin causes itchiness. 

Illustration ©Tim Phelps / Department of Art as
Applied to Medicine, Johns Hopkins University, 2012

Itching to Be Discovered

A newly identified receptor in nerve cells senses itch.

Humans do, and mice as well. Dogs and cats? Definitely. Itch is a near-universal experience. But, until recently, understanding how it works has remained a mystery. For decades, scientists have been trying to figure out if the nerve cells that detect itch and pain are one and the same. This winter, HHMI early career scientist Xinzhong Dong and his colleagues resolved the debate.

In 2009, Dong, whose lab is at the Johns Hopkins University School of Medicine, discovered a family of proteins in sensory nerves that is activated by multiple itchy compounds. In follow-up experiments, he and his colleagues used a glowing protein to label cells that express one member of this family—MrgprA3. As they report in the February 2013 issue of Nature Neuroscience, they learned that these MrgprA3-expressing neurons extend only to the skin. “They don’t go to deeper tissue like muscles, bones, or visceral organs,” says Dong. “That really explains why we feel itch only from our skin and not from deeper tissue.”

The glowing labels also enabled the team to see the MrgprA3-expressing neurons in live mice and stimulate those cells with irritating compounds. When the scientists destroyed the neurons with a toxin, the animals scratched less, but they still responded to pain.

“To prove that the neurons only sense itch and not pain, we did the ultimate test,” explains Dong. He and his colleagues modified mice so that their MrgprA3-expressing neurons contained a receptor that binds to capsaicin, the chemical that gives heat to chili peppers. When the scientists rubbed capsaicin on rodents’ skin, the animals didn’t react as if they were in pain. Instead, they scratched.

Now that Dong and his team have pinpointed the nerve fibers responsible for itch, they are looking for small molecules that will block Mrg receptors to silence the itch-inducing nerves. If they succeed, there will be many fewer itches to scratch.