No one would confuse the pain of a bee sting with the itch of a mosquito bite. But neuroscientists have had a hard time figuring out how the body makes these distinctions. Now researchers have identified a previously unstudied set of spinal neurons in mice that communicates only itch. The discovery could lead to novel treatments for the irritating ailment.
Prevailing theory suggests that pain and itch are linked in the nervous system. In fact, doctors often prescribe pain medication to patients with chronic itch. But some neuroscientists favor a "labeled-line" theory, in which itch signals have their own neural circuits--or lines--to the brain. In 2001, researchers supported this idea by claiming to find itch-only neurons in the spinothalamic tract (STT), a set of cells that travel up the spine to the brain's thalamus. Subsequent studies, however, revealed that these neurons also respond to the burning pain of capsaicin--the spicy chemical in chili peppers.
Now, neuroscientist Zhou-Feng Chen of Washington University School of Medicine in St. Louis, Missouri, and colleagues believe they have found the most compelling evidence yet for an itch labeled line. Two years ago, the group discovered a gene necessary for itch, but not pain, called the gastrin-releasing peptide receptor (GRPR). In the new study, Chen and colleagues tried to figure out if cells expressing GRPR were the long-sought itch-only neurons. So they selectively killed GRPR cells in mice spines with a toxin called saporin tethered to a peptide that targets GRPR proteins. After 2 weeks, they had destroyed more than 75% of GRPR neurons.
To test the labeled-line hypothesis, the researchers gave the mice a battery of itch and pain tests. They separately injected six chemicals that make humans itch, such as histamine and the antimalarial drug chloroquine, under the mice's skin and noted how much the animals scratched. They also tested an alopecia drug that causes chronic itch in people. Chen and colleagues report online today in Science that mice without GRPR neurons scratched significantly less than normal mice did--about 80% less in each case. Next, the scientists tested the animals' response to pain in a number of different ways, including poking the mice's feet and injecting capsaicin under their skin. The normal animals and those without GRPR neurons exhibited similar pain responses.
The GRPR neurons appear to be distinct from the STT neurons that have been the center of the ongoing labeled-line debate, the researchers report. For one thing, the researchers still detected a marker found on most STT cells in the mice without GRPR neurons. And mice missing GRPR neurons did not experience less pain sensitivity, as opposed to what has been seen when STT cells are damaged. "We are looking at a different subset of neurons that were previously unknown," Chen says.
The findings provide "a candidate target for future therapies that relieve itch without minimizing the capacity for pain," says Robert LaMotte, a neuroscientist at Yale University. Gil Yosipovitch, a dermatologist at Wake Forest University Baptist Medical Center in Winston-Salem, North Carolina, agrees. But he points out that because patients experience multiple types of itch, the new findings don't diminish the importance of the STT in sending itch information to the brain. "There could be multiple itch pathways," he says.
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