O.K., so it doesn’t quite rank up there with unraveling the cause of Alzheimer’s or Parkinson’s disease. But with mosquito and poison-ivy season on the way, plenty of folks would be grateful for an answer to a more mundane question: What is the neurological basis of the pruritic response? Or in plain English: Why do we itch?
At least part of that mystery has now been solved by scientists at one of the less celebrated units of the National Institutes of Health. Writing in Science, molecular biologists working at the National Institute of Dental and Craniofacial Research report that a molecule known as neuropeptide natriuretic polypeptide b (Nppb) that is released by nerve cells far from the actual itch site triggers an electrochemical cascade that ultimately tells the brain it’s time to get scratching.
“This is an important breakthrough,” says Sarah E. Ross, a neurobiologist at the University of Pittsburgh. It was also, says the report’s senior author, Mark Hoon, “really fun work. It was like a roller coaster of discovery.”
That may sound a little over the top when the subject is itching, but chronic itch caused by dry skin, psoriasis, diabetes or even liver disease can be maddening, and the cause has long been a true medical mystery. “The classical view,” says Hoon, “was that a single class of nerve cells detected both itch and pain.” According to this theory, the type and intensity of the stimulus told the cells which sensory message to send up to the brain. The nervous system would then respond accordingly.
At one level, the theory is correct: pain and itch, as well as heat, are all transmitted by a class of nerve cells known as TRPV1-expressing neurons. When scientists use genetic engineering to create mice that don’t have these cells, the animals don’t feel any of those three sensations.
But over the past five or 10 years, says Hoon, research in his own group, and also what he calls “some beautiful work by others,” has shown that at a deeper level, the one-neuron-fits-all hypothesis is wrong. Evolution has evidently provided us with a subset of TRPV1-expressing cells, and it’s the ones in that specialized group that do the actual work of making us itch.
What makes these cells special, say Hoon and his co-author, Santosh Mishra, is that they, unlike their pain-sensing cousins, produce Nppb. When the skin is stimulated by a feather or a mosquito bite or a chicken-pox lesion or a drop of urushiol (the itch-inducing oil in poison ivy), a signal zips up to the other end the nerve cell where it triggers the release of Nppb molecules. The molecules leap across a gap, or synapse, to an adjacent nerve cell that carries the signal up the spinal cord toward the brain. All nerve signals travel this way, and all require neurotransmitting chemicals to vault the synaptic gap. But itching needs the particular assistance of Nppb to do that job.
The Nppb, molecule was actually first identified in an entirely different part of the body. “It’s released by the heart,” says Hoon, “to control blood sodium and blood pressure. It’s a cornerstone of biology that a lot of these neurotransmitters are used in different parts of the body for different purposes.”
When they found this heart peptide in some TRPV1 neurons as well, Hoon and Mishra engineered mice that lacked that variation of the neuron. The result: the animals could feel pain and heat just fine but were quite itchless. “The answer just fell into place,” says Hoon. “Sometimes in science you have an idea of how something works, but you just hit a brick wall. This time, that wasn’t the case.”
Identifying the role of the Nppb molecule doesn’t necessarily mean a cure for itching is at hand quite yet. Since Nppb operates not at the skin, but deep inside the body, you’d want to neutralize it with a treatment patients could take orally. “But it also regulates blood pressure, so that wouldn’t be good,” Hoon says. In severe cases, he says, you might consider injecting an Nppb blocker directly into the spinal cord. That too, however, he says with some understatement, “is not a trivial thing to do.”
Even before a safe delivery system for an Nppb blocker is developed, scientists are already pondering the next great question: Why does an itch go away when we scratch? Evolutionarily, the phenomenon makes sense. An itch often suggests the presence of a pest like a mosquito or lice, and a vigorous scratch will kill or disperse them. But what is the neural mechanism that leads to the feeling of relief?
“That’s an excellent question,” says Hoon. “We really don’t know.” A leading hypothesis argues that there may be yet another specialized set of nerve cells that responds to scratching by sending a “stop” signal up to the spinal cord. “We’re investigating this idea,” says Ross, “and hope to submit a paper soon.” When they do, the riddle of the itch will have moved closer still toward being solved at last.
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