Itching to know the molecular basis of itch

In 2008, one of my favorite writers, Atul Gawande, wrote about neurophysiology of itching in the New Yorker. If you haven’t read the article, you should. It got me fascinated by the phenomenon so I was excited to see this paper, just fresh out in Science, which describes a peptide that appears to be the primary molecule needed by all itch receptor cells to communicate with both the brain and the neural circuit during an itch.

The work was carried out in mice by Santosh Mishra and Mark Hoon at the National Institute of Dental and Craniofacial Research. Hoon says he has a long-term interest in sensory biology, in how touch, pain, heat and itching are sensed. “The genesis of this project began with a discovery program in which we aimed to identify signaling molecules expressed in functionally distinct populations of neurons,” he says. “We were interested in molecules found in a subset of somatosensory cells that express the ion-channel TRPV1.”

These somatosensory cells are required for itch, some forms of pain and temperature perception. The investigators screened the major neurotransmitters produced by these neurons and came across natriuretic polypeptide b (Nppb). “We generated mice deficient for Nppb, and they exhibited a remarkably specific loss of itch responses but no change in other sensory qualities,” says Hoon.

Based on the data from the knockout mice, Mishra and Hoon hypothesized that Nbbp was a transmitter of itch in the central nervous system. This meant they should be able to induce itching by merely injecting the neuropeptide at a synapse where primary neurons are located. Sure enough, when they did that experiment the mice began scratching. But mice that got the peptide injected under the skin, where primary neurons aren’t located, didn’t scratch.

More mouse experiments revealed that the peptide was involved in responding to a variety of substances that induce itching. These data point to the existence of a neurological circuit dedicated to the itching sensation, pushing aside earlier hypotheses that itching usurps neural circuitry involved in the sensations of pain and temperature.

Hoon does caution that the work was done in mice. “We do not know what the animals are thinking, thus we do the next best thing: carefully observe them,” he says. “The behavior of mice to compounds that cause them to scratch is extremely stereotyped and is the same as that produced in humans. It is reasonable to draw direct comparisons, but we do not know with certainty if they experience what we humans call ‘itch.’

The work is a great example how science can veer off into unexpected, interesting directions. “Although we were not interested at the beginning in finding the source of itch per se, we succeeded in answering our question of how itch is distinguished from temperature and painful stimuli,” points out Hoon.

The investigators are now focused on finding out if similar biocircuitry exists in humans and identify any unique molecules that can be targeted to turn off chronic itch without causing unwanted side effects. Nbbp is a multipurpose peptide, with functions in organs, such as the heart and kidneys. Targeting it in the nervous system may have undesirable side effects elsewhere.

And now here’s Baloo the bear from “The Jungle Book” taking good care of an itch: