US scientists have found a molecule that triggers the sensation of itching in mice. They say the finding solves a mystery about itching: it is not a low level of pain but a separately wired circuit with a direct line into the brain. If studies show the same is true of humans, the discovery could lead to new drugs to relieve symptoms in chronic itching conditions like eczema.

Santosh Mishra and Mark Hoon of the National Institute of Dental and Craniofacial Research, which is part of the National Institutes of Health, write about their discovery in a paper published online in the journal Science on 24 May.

They discovered a neurotransmitter (a small molecule that carries signals from cell to cell of the nervous system) natriuretic polypeptide b (Nppb) that is released in the spinal cord activates a circuit that results in the brain experiencing the sensation of an itch.

The circuit is activated when Nppb plugs into a specific nerve cell in the spinal cord. This then relays a signal to the brain.

When Mishra and Hoon removed either Nppb itself or the specific nerve cell in mice, the animals stopped scratching themselves when exposed to a range of itchy substances.

They deduced this meant that the signal had been interrupted and the circuit was not delivering the itching message to the brain.

Itch Has Separate Circuit to Pain

The discovery answers a question that had been lingering for some time among researchers: is itching a type of low level pain?

It seems not: itching has its own circuitry that is separate from that of pain sensations, as Hoon, the paper's senior author explains in a statement:

"Our work shows that itch, once thought to be a low-level form of pain, is a distinct sensation that is uniquely hardwired into the nervous system with the biochemical equivalent of its own dedicated land line to the brain."

Mice have similar nervous systems and circuits to humans, which is why they are useful models for this type of research. If further studies in humans can find a similar biocircuit for itch as this study has found in mice, then it offers a natural starting point to look for unique molecules that could be targeted with new drugs to switch off the itch circuit and stop the sensation reaching the brain.

Such a discovery could help millions of people with chronic itch conditions like eczema and psoriasis.

The Search Began with Screening Signals from TRPV1 Neurons

Hoon says the discovery came when they were looking for molecules that are involved with carrying signals to and from nerve cells that contain a molecule called TRPV1.

These nerve cells or neurons have long fibers that reach into tissue like muscle and skin and detect environmental conditions like temperature and also pain.

The researchers wanted to discover how these neurons distinguish among the different kinds of sensory inputs and know which circuits to use to send the correct sensation signal to the brain.

So they started by looking at the particular neurotransmitters that TRPV1 neurons produce. They used lab mice to identify them one by one and then tested which particular sensation corresponded to which particular molecule. One of these molecules was Nppb.

Nppb Necessary to Respond to Range of Pruritic Substances

Mishra, the lead author of the study and a scientist in in Hoon's lab, says at first, when they tested Nppb against various sensations they couldn't pinpoint which one it corresponded to. But then:

"When we exposed the Nppb-deficient mice to several itch-inducing substances, it was amazing to watch. Nothing happened. The mice wouldn't scratch."

The sensation of itch is known as pruritis. In further experiments Hoon and his team discovered the molecule was necessary to respond to a broad range of pruritic substances.

Locating the Receptor for Nppb

When they looked for the circuit that the neurotransmitter plugs into, the eventually found a group of cells in the dorsal horn, a junction in the spine where peripheral sensory signals are relayed to the brain. These cells express the receptor that Nppb docks onto to activate the itch circuit. The receptor is already well-known as the protein Npra.

"The receptors were exactly in the right place in the dorsal horn," says Hoon.

"We went further and removed the Npra neurons from the spinal cord. We wanted to see if their removal would short-circuit the itch, and it did," he explains.

Itch Has Separate Biocircuit to Pain and Others

That part of the study led to another finding: removing the receptor neurons for Nppb did not disrupt other sensory circuits, such as those that relay sensations for pain, touch and temperature. This means, conclude the authors, that the itch biocircuit is separate and dedicated to that sensation alone.

However, the discovery has also triggered another question. Other studies have already proposed that the neurotransmitter called GRP is responsible for itch. So where does the discovery about Nppb leave GRP?

In another experiment where they looked for neurons that express GRP, the researchers discovered that it does play a role: it relays the signal later on the circuit; it only enters the process after Nppb has kicked it off.

Nppb May Not Be a Good Target for Drugs

These findings on their own would suggest that Nppb is an obvious target for drugs to stop itch. Except, like other neurotransmitters in the body, Nppb does more than one job. It also carries signals in circuits that serve the heart, the kidneys, and other organs.

So perhaps using Nppb as the target is not the way to go in developing drugs that stop itch.

Nevertheless, says Hoon, they have made an important start and established the "larger scientific point". Using mice they have located the primary itch-initiating neurons, and established the first steps in the pruritic pathway.

"Now the challenge is to find similar biocircuitry in people, evaluate what's there, and identify unique molecules that can be targeted to turn off chronic itch without causing unwanted side effects," he urges.

In another recently published study, researchers from the University of North Carolina School of Medicine offer new insights into how the nervous system processes hot and cold temperatures, and give some clues as to why TRPV1 antagonists cause some patients to shiver and feel cold at the onset of hyperthermia, an abnormally elevated body temperature.

Written by Catharine Paddock PhD