The Itch Molecule
May 24, 2013

The Molecule That Makes You Itch

April Flowers for - Your Universe Online

Using mouse models, researchers at the National Institutes of Health (NIH) have discovered a small molecule that is released in the spinal cord that triggers a process later experienced in the brain as the sensation of itch. The results of this study were published in a recent issue of Science.

The molecule, natriuretic polypeptide b (Nppb), selectively plugs into a specific nerve cell in the spinal cord. This nerve cell sends the signal onward through the central nervous system. When the researchers removed either Nppb or the nerve cell, the mice stopped scratching at a broad array of itch-inducing substances.

The researchers say that the nervous systems of mice and humans are very similar, meaning that a comparable biocircuit for the itch sensation is likely present in humans. If so, this start switch could give scientists a place to look for unique molecules that can be targeted with drugs to turn off the sensation more efficiently. This could mean relief for millions of people with chronic itch conditions, such as eczema and psoriasis, as well as solving a lingering scientific issue.

"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," said Mark Hoon, Ph.D., a scientist at the National Institute of Dental and Craniofacial Research, part of the NIH.

Initially, Hoon´s group searched for the signaling components on a class of nerve cells, or neurons, that contain a molecule called TRPV1. With long nerve fibers extending into the skin, muscle, and other tissues, the neurons help to monitor a range of external conditions. These conditions include extreme temperature changes and pain.

Very little is known about how these neurons recognize the variety of sensory inputs, or how they are able to route these inputs correctly to the appropriate pathways in the brain.

In an attempt to fill in those details, the research team identified some of the main neurotransmitters that TRPV1 neurons produce in mice. Neurons selectively release these small molecules when they are stimulated, much like a quick pulse of water from a faucet. The neurotransmitters communicate sensory signals to other nerve cells. To see which neurotransmitters correspond with which sensation, the team screened a variety of them, including Nppd.

"We tested Nppb for its possible role in various sensations without success," said Santosh Mishra, a researcher in the Hoon laboratory. "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 researchers experimented further, establishing that Nppd was essential to initiate the sensation of itch, clinically known as pruritus. The molecule was necessary to respond to a broad spectrum of pruritic substances as well. Previous studies had suggested that finding a common start switch for the itch sensation would be unlikely, given the sheer number of proteins and cell types that were seemingly involved in processing the sensation.

The dorsal horn is a junction point in the spine where sensory signals from the body´s periphery are routed on to the brain. The team looked within this nexus of nerve connections for cells that expressed the receptor to receive the incoming Nppd molecules.

"The receptors were exactly in the right place in the dorsal horn," said Hoon. They discovered that the receptor for Nppd is the long-recognized protein Npra. "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."

Removing the receptor added another crucial bit of information, as it did not impact other sensory sensations, such as temperature, pain or touch. This told the researchers that the connection forms a dedicated biocircuit to the brain to transmit the sensation of itch.

Previous studies had suggested that a neurotransmitter called GRP might initiate itch, leading the team to question how GRP fit into the process. What they found is that GRP is part of the process, but that it enters the picture after Nppd has already set the sensation in motion.

Based on these findings, it would seem that Nppd would be an obvious first target to control itch. That´s not necessarily correct, however, as Nppd is also used in the heart, kidneys and other parts of the body, and thus attempts to control the neurotransmitter in the spine and have the potential to cause unwanted side effects.

"The larger scientific point remains," said Hoon. "We have defined in the mouse the primary itch-initiating neurons and figured out the first three 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. So, this is a start, not a finish."


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