First Stop on the Itch Express

You will probably not be able to read this piece without feeling a little itchy. I apologise in advance.

In a laboratory at the National Institutes of Health, Santosh Mishra and Mark Hoon have bred a group of mice with an enviable super-power—they’re immune to itching. You can dab their skin with substances that would send most of us into a scratching frenzy, and they’ll be completely unfazed.

Compared to normal mice, these rodents are missing just one gene called Nppb. It produces a similarly named neuropeptide—a protein fragment that neurons use to communicate with each other. If you inject mice with Nppb, they scratch furiously. If you remove the gene for it or kill the neurons that make it, the mice never itch again. Their other sensations are untouched. They can still feel their own body parts, the touch of others, painful substances, or heat. They just don’t itch.

Mishra and Hoon think that neurons that produce Nppb are the root of itching. They’re the first to detect itchy substances on the skin. When this happens, they use Nppb to trigger other neurons, creating a relay of signals that ends in the brain and creates the perception of an itch.

Itching probably evolved to protect us from parasites and other threats on our skin. By reacting in the instinctive way—having a good scratch—we remove the danger. But even though itchiness is a universal sensation, we’ve only recently started to understand how it works.

For the longest time, scientists regarded itching as a milder cousin of pain. But Zhou-Feng Chen’s group at Washington University buried that idea. In 2009, they found itch-specific neurons in the spines of mice, which produce another neuropeptide called gastrin-releasing peptide (GRP). When they deleted the gene for GRP or removed the neurons that make it, mice never scratched but could still feel pain, heat, pressure and inflammation.

It looked like the team had found the root of itching, but Mishra and Hoon disagree. They believe that Nppb comes first. “The papers on GRP were a huge breakthrough and 95% of their data still hold, but they over-reached in interpretation,” says Hoon. “It was thought that GFP was the primary neurotransmitter. It’s not; it’s the secondary one.” In the itching relay, GRP certainly carries the baton but Nppb that starts the race.

Mishra and Hoon’s study began with a broader aim: They wanted to understand how we tell the difference between different sensations on our skin, like heat, pain or itchiness. They had previously engineered mice that couldn’t register any of these feelings, because none of their neurons had a protein called TRPV1. Mishra and Hoon wanted to know if some of them were specific to particular sensations. For example, are some of the TRPV1 neurons devoted itch sensors?

The answer was yes. A small subset of these neurons produces large amounts of Nppb. Without this peptide, mice became completely insensitive to a wide range of itch-inducing chemicals, even though they could still feel their other sensations. And when the duo injected Nppb back into the rodents, they regained the ability to itch.

Buoyed by these experiments, Mishra and Hoon started to outline the path that itch signals take from the skin to the brain. So far, they’ve worked out the first three “stations” on the way.

The Nppb neurons are the first stop. They sit in nodules called the dorsal root ganglia, which are found on either side of the spine. From there, they send long branches to skin, muscle and other parts of the body. When these branches detect something itchy landing on the skin, the neurons release Nppb.

This peptide travels deeper into the spine. It docks at a protein called Npra, which is found on neurons within the dorsal horn—a routing station where sensory information gets collated and sent to the brain. This is the second stop. (Again, if Mishra and Hoon selectively killed off any neurons carrying Npra, they removed the ability to itch).

Here’s where GRP comes in–Mishra and Hoon think that the Npra neurons release GRP, which carries the signals onwards. That’s the third stop.

They base that conclusion on two lines of evidence. First, if you knock out Nppb, you can still make mice itchy by injecting them with GRP. But this doesn’t work the other way round—Nppb does nothing for mice that can’t make GRP. This implies that Nppb comes first. Also, they only found tiny amounts of GRP in the dorsal root ganglia—the first stop on the path between skin and brain—but lots within the spine itself. So, it can’t be part of the primary itch sensors.

But Chen (who published the GRP papers) is not convinced. “GRP is definitely [found] in dorsal root ganglion neurons,” he says. “The fact that they don’t see it doesn’t mean that what others observed is wrong.” Besides, he notes, a peptide doesn’t need to be present in large amounts to effectively transmit signals between nerve cells. A little will do.

Chen also says that other studies have shown that Nppb is involved in sensing pain in the context of inflammation—something that Mishra and Hoon didn’t test for. So, perhaps Nppb isn’t an itch-specific messenger after all.

Given that our understanding of itching is still in its infancy, future studies may flip, tweak or strike out the suggested roles of GRP and Nppb. But for the moment, Xinzhong Dong at Johns Hopkins University School of Medicine, another researcher in the field, is impressed by the new study. “It’s very interesting and important,” he says. “Just like in all research, more experiments are needed to be done to support the “3-station” itch circuit model, but the findings definitely offer new molecular targets to treat the chronic itch that many patients suffer.”

He’s referring to cases like “M”, a woman who features in Atul Gawande’s astonishing New Yorker story about chronic itching. He describes it as “a constant, relentless itch [that] crawled along her scalp, and no matter how much she scratched… would not go away.” The condition is so bad that one night, M scratched through her skull, all the way into her brain.  Cases like these show that itch circuits can malfunction in spectacular fashion, with life or death consequences.

The Nppb discovery doesn’t mean that treatments are around the corner. In the brain, the peptide may only be involved in itching. But beyond the brain, it also helps to control blood pressure in the heart, kidneys and other organs. If you knock it out, you could get lots of unwanted side effects. Hoon hopes that by tracing the rest of the itch circuit, all the way to the brain, he’ll be able to find other potential ways of interrupting it, in people like “M” with the greatest need.

For more on itching, I highly recommend Atul Gawande’s piece.

Reference: Mishra & Hoon. 2013. The Cells and Circuitry for Itch Responses in Mice. Science http://dx.doi.org/10.1126/science.1233765