Itch-specific neurons discovered in mice

Itching is an unpleasant sensation that drives us to scratch reflexively in an effort to remove harmful substances from our body. It's also how I get most of my physical activity for the day. Not being able to scratch an itch is intensely frustrating and many scientists have long described itch as the milder cousin of pain.

But a team of scientists from Washington University's Pain Center (I wonder if they have problems with recruitment) have discovered a group of neurons in the spines of mice that are specific to itch but not to pain. Remove them, and mice hardly ever scratch when they're exposed to itchy chemicals, even though they can still feel pain as well as any normal mouse.

The discovery settles a long-standing debate about whether itch and pain are governed by separate neural systems. It confirms the so-called "labelled line" theory, which says that both sensations depend on different groups of nerve cells. 

Two years ago, Yan-Gang Sun and Zhong-Qiu Zhao discovered an itch-specific gene called GRPR that is activated in a small group of neurons in the spinal cords of mice. Without a working copy of this gene, mice became immune to itching but they still responded normally to heat, pressure, inflammation and the noxious flavour of mustard. The duo even managed to stop mice from scratching by injecting them with a chemical that blocks GRPR.

But neurons that activate an itch-specific gene aren't necessarily restricted to conveying the sensations of itching - they could also be involved in pain. To test that idea, Sun and Zhao injected mice with a nerve poison called bombesin-saporin, which specifically kills neurons that use GRPR. Without these neurons, the mice resisted a wide variety of substances that cause normal mice to scratch furiously, even though their movements were generally unaffected. Just compare the two mice in the video below - both have been injected with an itching agent but the one on the left lacks any working GRPR neurons.

However, even bereft of GRPR neurons, the mice felt pain just as any other mouse would, reacting normally to heat, pressure and noxious chemicals like mustard oil and capsaicin, the active component of chillies. Clearly, these neurons are specific to itch.

With such a striking result, it's important to check that no other groups of neurons were affected by the poison. Sun and Zhao did that with a variety of molecular markers that highlight the presence of other neuron types, none of which proved to be affected. They also managed to make mice immune to bombesin by slightly altering the structure of their GRPR protein. In these mice, the toxin didn't have any effect on their scratching behaviour. So even if bombesin does kill other neurons that don't GRPR, these other cells play little, if any, role in transmitting the sensation of itch.

Itches are often classified according to whether they involve the chemical histamine. Those that do, such as itch brought on insect bites, can be treated with antihistamines. But chronic itching, which doesn't involve histamine, has no effective treatment. But knocking out GRPR neurons renders mice largely immune to both types.

They scratched around 80% less than normal mice when their skins were directly injected with histamine or chloroquine, an anti-malarial drug that causes itching without any involvement from histamine. Sun and Zhao also treated some mice with diphenylcyclopropenone (DCP), a chemical used to treat alopecia, and whose side effects include intense itching. Mice suffer from these effects too but not those whose GRPR neurons had been killed off. 

That's promising news, for it suggests that this group of neurons might tell us more about the molecules involved in itching, and suggest ways of treating the severe scratch-provoking symptoms that afflict people with dermatitis, eczema and other conditions.  

However, it's clear that GRPR neurons are not the only ones involved in itch. A lot of research has focused on a separate group of spinal cells called STT neurons that aren't affected by bombesin, and that are involved in both itch and pain. How these cells interact with GRPR neurons, if at all, is still a mystery.

Until it's solved, I plan on continuing to lacerate myself in a series of small, angry furrows, especially given that writing about itching appears to be one of the most potent itch-inducers around...

Reference: Science 10.1126/science.1174868

Video and images courtesy of AAAS/Science