When it comes to the eye, itch has its quirks. It’s usually felt in the conjunctiva, the membrane that lines the eyelids and covers the white of the eye. Yet, itch is almost never felt in the cornea, the outmost layer of the eye that helps to focus incoming light.
According to new research led by Qin Liu at Washington University in St. Louis, that’s because of specialized nerve cells (neurons) present in one tissue but not the other. Unlike the cornea, the conjunctiva houses a set of itch-triggering neurons known to contain a protein called MrgprA3. By blocking the activity of these cells in mice, Liu and her colleagues found that they could ease allergy-related itching.
“In the end, [the set of experiments] gives us a little glimpse of what might be possible for treatment of a condition that’s really unpleasant,” says Mark Hoon, from the National Institute of Dental and Craniofacial Research, part of the U.S. National Institutes of Health, in Bethesda. Hoon was not involved in the work.
The study was published in the August 2018 issue of the journal Nature Medicine.
Liu’s itch to study the eye, so-to-speak, came from her own unpleasant experience with seasonal allergies.
“My eyes feel itchy every spring,” she said. “I use eye drops, but the anti-histamine doesn’t work so well. And, it makes my eyes dry.”
To find something better for her itchy eyes, Liu began wondering what happens at the cellular and molecular level when this kind of itch arises.
Within the skin, itch sensation involves three types of neurons, including the MrgprA3 cells. But when Liu’s team looked in the eye, they found just two of the three types. In the conjunctiva, neurons with MrgprA3 covered a greater area than those with MrgprD, a related protein. But in the cornea, none of the three cell types were present.
This anatomy pointed to a clear hypothesis—that in the eye, MrgprA3 neurons are the main contributors to itch.
To test the idea, the researchers killed off these cells in mice, and then delivered a host of chemicals that cause itch to the animals’ eyes. With each chemical, mice missing the MrgprA3 cells scratched themselves less than normal mice.
In contrast, when the researchers activated neurons that contained MrgprD (the protein related to MrgprA3) in normal mice, the animals did not start scratching. The MrgprA3 population, then, seemed to be the only one that could trigger itch.
A new way to treat itch?
With this knowledge, Liu’s group next tried to ease eye itching in mice exposed to an allergen (a substance that causes an allergic reaction). Using a chemical called QX-314, they first quieted the activity of the MrgprA3 neurons. Then, when the researchers applied an allergen to the eye, the animals showed less scratching for more than 24 hours. By comparison, the relief from an anti-histamine lasted less than an hour.
What’s more, this strategy achieved the same outcome in mice that were genetically modified to lack MrgprA3 and instead make the human version of the protein, called MrgprX1. And, in human eyes, neurons containing MrgprX1 were also found in the conjunctiva but not in the cornea.
“QX-314 could be remarkably effective for treating allergic itch, because it would only act” on neurons activated by an allergen, says Hoon. “Neurons that weren’t active wouldn’t be affected.” This is because QX-314 can only enter neurons that have been activated—by something that causes itch, for instance.
Even so, “there’s always a worry that things aren’t going to work exactly the same way as in a model system [used in the laboratory]. As soon as you start using a compound in people or even other animals, you start finding side effects that are perhaps unanticipated,” he added. “QX-314 sounds great in principle, but it needs to be tested in humans.” The compound has not yet been evaluated in a clinical trial.
In the meantime, Liu intends to unravel more of the story of how itch originates in the eye. She’s now trying to identify the molecule produced within the eye that attaches to and activates the MrgprA3 protein.
To read about the research in more detail, see the related IASP Pain Research Forum news story here.
Matthew Soleiman is a graduate student in the Department of History and Science Studies Program at the University of California, San Diego, US. Follow him on Twitter @MatthewSoleiman.