With chronic pain often comes allodynia—the painful sensation that arises from a normally non-painful touch. At its worst, allodynia can make showering, walking, or even wearing clothes unbearable.

Now, two groups of researchers have identified the protein responsible for this pernicious sensation in mice and in people. Called Piezo2, the protein could perhaps be silenced by a topical cream to treat allodynia, which affects millions of people with chronic pain, though the idea has not been tested yet.

The work comes from the laboratories of Ardem Patapoutian, a Howard Hughes Medical Institute Investigator at The Scripps Research Institute, La Jolla, US, and Alex Chesler at the National Center for Complementary and Integrative Health (NCCIH), a part of the U.S. National Institutes of Health (NIH), in Bethesda. Chesler’s study includes data from patients with a rare genetic mutation in Piezo2.

The two papers were published October 10, 2018, in the journal Science Translational Medicine.

Piezo2 is necessary for painful touch

Sensory neurons can detect many different types of stimuli, including innocuous temperatures and gentle touch. They can also detect unpleasant and potentially harmful things such as burning heat, chemicals, pinch and pinprick.

Exactly how sensory neurons respond depends on which specialized proteins they contain. These proteins can detect temperature, mechanical pressure, or chemicals. When they do so, they send electrical signals from the body into the spinal cord and ultimately up to the brain.

In 2014, Patapoutian and his colleagues discovered that Piezo2 was critical for normal touch sensation, including vibration and proprioception, the sense of our body in space. To test whether Piezo2 is also required for allodynia, both research groups created genetically engineered mice that lacked the protein.

In Patapoutian’s case, he and his team found that mice without Piezo2 were profoundly insensitive to touch stimuli like gentle brushing, but showed normal responses to temperature, and only subtle impairments in response to painful pinch or pinprick.

After an injection that causes inflammation, or after surgery to produce nerve injury—two animal models of chronic pain—the researchers found that normal mice developed allodynia: they responded to gentle brushing or poking of the paw with pain-like behaviors, including withdrawing, licking and shaking of the paw. Mice lacking Piezo2, however, did not respond, indicating that Piezo2 was required to develop allodynia.

The researchers also measured the electrical activity of sensory neurons during stimulation of the animals’ skin. Neurons in mice lacking Piezo2 responded normally to heat and pinch, but not to gentle touch. This again suggested the protein could play an important role in allodynia.

Human equivalent

Chesler and collaborators at the NIH also identified four patients with rare genetic mutations that cause Piezo2 to be completely non-functional. As a result, these patients could not experience any sensations of gentle touch, vibration or proprioception. The individuals with these mutations did respond normally to pinch and pinprick.

“When we pinch humans, they still say ‘ouch.’ They still feel it,” Chesler said.

But they did not experience allodynia, according to an experiment by co-lead author Jaquette Liljencrantz. She rubbed one area of the forearm (which was hidden from the patient’s view) with a cream containing capsaicin, the hot ingredient in chili peppers, and another area with a placebo cream (which had no active ingredient).

When the investigators gently brushed the skin, normal subjects rated brushing of the capsaicin area as more painful than the placebo area every single time, as would be expected. But people with the Piezo2 mutation could not distinguish between the capsaicin and placebo creams; when forced to choose which was more painful, their answers were no better than chance.

“It’s a clear-cut, single-result finding: in mice and humans, if you don’t have Piezo2, you don’t have allodynia,” said Chesler.

Crossed wires

Before the new research, there were two main views of how allodynia arises. According to one, allodynia comes about because the signal from neurons that normally respond only to gentle touch is somehow interpreted in the brain as pain. According to the other view, during chronic pain after injury, pain-sensing neurons somehow become sensitive to touch.

While some details remain unknown, the new research comes down firmly in favor of the first theory.

“Under physiological [normal] conditions, there are [spinal cord] neurons that inhibit the signal from [touch-sensing] neurons,” said Swetha Murthy, lead author of the Patapoutian study and a neuroscientist at Scripps. “Under conditions after injury, that inhibition is lost. So information from touch neurons intersects with the pain pathway.”

As for a potential therapeutic targeting Piezo2 in order to relieve allodynia, Chesler said, “the gulf is large, but you could imagine a Piezo2 antagonist [a drug that inhibits the activity of the protein] applied topically in a cream to attenuate touch responses but keep all other responses intact.”

To read about the research in more detail, see the related Pain Research Forum news story here.

Stephani Sutherland, PhD, is a neuroscientist and freelance journalist in Southern California. Follow her on Twitter @SutherlandPhD