Researchers have discovered that the gene PIEZO2, which has previously been shown to control the human sense of our bodies in space and the experience of gentle touch, may also be responsible for tactile allodynia—the skin’s reaction to injury that creates a sensation of pain in response to gentle touches.
These findings come from two papers in Science Translational Medicine: (Oct. 10, 2018; 10(462):eaat9897, and Oct. 10, 2018; 10(462):eaat9892), and show that the gene may play an essential role in the nervous system’s reaction to injury and inflammation. This suggests PIEZO2 may be a target of interest for developing treatments for the relief of pain caused by cuts, burns, and other skin injuries.
NIH funded studies found that the PIEZO2 gene may control the skin’s reaction to injuries, like sunburns, that make gentle touches feel painful. Photo by: Chesler lab, NCCIH.
“For years scientists have been trying to solve the mystery of how gentle touch becomes painful. These results suggest PIEZO2 is the gene for tactile allodynia. We hope that these results will help researchers develop better treatments for managing this form of pain,” said Alexander T. Chesler, PhD, in a press release. Dr. Chesler is a Stadtman Investigator at the U.S. National Center for Complementary and Integrative Health (NCCIH) and a senior author of one of the studies.
The PIEZO2 gene encodes for a mechanosensitive protein, which produces nerve signals in response to changes in cell shape, such as those caused by touching the skin.
In 2016, Dr. Chesler and colleagues worked with the group of Carsten G. Bönnemann, MD, senior investigator at the U.S. National Institute of Health’s (NIH) National Institute of Neurological Disorders and Stroke (NINDS), on a project which showed that two patients who had mutations in PIEZO2 that eliminated its activity lacked proprioception, as well as lacking the ability to feel vibrations. The two patients were also less sensitive to certain forms of gentle touch.
In this new research, Drs. Chesler and Bönnemann worked with pain expert Catherine Bushnell, PhD, at NCCIH, to examine four more patients at the NIH’s Clinical Center. Through their investigation they found that PIEZO2 controls tactile allodynia after a skin injury.
The test for allodynia involved participants sitting at a table facing a barrier that blocked their view of their arms, after which two creams—a placebo and one containing capsaicin, were applied to their forearms.
Stark differences were seen between how the capsaicin cream affected control participants versus those patients with mutations in PIEZO2. Swiping a cotton swab around the capsaicin patch consistently caused control participants to feel pain, which allowed each one to correctly identify where the inflammation was even though they could not see their arms. In contrast, the participants with the PIEZO2 mutation felt no difference between the areas where capsaicin and placebo had been applied.
“What’s remarkable about the PIEZO2-deficient participants is the ‘clarity’ of their conditions. With their help we’re getting fundamental new insights about how the loss of PIEZO2 affects them specifically and learning what PIEZO2 is normally used for, which could be of immense medical importance to all other people,” said Dr. Bönnemann in the release. “This type of PIEZO2-dependent pain makes it very hard to apply bandages to burns and wounds that are important for healing. Most pain treatments numb large areas of the body. Our results suggest that if we could shut down PIEZO2 in the area of a wound, we would hopefully relieve the pain and speed recovery.”
Although neither study shows exactly how inflammation causes pain, their results suggest that inflammation does not alter the ability of PIEZO2 to detect gentle touches.
Dr. Chesler’s group showed in a mouse model that inflammation in control mice had no major effect on how the PIEZO2-containing neurons fired in response to gentle brushing.
The investigators say that instead, their results support the Gate Theory—the idea that inflammation causes gentle touches to feel painful because neurons in the brain or spinal cord reinterpret signals from the rest of the body.
“It appears that inflammation doesn’t change the ability of neurons in the skin to sense gentle touch but instead reroutes the information that’s sent throughout the rest of the nervous system,” said Dr. Ardem Patapoutian, PhD, from Scripps Research, La Jolla, Calif., in the release. “We hope these results help pain researchers better understand the mechanisms behind tactile allodynia.”
Dr. Patpoutian led the team that first discovered the PIEZO2 gene in mice, and was the lead author of one of the two new papers.