After a bad sunburn even the feeling of clothing brushing against the skin can be unbearable. The phenomenon in which normally unremarkable sensations become painful is called allodynia. Now researchers have pinpointed the tiny protein on nerve endings, called Piezo2, which triggers those painful sensations in mice and humans. The results were published last week in two complementary papers in Science Translational Medicine.
Allodynia is a daily symptom for millions of people with chronic pain conditions, including inflammatory pain such as that caused by osteoarthritis as well as from nerve damage related to diabetes or chemotherapy. The new findings could pave the way for a future treatment for people with chronic pain or those recovering from burns or wounds—without compromising normal pain sensations, the studies suggest. “You could imagine a Piezo2 [blocker] applied topically in a cream—it would attenuate touch responses but keep all other responses intact,” says Alexander Chesler, senior author of one of the papers and a researcher at the National Center for Complementary and Integrative Health (NCCIH). And according to the findings, Chesler adds, “if you don’t feel touch, you won’t get allodynia.”
Sensory neurons are specialized to detect particular stimuli—from a feather’s touch to a pinprick, pinch or vibration, says Swetha Murthy a neuroscientist at The Scripps Research Institute, and lead author of the second paper. Murthy’s group, led by researcher Ardem Patapoutian at Scripps, discovered several years ago Piezo2 is a mechanically activated ion channel that makes nerve cells fire in response to gentle touch, vibration and proprioception—the sense of the body’s position in space. The new work extends Piezo2’s role to conveying painful sensations.
Both groups of researchers performed studies in genetically engineered mice that lacked the Piezo2 ion channel in some or all of their sensory neurons. Sensory cells lacking Piezo2 were unresponsive to gentle touches, but still responded to noxious pinches. After an injection to the paw with capsaicin—the burning ingredient in hot chilis—normal mice responded to gentle brush strokes by flinching and licking, indicating allodynia had developed. In contrast, mice lacking Piezo2 did not display such behaviors.
Perhaps most exciting, says Rebecca Seal, a pain researcher at the University of Pittsburgh who was not involved in the work, is this protein appears to function similarly in human patients.
Chesler and colleagues identified four people who lack Piezo2 due to genetic mutations. The individuals did not have any sense of gentle touch or vibration but responded normally to pinch and pinprick. The researchers then applied capsaicin and a placebo cream to subjects’ forearms, which were hidden from view. Control subjects reported gentle brushing of the capsaicin patch as more painful than the placebo patch every time. But subjects without Piezo2 could not detect the stimuli at either site. When forced to choose which site was more unpleasant, the ratings were evenly split.*
Seal says the work “solidifies the idea that tactile allodynia is Piezo-dependent, and that makes sense, because these nerves mediate touch. And allodynia is basically just touch that turns into pain in the spinal cord.” What changes in the central nervous system to make touch signals feel painful is still under investigation.
There are two main theories of what causes allodynia: One idea holds that mechanically sensitive nerve endings pick up gentle touch signals as usual, but those signals are somehow perceived as painful in the brain. An alternative notion is that the painful signals actually originate in pain-sensing cells. “It’s still hotly debated,” Chesler says. But both studies together suggest “you must have Piezo2 for allodynia—it is required.”
The findings suggest a new potential target for treating this condition. “The dream is to understand what molecules are involved in which aspects of pain,” Chesler says. “In the future we hope to use not one [type of drug] like opioids to blunt the whole system but very specialized agents aimed at specific targets.”
*Editor’s Note (10/16/18): This paragraph was updated after posting. The original incorrectly identified the Piezo2 protein as the PIEZO2 gene.