Illustration by Scotty Reifsnyder
Zhou-Feng Chen went looking for pain. He identified a possible pain receptor gene in the spinal cord. He injected a peptide known to activate that gene, and waited. The mice showed no sign of pain. Instead, they immediately began to scratch.
And the more peptide he injected, the more they scratched.
The clincher? When mice were exposed to things that make them itchy, those without that particular pain receptor (the gastrin-releasing peptide receptor, GRPR for short) scratched less than their littermates.
Chen’s disappointment quickly changed to fascination. His discovery had profound implications: Until recently, scientists thought of itch as just a minor form of pain, and assumed its sensation traveled the same pathways. Chen’s receptor indicated a clear separation. It was time to start hunting for the pathways of itch.
This spring, Washington University School of Medicine announced that it was opening a multidisciplinary Center for the Study of Itch. Chen, professor of anesthesiology, psychiatry, and developmental biology, will direct the center, with Dr. Lynn Cornelius, professor and chief of dermatology, as co-director.
“Zhou-Feng’s discoveries were a breakthrough in an area of medicine that’s been neglected,” Cornelius says, “probably
because it’s not clear-cut or homogeneous. There are so many things that can cause itching.”
We talk about physical and psychological itches interchangeably. There’s the seven-year itch. The itch to do something. The wriggly, maddening, intolerable itch that knocks every other thought or sensation out of the way. Our language doesn’t differentiate by severity or duration, either: Itching can be caused quite simply, by winter’s dry skin or summer’s bug bites, poison ivy, and sunburn. Allergic responses often include itchiness; histamines are nature’s favorite transmitters of the itch signal. Fungal or bacterial infections, rashes and inflammations, shingles, scabies, lice, dandruff, dried sweat—all itchy. Heroin and cocaine can give you the crawlies.
Some prescription drugs cause itching, too; so do liver and renal failure, possibly because certain proteins or enzymes aren’t cleared as effectively from the body. Skin cancer can itch—and cutaneous T-cell lymphoma is fearsomely itchy. It’s the first thing doctors worry about when patients mention a puzzling, recurring itch. Some itches are pointedly localized: an outer-arm itching that worsens in sunlight is caused by a crimp in the neck. Then there’s that old trilogy: eczema, seborrhea, and psoriasis. But there’s also obsessive-compulsive disorder, nervousness, and plain old embarrassment.
Chronic itching is the most mystifying condition of all; it sometimes outlasts its cause, because the brain conjures a trigger and continues supplying the sensation itself, even without messages from its receptors. And in that cycle, we don’t yet know how to turn off the brain.
“An itch is a perception,” explains Chen. “It comes from your brain. No brain, no itch. But most of the time, the stimulus comes from the skin. The nervous system receives this information from the skin and imports it to the brain, which perceives it as either itch or pain and tells the body how to respond. If it’s an itch, you scratch!”
An itch is a temptation hard to ignore. Thoughts alone can make us itch, and an itch is almost inseparable from the impulse to scratch. Just seeing pictures of itchy things—like fleas, or other people scratching—tends to make us scratch more. When we scratch, the relief’s temporary, though, as relief so often is. Mom’s old warning, “Stop scratching; you’ll just make it worse” turns out to be accurate. People with chronic, severe itches often have to have their hands bound or their heads helmeted at night, because the urge to scratch is so intense and the involuntary scratching can do such damage.
It wasn’t until 1997 that researchers identified a type of nerve specific for itch. These itch fibers are extraordinarily sensitive, able to pick up an itchy sensation more than three inches away. They conduct slowly, which is why itches build gradually (and subside even more gradually).
Nine years after the nerve fiber was identified, Chen pinpointed one of the long-rumored receptor genes. Now the almost dismissive notion of itch as a lesser kind of pain has been scotched for good. Itch is a torment all its own. If it’s mild and brief and fun to scratch, count yourself lucky.
Steroid creams and antihistamines can help simple itches; ultraviolet treatments, SSRIs, Neurontin, and anesthetizing patches are the next level—and are frequently ineffective. “Itches can be very difficult to treat and are often a patient’s most bothersome symptom,” Cornelius says. “My most memorable patient was a guy who had cutaneous T-cell lymphoma, and he was pretty nearly suicidal from the itch.”
Why do we itch? “Evolution,” says Chen. “Millions and millions of years ago, in the forests, people needed a mechanism to protect themselves, an alert if something bad happened to the body.” Pain wasn’t enough; pain provokes withdrawal, and some bad things, like infectious bug bites and toxic plant substances, are stuck to the skin. There’s no withdrawing from them, so you need a different kind of alert, hopefully one that will brush the pest or substance away before it can do harm.
That ancient response is one we share with other animals, who seem equally bemused by it. “Now we’re learning there are many, many pathways, many genes involved,” Chen says. “It is so complex. We need more people coming to join us, to study how itch is transmitted, how it can be separated from pain, and how it can be treated.”
Cornelius agrees vigorously. “We have to stress that this is really a research center,” she says, terrified that she’ll come to work and find a long line of patients outside her door scratching madly, desperate for a cure. She predicts collaborations with a long list of colleagues, from neurologists and psychiatrists to gastroenterologists and oncologists, whose patients often suffer from unbearable itching. “They’re saying, ‘Oh my God, please, if you guys can develop something, I’m in.’
“We are looking to recruit a physician scientist who is interested in the research of itch and will marry that with a clinical practice that focuses on itch,” Cornelius continues. “We also hope to develop a good clinical-trial arm” to test commercially developed treatments, and eventually use the center’s own research findings to develop new therapies.
“The NIH [National Institutes of Health] is starting to look at this, but we have been the first to move forward with a research-based center,” she says. “I think as the research center grows, we will be able to tease out the differences in itch in all these different patient populations.” Then therapies can be targeted; pathways can be blocked.
There will be no shortage of patients: Cornelius’ department marks diagnosis codes for patients, and often if there’s an obvious diagnosis, like psoriasis, the “itch” box isn’t even checked. Nonetheless, last year alone, 500 patients were coded with “itch.”
“I can tell you,” she adds, “that’s an underestimate.”
