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Why Do We Itch?

By Greg Rienzi
Is itching the same as pain, or entirely different? Are you itching right now? Before scientists can ease itching, they need to figure out what, exactly, it is.
It starts when it wants.
It’s on my right leg now—middle front calf to be exact.
Think of something else. Baseball. 
No good. It wins.
It always wins.
 
It is an itch. (And excuse me while I scratch it.) All humanity can relate to the sensation. We itch every day, sometimes plenty. But why, and just how does the feeling start and stop?
 
Long overshadowed by its sensation sibling, pain, itching is now getting its due. Within just the last decade, the literature on possible causes of itching and how to find relief has increased exponentially. Temple University dermatologist Gil Yosipovitch, dubbed “The Godfather of Itch,” has vocally led a crusade to classify itching as a disease, not just a nuisance.
 
In 2001, Yosipovitch organized the first worldwide summit on itching, held in Singapore. Four years later he founded the International Society for the Study of Itch, a multidisciplinary association of clinicians and researchers dedicated to improving understanding and treatment of what science calls pruritus. 
 
“The field is growing, no question,” says Yosipovitch, author of Living with Itch: A Patient’s Guide (Johns Hopkins University Press, 2013). “For me, this is the most exciting time in the 20 years I’ve been in the field. Not that long ago, I could count on one hand the number of professionals interested in itching. Today, there are more than 200 researchers focused on this issue.”
 
Why itch at all? Many call it an evolutionary warning sign to stay clear of itch-inducing toxic plants and insects that might spread diseases like malaria or dengue fever.
 
These scientists want to identify the mechanisms of itching (and scratching) and how our brain interprets itch signals and differentiates them from pain, in essence distinguishing the sensation of a brush of a fuzzy sweater from a hand held too close to the fire. A team of Johns Hopkins and Yale molecular biologists and neuroscientists believe they have identified an itch-mediating neuron activated in mice. In a 2013 study published in the journal Nature Neuroscience, the researchers sought to end the decades-long debate on whether humans and animals possess separate pathways for pain and itch, or if those sensations travel along a similar route. 
 
Xinzhong Dong, a professor of neuroscience at Johns Hopkins and senior author of the study, says the findings were significant but fall short of being the final say on the argument. “We now have some compelling evidence that itch-specific neurons exist in the mouse, but how that translates to primates is not clear,” he says. “The sensory neurons that mediate pain and itch in humans are very much alike, so it’s hard to know which one mediates itch or pain, or if they are the same group. We still don’t fully understand the itch, although we appreciate the mystery more and more.”
 

More than 350 years ago, German physician Samuel Hafenreffer first defined the itch as an “unpleasant sensation” that makes people want to scratch. We itch on our skin and in our throat, but mercifully not internally. Imagine an itchy spleen? The common itch sensation, scientists believe, results from the excitation of nerve endings in our skin. This feeling forms in the cortex of the brain and is encoded in the central nervous system.  Some of what we know relies on the groundbreaking work of Glenn J. Giesler, a neuroscientist from the University of Minnesota who recorded spinal cord neuron itch circuits in monkeys and rats. Giesler’s work, published in 2009, tells us that primary sensory neurons fire in the presence of an itchy substance. Those neurons then relay the signal to the spinal cord, thalamus, and then the cortex. And then we want to scratch. But why itch at all? Many call it an evolutionary warning sign to stay clear of itch-inducing toxic plants and insects that might spread diseases like malaria or dengue fever. “People generally believe itching provides a protective mechanism,” Dong says. “You feel bad, you scratch it. Maybe it removes something from the skin that shouldn’t be there. But what if an insect bite or poison ivy is already on the skin? Maybe that’s nature telling you to try to avoid the substance, or area, in the future.”

 
All itches, Dong says, are not created equal. They’re broken down into two forms: acute and chronic. Acute itch is typically produced by mechanical means like a gentle touch, pressure, or contact with an itchy substance such as wool. Heat and friction can also produce itch, like wearing tight pants or walking into a room with the central heating kicked up high. The colder months yield what is known as “winter itch,” as low humidity levels draw the moisture from our skin, leaving it dry and flaky. 
 
Perhaps the most common type is spontaneous itch, the one you might be feeling reading this story. It’s itching without an obvious stimulus—and it’s contagious, like a yawn. Dong theorizes that unlike pain nerve fibers, where the body needs a high threshold to fire, our itchy receptors balance on a hair trigger so that even the thought of itching can set them off. “Maybe the itchy fiber is always near the threshold,” he says. “Your guess is as good as mine.”
 

It’s chronic itch that makes someone truly miserable. 

 
In his clinical practice, Yosipovitch has witnessed the debilitating effects of chronic itch, which lasts six weeks or longer and can cause sufferers to scratch uncontrollably and without relief. Some people have trouble sleeping, scientists believe, because their itching intensifies with the evening rise in skin temperature (think indoor heating and being under sheets); studies have also suggested the nerves that secrete itch-causing chemicals are more active during nighttime. Chronic itch sufferers have to live with the embarrassment of constant scratching in public, and may be forced to cover up eroded areas on the skin due to excessive scratching. “Without question, chronic itching can negatively impact quality of life,” Yosipovitch says. “I’ve seen cases where the urge to scratch is so powerful you can’t turn it off. It can be misery.” 
 
The affliction impacts millions, and it’s estimated that nearly 20 percent of children and 5 percent of adults have some form of chronic itch, which has multiple causes. A host of diseases—kidney, liver, HIV, leukemia, lymphoma, and others—carry what is called neurogenic itching as a symptom. Unlike itch activated by primary sensory fibers on the skin, neurogenic itch involves neurons in the spinal cord or brain that somehow get triggered. The result can leave you scratching all over.
 
Severe burns and nerve damage, as with shingles, can also cause chronic itch.
 
There’s also psychogenic itch, or phantom itching, which happens when you’re not as engaged with your surroundings or otherwise distracted by an activity like talking or walking, or it can be linked to psychiatric conditions such as obsessive-compulsive disorder. 
 
“So itching is very complex, and we are only just starting to learn the very basic mechanism of the itch right now,” Dong says. “You can imagine there are many stimuli, chemical and mechanical, that can induce itch, including itch mediators inside the body like histamine.”
 
 “We’re trying to block the sense of itch. If we’re successful, we will probably develop a nonsteroid cream because FDA approval is easier than for a pill or injection.”
 
Over-the-counter antihistamines relieve some types of itching and are effective for treating mild allergies and conditions where histamines are the major culprit, such as insect bites and hives. These drugs block the itch receptors and can inhibit scratching—a good thing. For all its pleasures, scratching can make matters worse by damaging the upper layers of the skin, leaving it exposed to other irritants. In the case of poison ivy, scratching spreads the toxin to other parts of you. But the urge to scratch is strong. Studies have found that scratching your ankle can feel as good as sex.
 
Nearly two-thirds of chronic itch, and some acute forms, however, cannot be treated with antihistamines because, as the name suggests, these drugs can only target histamine receptors. Currently, the medical profession has no good remedies for people who have such severe itching. To help find a cure, Dong and his colleagues wanted to understand how primary sensory neurons—the nerve endings that first detect itchy compounds—work in mice.
 
They first genetically engineered mice by placing green fluorescent protein in nerve cells located near their spinal cord so that, using a fluorescent microscope, they could observe what cells are activated. Next, they exposed these mice to itch-inducing substances like histamines to see what cells fired—basically, which ones glowed green. What they found were some nerve cells in the spine that responded only to itch.
 
To test the findings, the researchers modified these nerve cells to bind to capsaicin, the chemical that makes chili peppers hot and painful. They rubbed capsaicin on the mice’s skin and, instead of the mouse equivalent of “ouch,” the animal scratched, demonstrating that these cells transmitted only itching. In another experiment, researchers killed these same nerve cells with a toxin and then exposed the mice to itchy chemicals. The mice scratched much less—compared with control animals in which the itch-sensing neurons weren’t killed—but still received pain signals. The findings gave researchers a new target for clinical treatment. Here were cells that, if we could turn them off, would reduce itch but wouldn’t inhibit the practical ability to sense pain.
 
The work on itch-mediating nerves found in mice now needs to be translated to primates. That’s the type of work currently being done in the labs of Yale neuroscientist Robert LaMotte and Johns Hopkins neuroscientist Matthias Ringkamp. LaMotte is looking at inflammation on the skin by experimenting with contact allergens, similar to the chemical in poison ivy. His task is to look at how the properties of cutaneous sensory neurons react to this stimulation and then contribute to itch. “We basically want to know how the itch is presented in humans,” LaMotte says. “What is being activated, and what is being turned off when we scratch.”
 
In Ringkamp’s lab, researchers are investigating electrical activity in cutaneous nerves, which are the ones responsible for providing sensory stimulation to the skin. Bigger picture: Ringkamp wants to find out more about how the central nervous system encodes itch versus pain in humans.
 
Perhaps the most common type is spontaneous itch, the one you might feel reading this story. It’s itching without an obvious stimulus—and it’s contagious, like a yawn.
 
The association of itch and pain comes together neatly in the form of scratch-ing. A prevailing theory is that the act of digging fingernails into skin activates the pain pathways and inhibits the itching response. The pain overrides the itch, so you’re in effect trading sensations. One piece of research suggested that scratching “quiets” nerve cells associated with itch, releasing inhibitor interneurons that stop the nerve cells from firing. “Of course, in some cases, the act of scratching simply removes the irritant,” Dong says.
 

Dong’s hypothesis is that this scratching pain signal activates a bigger population of neurons that drowns out itch. But it doesn’t work the other way around. “We can’t scratch pain away. Only if an itch-inducing signal goes in can we inhibit. Why? That is hard to understand.”

 
Dong says that once we better understand the basic mechanisms of itch in humans, we can start working on clinical trials. The answers the medical community finds could provide much-needed comfort for those suffering from acute and chronic itch that cannot be treated by antihistamines or topical creams. They have identified some receptors in mice and humans, the genes expressed in the nerve pathways to detect those itchy signals, and currently have a drug development program in the lab to develop blockers for those receptors.
 
“We’re trying to block the sense of the itch. But it’s a hard job,” he says. “If we’re successful, we will probably develop a nonsteroid cream because FDA approval is easier than for a pill or injection.” 
 
Dong says there has been a general lack of interest from the pharmaceutical companies to develop anti-itch drugs. One reason, he says, is that drug companies think the market is not particularly big. Another is that clinical trials will be difficult because the placebo effect is strong for topical treatments. “When people see something applied to the skin, they feel better, even though there is nothing in it. That can really mask the effect of these drugs.” Finally, Dong says that research into pain tends to get more industry attention. “If you present two projects and one is treating pain and one is treating itch, the drug company will pick the pain every time,” he says.
 
Dong and his colleagues are currently focusing their research on the spinal cord in mice to see how the itch signal is received from the skin. Having already identified the primary neurons to detect itch information, they now want to identify the secondary neurons involved in this signal chain. It’s a game of connect the dots. “You need a series, or chain, of neurons connected with each other through their nerves in order to have sensory information like itch be relayed to the brain,” Dong says. “A single neuron cannot send the information to the brain. There are at least three to four neurons connected in the series, called a circuit.”
 
Science is now a few years closer to unlocking all of itching’s mysteries. “Yet in some ways,” Dong says, “we are still at the very beginning of this type of research using mice genetics and molecular approach to studying the mechanism. Previously, most of what we knew was observations. Now, we’re getting down to the details.”
Just don’t think about the itchy details too much. You’ll regret it.  
Illustration of a distressed woman scratching her body
Andre Wee
Xinzhong Dong is a professor of neuroscience 
at Johns Hopkins and author of a study that tried to determine whether itch and pain are the same. “We still don’t fully understand the itch,” he says.

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