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It seems hard to believe that a basic human sensation — one that can be evoked by a simple mosquito bite — still has scientists scratching their heads. Yet despite centuries of study, understanding itching is still fraught.

Itch, write two scientists in a review in the journal Immunity, "has been described as one of the most . In Dante's Inferno, falsifiers were eternally punished by 'the burning rage of fierce itching that nothing could relieve.'" Yet, the researchers note, "There have been very few advances in itch treatment in over 360 years."

That's finally starting to change. In the past decade, scientists have made strides toward understanding this infuriating sensation. They are untangling itchiness from other noxious stimuli, such as pain. They are even starting to distinguish one type of itch from another, by poking study participants with itch-inducing plant spikes or deleting itch-related genes from mice.

This wide-ranging research is gradually going beyond an understanding of familiar acute histamine-driven itch — the mosquito or poison ivy variety — to reveal the complicated mechanisms and players involved in the often debilitating type of itching that lasts for weeks and sometimes years. Chronic itch, as it's termed, can be generated by a multitude of factors, from chemicals secreted within the body to nerves gone haywire, and in many cases, has no known cause or cure.

This inquiry is more than an academic exercise (or a quest to make mosquito welts recede faster). While acute itch is fleeting, chronic itch may plague some 7 percent of people each year, and one in five people will experience it at some time in their lives. Beyond a maddening persistent urge to scratch, the condition can lead to depression, sleep deprivation and a drastic decrease in the quality of life. "It can be as devastating as chronic pain," says Robert LaMotte, an itch researcher at the Yale School of Medicine.

And pain is actually where the itch story starts.

Identifying itch

For much of the last century, itch was considered a lower-tiered version of pain. In the early 1920s, for example, Austrian-German physiologist and pain researcher Max von Frey documented in an influential study that a slight skin prick gave research participants the aftersensation of itch. This conceptual model continued to feed the field of itch for decades.

But eventually, the idea that itch was simply a subset of pain began to crumble. Scientists determined, for example, that they could not reliably turn a pain into an itch just by decreasing the pain's intensity — or turn an itch to a pain by increasing the itch's intensity. Yet the nerves and pathways of pain and itch appeared to be so similar and deeply intertwined that for years scientists lacked a clear understanding of how the two responses were wired into the body.

GUSTAVE DOR脡 / WIKIMEDIA COMMONS

Chronic itching is so brutal that it is one of the punishments suffered by souls in Hell who have committed fraud or treachery in Dante's Divine Comedy, shown
here in an 1892 illustration by Gustave Dor茅.

Then, in 2007, the sensation of itching finally crawled out from under the shadow of pain and into its own light.

That year, a seminal paper in Nature reported the first — a protein on nerve cells in the central nervous system that responds specifically to itch but not pain, indicating that the sensation might travel its own separate pathway to the brain. Zhou-Feng Chen, at Washington University School of Medicine in St. Louis, and colleagues showed that mice engineered to lack genes for this receptor — called the gastrin-releasing peptide receptor — could still feel pain but barely felt itch, no matter what the researchers tried.

"This changed the paradigm," says Brian Kim, a dermatologist and codirector of the medical school's , who now works with Chen. Revealing itch as a sensation in its own right with a dedicated pathway was a crucial step forward in understanding it, he says.

Since the discovery of this first itch receptor, researchers have discovered more cellular players involved in chronic itch, separating it out from acute itch. They have learned, for example, that chronic and acute itch are relayed by different sets of neurons that send signals along their own dedicated tracks in the nervous system. When researchers have simulated chronic itch in experiments with healthy volunteers, MRI scans reveal that the two itch types spur .

There are many routes to itch, but scientists have uncovered two, independent subtypes of neurons that relay the itch message to the spinal cord and brain. The histamine pathway (left), which is involved primarily in acute itch, is engaged when a trigger such as a mosquito bite spurs the release of histamines by the body's immune system, which activate histamine receptors. Non-histamine itch (right) can be set off by a wide range of internal and external triggers, including immune system molecules such as cytokines, enzymes called proteases that cut up proteins and the antimalarial drug chloroquine. After a trigger activates receptors in either pathway, enzymes are kicked into gear that spur the opening of ion channels, prompting the nerve to fire and send the itch signal to the spinal cord and brain.

These most foundational observations reveal just how much more we have to learn about itch. But they also help create a path to bringing relief to those who experience debilitating chronic cases. The sensation can be so bad that, for instance, some people with liver disease receive transplants precisely because of their itching. Others choose to go off of essential cancer medications because of the itching the drugs can cause.

And for years, researchers were focused on the low-hanging fruit of histamine-driven itch, which is easier to study, in part because it is being driven by a single chemical compound. Experimenters could spread or inject known irritants on or into the skin, cuing the body to make histamines, producing that familiar welty reaction that can be soothed by antihistamines like cortisone. But most chronic itch (technically, itchiness that lasts more than six weeks) doesn't involve histamines. And the routes — there are many — to chronic itch are far more complicated.

Now, as scientists refocus their investigations on chronic non-histamine itch, they're doing much of the research the old-fashioned way: by making people and animals itchy.

Itch by itch

Initiating an itch is not as simple as it seems. One approach that's been especially fruitful for zeroing in on non-histamine itch is to poke people with tiny hairs (or spicules) from a tropical plant called cowhage, or velvet bean.

In a key series of experiments, LaMotte and his colleagues took about 10 of these spicules, which are a few microns wide at the tip, and inserted them about 0.2 millimeters into the skin of study participants. Every 30 seconds, for up to 20 minutes, the thus-pricked people reported sensations they felt, such as pricking, burning or itching, as well as the intensity. The studies confirmed that an unusual compound within the minute hairs, called mucunain, rapidly causes itchiness but — unlike many plant-based itch-prompting compounds — doesn't activate histamines. That makes cowage spicules a powerful way to investigate the circuitry of non-histamine itch and possibly provide insight into mechanisms for chronic itch.

Next, LaMotte and his colleagues incubated human cells with mucunain in lab dishes to tease apart which receptor proteins might be receiving and responding to the incoming itch. They found responses in two types of such receptors — known as PAR2 and PAR4. Identifying itch-related receptors like these can help get medicine closer to a potential treatment.

To more fully understand the basics of itch and help disentangle it from pain, LaMotte and colleagues took a deep dive into the subtleties of the scratching behavior of mice. They learned where on the mouse body to inject their various irritants so as to reliably distinguish itchy types of scratching from pain types of scratching.

More than a decade on, the researchers can take advantage of the many biological mechanisms underlying itch — such as receptors and nerve pathways — that are similar in mice and people. That means they can now move back and forth between the two, injecting similar chemicals, for example, and tracking behavior (self-reports for humans, actions for mice) for intensity and duration.

Meanwhile, the lab of Xinzhong Dong, an itch researcher at Johns Hopkins University, has used mice to pinpoint nerve endings that are truly itch-specific. "You can activate those nerves, and you've got an itch sensation; you don't feel pain," he says. When he and his colleagues inactivated these dedicated itch neurons, mice were but still felt pain, the researchers reported in 2012 in Nature Neuroscience.

Other researchers aim to unlock itch's secrets with a more pure form of laboratory itch.

Dermatology researcher Akihiko Ikoma, then of Kyoto University, and colleagues took a mechanical approach to the problem. Instead of relying on chemical compounds, the team developed a that vibrates at a specific frequency. As the team described in 2013 in the journal PAIN, when the loop is touched to the fine hairs on people's faces, it creates an itch that takes more than 10 minutes to completely dissipate. This work has helped scientists to pinpoint itch-specific neurons around the skin that work independently of histamines or various other chemicals that stimulate itching.

The hope, for both methods, is to identify neurons and pathways specific to different kinds of itch. This will eventually help scientists investigate drugs that could relieve chronic itch in long-time sufferers.

But there remains more to untangle about itching's complex circuitry, with new receptors and nerve cells still being uncovered.

A partnership with pain

Despite all these advances — and despite the fact that itch is found throughout the animal kingdom, from fish to primates — "much of itch perception is ," Dong and Hopkins colleague Mark Lay note in the 2020 Annual Review of Neuroscience.

For one thing, even though there's been progress, the intertwined nature of itch and pain is still difficult to untangle. One reason may be that both originated as self-protection. Just as pain sends the signal to withdraw from something dangerous, itch prompts scratching, which could, for example, prevent infections by shooing away parasites. Scratching also appears to help recruit local immune cells that can fend off infection.

Itch and pain also have a peculiar overlap that even occasional scratchers are familiar with: Scratching can generate mild pain, which can often override the sensation of itch. Some researchers have proposed that when groups of neurons are activated — some of them itch-specific and some of them pain-specific — the pain stimulus, if strong enough, can mask the itch signals.

And despite the new itch-only discoveries, many nerves do seem to be involved in communicating both painful and itchy stimuli. The confusing overlap is exemplified in people with chronic conditions like atopic dermatitis. In these cases, nerves in the skin become hyper-sensitive to itch, and perceive as itchy stimuli that are normally painful — or simply mechanical or thermal. This is similar to what's experienced by some people with chronic pain, where light touch can actually hurt. And basic nervous system malfunctions like a pinched or damaged nerve can generate pain in some people but itch in others.

The overlap with pain is also present in the ways — still poorly understood — in which itch travels from the peripheral nerves in the skin to the spinal cord and up to the brain, Dong says.

All of these lingering mysteries mean that itch — especially chronic itch — has been extremely difficult to effectively treat. "Like in pain, there's not just one painkiller that destroys all types of pain," says Gil Yosipovitch, a dermatologist at the University of Miami and founder of the .

"I have patients who have a lot of complexities, and they require more than one pill or one cream, similar to patients who have chronic pain. And it requires a lot of time and patience."

For most of the population, itch is still a passing irritant, perhaps from bug bites in the summer or dry skin in the winter. But as a clinician and a research scientist, Kim says all of the suffering he sees from chronic itch keeps him working harder in the lab to understand this torturous sensation and correct too many years of inattention..

"It's just this cascade of neglect," he says.

This article originally appeared in , an independent journalistic endeavor from Annual Reviews.