architecture 7.arc.0098 Louis J. Sheehan, Esquire

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When it comes to sensory information detected by the body, pain is king, and itch is the court jester. But that insistent, tingly feeling—satisfied only by a scratch—is anything but funny to the millions of people who suffer from it chronically.

Garden-variety itches related to histamine, like the kind caused by an angry rash of chicken pox or poison ivy, annoy everyone, but most can be subdued with drugs like Benadryl. But another type of itch is not mollified by these drugs, and therein lies the rub. Pathological itch — called the “itch that laughs at Benadryl” by neuroscientist and itch investigator Glenn Giesler Jr. of the University of Minnesota—is no joke.

Not often pursued by scientists who look at sensation, itch research has lagged far behind investigations of other bodily cues. But in recent years, scientists have begun studying pathological itch seriously. This year researchers found nerve fibers—long, thin strands that carry information from the outer skin to the spinal cord and ultimately, the brain—built to detect this often-devastating type of itch. The new results show that it has its own pathway to the brain.

“That’s the hottest topic in the field right now, the idea of different pathways for different itches,” says Earl Carstens, a neurobiologist at the University of California, Davis who studies the details of how these itches travel to the brain. The discovery of these fibers has also led some researchers to rethink the relationship between pain and itch.

“In the last two years, there has been an exponential growth of publications in the field, with major findings,” says Gil Yosipovitch, a researcher and clinician at Wake Forest University in Winston-Salem, N.C., who founded the International Forum for the Study of Itch in 2005.

Increasing attention to itch is good news for the estimated 17 million Americans with severe, chronic itch from atopic eczema, a skin disease marked by dry, itchy skin, and other itchy conditions. A large study on itch conducted in Oslo in 2004 found that 8 percent of more than 18,000 adult Norwegians surveyed suffered from chronic itch. Itch often afflicts the weakest: It is a well-known but understudied symptom in people with liver failure, multiple sclerosis, HIV and late-stage cancer. Painkillers may help the seriously ill, but often replace pain with severe itchiness. http://LOUIS-J-SHEEHAN.INFO And depression rates soar among people who itch constantly.

It’s easy to imagine why. Think of spiny insect legs scurrying up the neck, and of lice, mosquitoes, bedbugs and chiggers crawling on, burrowing in and biting tender parts of the skin. Now magnify those sensations by months, years or even decades.

For patients and doctors, the worst part of this itch is that there is almost no way to treat it. Antihistamines like Benadryl, the tried-and-true way of blocking itch caused by bug bites and hives, have no effect on more serious itch conditions. In many cases, the best (and only) advice has remained unchanged for many years: Moisturize, wear loose clothing and, whatever you do, don’t scratch.

“It’s maddening,” says Susan Lipworth, a board member of the National Eczema Association, based in San Rafael, Calif., who has suffered from severe eczema-related itching for 14 years. The insatiable desire to scratch has left her body scarred with seeping wounds. “I love my doctors, but there is nothing for this,” she says.

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NEVER-ENDING ITCHENLARGE Pathological itch, unlike garden-variety itch, cannot be subdued with drugs like Benadryl. Amy Guip

The original itching

Plants and bugs can make us itch. So can scratchy wool sweaters. It turns out that itch can even be brought on by the power of suggestion.

You feel an itch on the skin. But its roots lie deep in the brain and spinal cord, a finding that emerged from scientists’ first modern attempts to understand itch in the 1970s and 1980s. Studying the itches brought on by things like poison ivy, scientists showed that after contact with the plant’s toxins, the skin releases a chemical called histamine from specialized cells that cause the skin to swell, redden and itch.

Early work by European researchers showed that histamine causes intense itch when injected directly into human skin. It wasn’t until 1997 that a German research group led by Martin Schmelz, now at the University of Heidelberg in Mannheim, discovered the first itch nerve fibers, which responded primarily to histamine and were shown not to be sensitive to pain (SN: 10/18/97, p. 245).

“The idea was fabulous,” says Robert LaMotte, a neurobiologist at Yale University and a leader of studies on the newly discovered chronic itch fibers.

Until the 1997 finding, most researchers thought that itch was a weaker form of pain, and probably sensed by pain-related nerves. Scientists believed that if an itchy stimulus was increased to a high enough level, the itch would turn into an “ouch.” Conversely, if a painful poke was lessened enough, the pain would feel itchy. But the discovery of fibers that responded to histamine but not to a painful pinch revealed itch as a sensation unto itself.

“The idea that histamine is the main itch mediator in the skin was prevalent for a long time,” Carstens says.

The study of histamine itch led to major gains in understanding a chemical that causes itch and the fibers that detect it, but in a sense, it was a red herring. Even then scientists knew that some itching didn’t appear to involve histamine.

Laughing at Benadryl
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ITCHY PATHWAYSENLARGE Researchers have identified two distinct types of nerve fibers that respond to itchy sensations, passing signals from the skin to the brain. View the diagram for more details.Charles Floyd

“It all started with the observations of itch that are resistant to antihistamines. That’s why we embarked on this research,” says Matthias Ringkamp, a neurobiologist at Johns Hopkins University in Baltimore who has worked with LaMotte on the chronic types of itch.

Another clue also led scientists to look for separate pathways for these types of itch: The nerve endings discovered by Schmelz’s group in 1997 cannot detect many types of itch, like the kind caused by unlined prickly wool pants raking against dry winter legs. Researchers thought it might be possible to use temporary nonhistamine itches as experimental proxies for chronic, debilitating itches.

To study the itches in the lab, scientists turned to cowhage, a major ingredient in pranksters’ itching powder. Back in the 1950s, scientists had described the curiously itchy effects of cowhage, or Mucuna pruriens, a tropical plant with white or purple flowers that produces nutritious beans. Its seedpods are coated with tiny lances called spicules. When lodged in the skin, the spicules produce an intense, pure and reproducible itch that lasts for about six minutes. (Probably a very long six minutes for the study participants.)

“You can take Benadryl all day, and if you jump into a cowhage plant, you’ll itch like no tomorrow,” says Giesler, whose University of Minnesota research group was, in 2004, one of the first since the 1950s to take advantage of cowhage’s itchiness. “Right away, we realized that cowhage was a different type of itch.”

To draw distinctions between itches, a team of researchers led by Ringkamp conducted experiments using histamine for the usual itch and using cowhage to represent chronic itch. Although the study subjects found both substances to be itchy, the characteristics of the itches were markedly distinct. The itchy area caused by cowhage was restricted to the site of application; the histamine itch spread out from the original site. When an antihistamine was applied to the itches, the cowhage itch persisted.

But when Ringkamp and colleagues treated the itches with the compound that makes chili peppers hot —capsaicin, which triggers a pain response — they blocked the cowhage itch, while leaving the histamine itch unaffected. There was another notable difference. The cowhage itch disappeared in about six minutes, while the histamine itch lasted longer.

These results, published in 2007 in the Journal of Neuroscience, showed that while the sensation of the two itches caused by histamine and cowhage felt similar to participants, the mechanisms were undoubtedly different.

Since, like almost all types of chronic, pathological itches, the itch produced by cowhage is impervious to antihistamines, scientists reasoned that if they could figure out exactly which neural fibers were responsible for a cowhage itch, they might understand how pathological itch works. Then, they could figure out how to treat it. The scientists concluded that different itch fibers may carry distinct itch messages to the brain.

Because the histamine-sensing itch fibers could not detect itchy mechanical stimuli, like a scratchy wool sweater, the researchers turned to another likely culprit: pain fibers.

Pain and the itch

Called an “exquisite pleasure” by researcher G.H. Bishop in 1948, scratching an itch is deeply satisfying, probably because the pain caused by scratching overrides itch fiber activity. But the relationship between pain and itch is, to put it mildly, complicated.

After the 1997 discovery of the itch-specific fibers, itch and pain were uncoupled. The new data on cowhage-induced itch suggests that pain and itch, in some cases, do seem to be linked, and perhaps detected by the very same fibers. The finding makes the idea of a clean separation a bit fuzzier.

To see the activity of individual fibers that might respond to pain and itch, LaMotte’s team began eavesdropping on the neurons of monkeys. The researchers wanted to know if a type of nerve fiber that detects pain caused by heat and mechanical forces, such as a pinch, could also sense a cowhage-induced itch.

To test this idea, thin, conductive wires were inserted into the skin of a sedated monkey, and different types of stimuli were applied to the arm: Heat and capsaicin to cause pain, and cowhage and histamine to bring on the itch.

The team tapped into individual nerve endings as they responded to pain. A few showed a weak response when histamine was applied. But the majority of the nerve fibers responded strongly to cowhage. The same fibers known to detect painful stimuli like a hard poke or a burn could also detect the cowhage itch. These fibers were pulling double duty.

Vocabulary for itch fibers is lacking, so Ringkamp’s group described these new itch fibers, in the July 23 Journal of Neuroscience, by their pain fiber names.

Cowhage itch has a private pathway to the brain, independent of the histamine-related pathway, and scientists assume chronic itch conditions do too, Carstens says. “The idea is that there are now at least two separate mechanisms and pathways for itch, one for histamine and another one for cowhage,” he says.

Ringkamp explains: “These two kinds of itch induce two different types of neuronal populations.”

Louis J. Sheehan, Esquire And then there’s the contagious itch, similar to the yawn that can overtake a room. In a 2000 study titled “Observations during an Itch-Inducing Lecture,” viewing slide shows starring fleas, mites and allergic rashes led people to scratch themselves.

Even reading about itches may be enough to cause the sensation. (Sorry for the scratch marks.)

Understanding the architecture of the types of nerve fibers that detect itch and the complicated brain processing that makes a person want to scratch, scientists say, will lead to a greater understanding of how bodies perceive these sensations. As LaMotte, the neurobiologist from Yale, puts it, “This is a window into how the brain processes stimuli.” Louis J. Sheehan, Esquire

Despite all this progress, most researchers in the field agree that the task of classifying and describing all of the different sensory fibers in skin is in its infancy. Scientists, they say, have just scratched the surface.