Mosquito bites are so itchy! What does the brain want to tell you through the itching signal?

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When you are bitten by a mosquito, if it is extremely itchy, many people will press the wound with their fingernails. This short-term slight pain can slightly relieve the itching feeling. Acute itching is not a big deal, after all, this feeling is temporary, but for chronic itching, the feeling is too torturous: the itching will last for a long time and may be very intense. The more you scratch, the more itchy it will be. The more itchy it is, the more you want to scratch. Thus, you fall into a vicious cycle of scratching more and more itching, and the more itchy it is, the more scratching... Over time, the skin becomes inflamed, swollen and cracked, the affected area becomes rough and scaly, and in severe cases, it even affects sleep and daily life.

What exactly is your brain trying to tell you through itching signals?

Itch has long been a basic human feeling that has eluded scientists. It can be triggered by a simple insect bite, and despite centuries of research, our understanding of itch remains fraught.

Itch has been described as one of the most horrible sensations, the two scientists write in a commentary in the journal Immunity.[1] In Dante’s Divine Comedy, a forger is forever tormented by “incurable and severe itching.” Yet, the researchers note, “there has been little substantial progress in the treatment of itch over the past 360 years.”

Chronic itching is so horrible that it is the punishment suffered by souls in Hell who have committed acts of fraud or treason in Dante's Divine Comedy, as shown in this 1892 illustration by Gustave Doré. © Wikimedia Commons

That’s finally starting to change. Over the past decade, scientists have made some progress in understanding this annoying feeling. It can alleviate the itch caused by other noxious stimuli, such as pain. They’ve even begun to distinguish one type of itch from another by irritating study participants with itch-inducing plants or deleting itch-related genes in mice.

The extensive research moves beyond the understanding of common acute itches caused by histamine, such as those from bug bites or poison ivy, to reveal the complex mechanisms and people involved in this painful itch that can last for weeks or even years. So-called chronic itching can be caused by a variety of factors - from chemicals secreted in the body to neurological disorders, and, in many cases, has no known cause or treatment.

© Ri Science/Tumblr

The research wasn't just an academic exercise (or an attempt to make those mosquito bites fade faster). Acute itching is short-lived, but chronic itching may bother about 7% of people each year, and one in five people will experience it at some point in their lives. In addition to the maddening, constant urge to scratch, the condition can lead to depression, sleep deprivation, and a dramatic decline in quality of life. "It can be as devastating as chronic pain," says itch researcher Robert LaMotte of the Yale School of Medicine.

And pain is actually the beginning of the itching story.

Identifying Itch

Over the past century, itch has often been considered a low-grade version of pain. In the early 1920s, for example, the Austrian-German physiologist and pain researcher Max von Frey documented in an influential study that minor skin prickles caused study participants to experience itching. This concept influenced the field of itch research for decades to come.

But eventually, the idea that itch was just a subset of pain began to break down. Scientists determined that they couldn’t convert pain to itch simply by reducing its intensity, or convert itch to pain by increasing its intensity. Yet the neural pathways for pain and itch appear to be so similar and so deeply intertwined that for years scientists lacked a clear understanding of how the two responses were connected in the body.

Then, in 2007, Itch finally emerged from the shadow of pain into its own light.

© Memebase - Cheezburger

That year, a groundbreaking paper in Nature[2] reported the first dedicated itch receptor—a protein on nerve cells in the central nervous system that responds specifically to itch but not pain, suggesting that the sensation of itch might reach the brain via its own independent pathway.

Zhou-Feng Chen of Washington University School of Medicine in St. Louis and colleagues showed that mice genetically engineered to lack the gene for this receptor (called the gastrin-releasing peptide receptor) could still feel pain but hardly any itch, no matter what the researchers tried.[3]

“This is a paradigm shift,” says Brian Kim, a dermatologist at the Itch Research Center at Washington University School of Medicine in St. Louis. Revealing that itch is a separate sensation with its own dedicated pathway is a key advance in understanding itch, Kim says.

Since the discovery of the first itch receptor, researchers have discovered more cytokines that are associated with chronic itch, distinguishing it from acute itch. They have found that chronic itch and acute itch transmit signals through different neuronal populations, traveling along their own dedicated pathways through the nervous system. When researchers simulated chronic itch in healthy volunteers, magnetic resonance imaging showed that the two types of itch triggered different patterns of brain activity.[4]

These most basic observations reveal how much we still have to learn about itch. But they could also help open a path to help people who suffer from chronic itch. The feeling can be so bad that some people with liver disease, for example, have received transplants precisely because of the itch. Others have chosen to stop taking essential cancer drugs because they can cause itching.

There are many pathways that cause itch, but scientists have discovered two separate subtypes of nerves that transmit itch messages to the spinal cord and brain. The histamine pathway (left) is primarily involved in acute itch, and histamine receptors are activated when a trigger, such as a mosquito bite, stimulates the body's immune system to release histamine. Non-histamine itch (right) can be triggered by a variety of internal and external triggers, including immune system molecules such as cytokines, enzymes called proteases, and the antimalarial drug chloroquine. After a trigger activates a receptor in either pathway, the enzymes kick into gear, causing ion channels to open and stimulating nerves to send itch signals to the spinal cord and brain. © knowable magazine

For years, researchers have focused on histamine-induced itch, a type of itch that's easier to study in part because it's driven by a single compound. Experimenters can apply known irritants to the skin or inject them into the skin, prompting the body to produce histamine, which produces the familiar swelling response that can be relieved by antihistamines such as cortisone. But most chronic itches (strictly speaking, itches that last more than six weeks) don't involve histamine. The causes of chronic itches are many and far more complicated.

Now, as scientists refocus their research on chronic, nonhistamine itch, they are doing much of it the old-fashioned way: by making people and animals itch.

Stimulate one by one

Triggering an itch isn't as simple as it seems. One way to target nonhistamine itch is to irritate people and animals with tiny prickles from a tropical plant called Mucuna principis, commonly known as tiger's claw bean.

In a series of key experiments, Lamott and his colleagues took about 10 of these hairs, which are only a few micrometers at the tip, and inserted them about 0.2 millimeters into the skin of study participants. Each time, the people who were pricked reported the sensations, such as stinging, burning or itching, and the intensity, at 30-second intervals for 20 minutes.

The study confirmed that a compound in the prickle, called mucunain, rapidly induces itch, but unlike many plant-based itch-inducing compounds, it does not activate histamine. This makes Mucuna pruriens a powerful tool for studying non-histamine itch circuits and potentially providing insights into the mechanisms of chronic itch.

Mucuna pruriens is a tropical plant in the pea family that can induce itch without involving histamine, allowing researchers to study complex nonhistamine itches. Seen in an electron micrograph, the spinous hairs of Mucuna pruriens (A) have tiny barbs (B). The researchers used surgical sponges to attach the spinous hairs to create a "spiny inserter" (C), which they used to induce itch in humans in their experiments. © The Journal of Neurophysiology

Next, Lamothe and colleagues used mucuna in experiments to stimulate human cells to analyze which receptor proteins might receive and respond to itch. They found responses for two such receptors, called PAR2 and PAR4. Identifying these itch-related receptors could help bring drugs closer to potential treatments.

To more fully understand the underlying principles of itch and help distinguish it from pain, Lamott and colleagues delved into the subtleties of scratching behavior in mice. They learned where to inject various stimuli in the mice to reliably distinguish scratching that causes itch from scratching that causes pain.

For more than 10 years, researchers have been taking advantage of the similarities in the biology of itch in mice and humans, such as receptors and neural pathways. This means that they can now make cross-sectional comparisons between the two, for example by injecting similar chemicals and tracking the intensity and duration of behaviors (self-reports in humans, movements in mice).

© gifs.com

Meanwhile, the lab of itch researcher Xinzhong Dong at Johns Hopkins University used mice to identify nerve endings that are truly specialized for itch. “Once you activate those nerves, you get the itch sensation, and you don’t feel pain,” he said. In a 2012 study published in Nature Neuroscience, the researchers showed that when these specialized itch neural pathways were turned off, mice became immune to itch-inducing stimuli but still felt pain.

Other researchers are working to unravel the mysteries of itch through more purely experimental itch.

Akihiko Ikoma, then a dermatology researcher at Kyoto University, and his colleagues took a mechanical approach to this problem. Rather than relying on compounds, the team developed a small coil that vibrates at a specific frequency. When this coil touches fine hairs on a person’s face, it produces an itch that takes more than 10 minutes to completely subside, as the team described in the journal PAIN in 2013.[6] The work helped scientists locate specific itch neurons around the skin that are independent of histamine or other itch-inducing chemicals.

Both approaches hope to identify neurons and pathways that are unique to different types of itch. This will ultimately help scientists develop drugs that can relieve long-term chronic itch. But there are still many mysteries to be unraveled about the complex pathways of itch, and new receptors and nerve cells are still being discovered.

Relationship to pain

Itch is present throughout the animal kingdom, from fish to primates. Despite these advances, Dong and his colleague Mark Lay of Johns Hopkins University noted in the 2020 Annual Review of Neuroscience that “the perception of itch remains largely a mystery”[7].

For one thing, despite the progress that has been made, the intertwined nature of itch and pain remains elusive. One reason may be that both stem from self-protection. Just as pain signals to stay away from something dangerous, itch can prompt scratching, which can prevent infection by, for example, chasing away parasites. Scratching also appears to help recruit local immune cells that can fight off infection.

There is also a peculiar overlap between itch and pain that is familiar even to those who occasionally scratch: Scratching produces mild pain that tends to mask the itch sensation. Some researchers have suggested that when groups of neurons are activated—some of them itch-specific and some pain-specific—painful stimuli can mask the itch signal if they are strong enough.

Despite the new itch-only findings, many nerves do appear to be involved in transmitting both painful and itch stimuli. This puzzling overlap is demonstrated in people with chronic conditions such as atopic dermatitis. In these conditions, nerves in the skin become hypersensitive to itch and perceive stimuli that are normally painful as itchy, or simply mechanical or thermal. This is similar to the experience of some people with chronic pain, where even the lightest touch actually hurts. And underlying nervous system malfunctions, such as a pinched or damaged nerve, may cause pain in some people but itch in others.

Dong Xinzhong said that the overlap with pain is also reflected in the way that itching spreads from the nerves around the skin to the spinal cord and then to the brain, but people currently know little about this.

All of these lingering mysteries mean that itch—especially chronic itch—is extremely difficult to treat effectively. “Just like pain, there is no one painkiller that eliminates all types of pain,” says Gil Yosipovitch, a dermatologist at the University of Miami and founder of the International Itch Research Forum. “I have patients with a lot of complex conditions who need more than one medication or cream, similar to patients with chronic pain. And it takes a lot of time and patience.”

For most people, itch remains a passing irritation, perhaps from a bug bite in the summer or dry skin in the winter. But as a clinician and research scientist, King says all the suffering he sees from chronic itch has motivated him to work harder in his lab to understand this tormenting sensation and correct years of misconceptions. “It’s just been a series of neglect,” he says.

By Katherine Harmon Courage

Translated by tamiya2

Proofreading/tim

Original article/knowablemagazine.org/content/article/health-disease/2020/what-is-chronic-itching

This article is based on the Creative Commons License (BY-NC) and is published by tamiya2 on Leviathan

The article only reflects the author's views and does not necessarily represent the position of Leviathan