Itching: the mind-numbing sensation

"It finished me. I had not a minute of rest; I couldn't concentrate on anything. It drove me crazy," Bravel says. In an effort to deal with the phenomenon, she developed a daily routine. At the end of a day's work as a kitchen designer, she would return to her air-conditioned apartment, take off her clothes, take two Benadryl pills, and make herself a cocktail of bourbon and Diet Seven-Up. "I would come home and cry; The itching was simply unbearable." Brawell made sure to always have ice packs on hand to soothe the itching a little and allow her to fall asleep.

Burwell's case is no exception. It is estimated that one in five adults will experience an itching sensation lasting more than six weeks during their lifetime. Chronic itching can be caused by any of a long list of diseases: skin diseases such as eczema or psoriasis, kidney failure, nerve damage caused by herpes or diabetes, as well as by a mite (a tiny parasitic insect) that burrows into the skin , due to an allergic reaction to medications and even due to pregnancy. In extreme situations, itching can cause severe disability and drive people to the point of suicide - a possibility that no doubt crossed Brewell's mind. But most doctors still tend to see itching as just a nuisance. "Those who do not suffer from itching do not see it as a problem, and it is difficult for them to understand what it really is. Only recently is the understanding that itching is a serious problem for many people," says Ethan Lerner, a dermatologist who studies the phenomenon of itching at Massachusetts General Hospital.

"Not all itching conditions are alike," says Gil Yosifovitz, a researcher at Temple University in Philadelphia. Transient itching that is not chronic, serves an important purpose, as a gatekeeper that warns and protects us from the dangers inherent in reptiles of various kinds and poisonous plants (see illustration). But until not long ago, researchers did not know much about how the factors that cause skin irritation work. And chronic forms of itching, like the one that afflicted Brawell, were a real mystery. However, there has recently been considerable progress in understanding the disease, and scientists are now closer than ever to developing treatment methods for both chronic itching and transient itchiness. A scientific achievement that deserves special mention in this context is the discovery of hitherto unknown molecular receptors that are sensitive to itchy substances - known as pruritogens. These receptors are located at the nerve endings in the skin and detect the presence of itchy substances. The researchers also discovered that part of the nervous system plays a dedicated role in transmitting the itch sensation, and that these nerve cells extend from the outer layer of the skin to the higher brain centers.

Classic itching

Itching in its most familiar form is caused when the body reacts to a simple mosquito bite. After the insect sucks the blood, it leaves behind chemicals and proteins that our immune system recognizes as foreign substances and reacts with a counterattack at the site of the bite. Immune cells in the skin release Cytokines, tiny chemical messengers that accelerate and intensify the reaction. We feel the tingling sensation for the first time in the skin, and it is enough to make us itch. The act of scratching, in turn, damages the outer protective layer of the epidermis. Then the immune cells release a surge of Histamine, a chemical known to be a powerful itch agent, as well as other itch-inducing substances. Histamine molecules activate the receptors that are sensitive to them, located at the ends of the sensory nerves in the skin, and this is how the familiar itching sensation arises. But is this really the case? It turns out that histamine plays a less central role in the sensation of itching than scientists have attributed to it for many years.

Until only a decade ago, scientists did not know any receptors other than histamine receptors, which detect the presence of itchy substances, and for that reason antihistamines were and still are the accepted treatment for itching, along with steroids to suppress the inflammation. But researchers have long suspected that not only histamine causes itching, but also other chemicals, which trigger other types of itching, mainly because they learned that in many cases, antihistamines do not improve the patients' condition. Antihistamines are effective in treating some allergic reactions, but not in most cases of chronic itching, says Lerner. "Doctors increase the dose, but the medicine only works because it puts the patients to sleep." This is exactly what Bravel experienced: all the doctors she turned to provided her, one after the other, with prescriptions for steroids, which in a short time added about nine kilograms to her body weight, along with a series of prescriptions for antihistamines, which had no effect on the itching. "The only drug that helped me was Benadryl - and that, only because it managed to calm me down a little and allowed me to fall asleep," says Bravel. In an attempt to discover unknown receptors for itchy substances, the scientists tried to follow the effect of unidentified substances that were known to be itchy, even though histamine was not involved in the process.

The first discovery was provided by a plant called velvet bean (cowhage), which is used as an ingredient in scratching powders that can be found in toy stores. "When histamine is injected into the skin, it causes a clear sensation of itching," says Lerner. "But if you ask patients suffering from eczema what they feel, they will describe a tingling or burning sensation. This is the feeling that the velvet bean evokes." Back in the 50s of the 20th century, he brought up My Walter The deceased, one of the pioneers of itching research, the hypothesis that the cause of itching in the velvet bean is a protein-degrading enzyme, Protease, which Shelley named mucunain. His hypothesis was confirmed in 2008, when Lerner discovered that mucoine activates a receptor located in skin cells and nerve cells, called protease-activated receptor 2 (PAR2). Certain protein-degrading enzymes, including muconin, can cut off a tiny piece of the PAR2 protein, thus activating the receptor. The discovery led to a new insight, which is that enzymes that break down proteins and the protein fragments (peptides) they produce serve as key mediators in the itch phenomenon, in the PAR2 receptor and other receptors. Such enzymes are common and found almost everywhere, including in insect saliva and bacterial secretions, and this explains why insect bites and bacterial infections sometimes cause such severe itching.

The second clue that led to the discovery of unfamiliar itch receptors came from a drug named Chloroquine, intended for protection against malaria. Ironically, it turns out that the drug does prevent the disease but causes itching. Because of this side effect, which antihistamines do not relieve, many residents of the malaria-ridden regions of Africa, who are exposed to the risk, refuse to take chloroquine. In any case, this side effect has made the drug a valuable tool in the hands of scientists involved in the study of itching. One of these scientists is Xinzong Dong, who at the time was researching the subject in David Anderson's lab at the California Institute of Technology. In 2001, Dong discovered a family of receptors activated by unknown chemicals, called protein-coupled receptors (GMrgprs . Some of the Mrgpr receptors were found only in sensory nerves, which indicated that they detect external stimuli, although it was not yet clear what kind of stimuli.

Dong exposed cells containing Mrgprs to chloroquine in order to test whether these receptors actually detect the presence of itch-inducing substances. In a study published in 2009, Dong, now a researcher at Johns Hopkins University, and Anderson created genetically engineered mice that lacked one of the Mrgpr receptors found in sensory cells, a receptor known as MrgprA3. "Healthy mice, which did not undergo genetic induction, responded with vigorous itching to chloroquine treatment," says Dong, and in contrast, the genetically modified mice, which lacked the MrgprA3 receptor, did not itch. "In the absence of MrgprA3, the animals simply did not feel the itch. And that was the turning point in our research," says Dong. Two other proteins in the Mrgpr receptor family have also been found to respond to pruritic substances.

Thanks to these two strange chemicals, scientists discovered, for the first time since the histamine receptors were described in the second half of the 20th century, some of the previously unknown itch sensors. "But the goal was not to find the receptor for chloroquine or velvet beans; "In fact, we're trying to find out what activates these neural itch sensors in chronic itch states that are not caused by histamine," she says. Diana Bautista, a scientist who studies the itch phenomenon at the University of California, Berkeley. These are the materials that researchers seek to identify today. "Apparently, there are a small number of molecules in the skin that activate the Mrgpr receptors, and if we manage to identify them, we can develop highly effective drugs and targeted treatment methods," says Lerner.

Is the itching sensation related to pain?

Another way in which scientists try to reach a more complete understanding of the phenomenon of itching is by investigating how the nervous system reacts to itching - which inevitably leads to the investigation of pain factors. Already in the 60s, scientists realized that different nerve cells that sense pain, and that recognize stimuli that may harm the body, differ from other sensory nerves. Some of them are sensitive to heat, others to cold and others react to mechanical stress. But what about itching? Do nerve cells that feel pain also feel itching or are there separate nerve cells designed to feel itching - and if indeed this is the case, is there more than one type of such cells?

"There is a close connection between itching and pain," says Bautista. When the pain associated with the wound subsides with healing, it leaves behind an itching sensation, similar to some pain relievers. At the same time, the pain accompanying the itching can make the itching sensation disappear. This overlap in sensations has led some researchers to associate the sensations of pain and itching together. "The hypothesis was that a relatively mild stimulus, such as the itchy sensation caused by a sweater made of wool, activates the same receptors and the same cells that transmit a sensation of pain," says Bautista. The assumption underlying this hypothesis was that mild stimulation evokes a sensation of itching, while stimulation of a higher intensity evokes a sensation of pain.

But it turns out that contact with the skin of histamine - or velvet beans or chloroquine - does not cause pain. On the other hand, painful stimuli evoke pain in varying degrees, but not an itching sensation. Moreover, the nerve cells that sense pain are located deep under the skin, while the skin is the only area of ​​the body where we feel itching. In recent years, the intensity theory, according to which what distinguishes itching from pain, is the intensity of the stimulus, has declined in importance. Most scientists now believe that the itch sensation is transmitted by nerves and receptors dedicated to this sensation. Moreover, it is now generally accepted that there are different types of itch-sensitive sensory nerves, each of which detects different itch stimuli. "The really important question raised by the velvet bean discovery was, is there more than one kind of itch, just as there is more than one kind of pain? And the answer is positive," says Lerner.

It turns out that the relationship between itching and pain is much more complex than scientists previously thought.

But in 2003, scientists from Germany and Sweden raised doubts about the existence of sensory nerves dedicated to itching, and this, after discovering that certain nerve cells in the human body that respond to histamine are also activated by painful stimuli that originate from heat and chemicals Capsaicin , the ingredient that gives the chili pepper its spicy taste. In light of this dual reactivity, it was hypothesized that neurons considered dedicated to itch sensation contain capsaicin receptors, the hallmark of pain-sensing neurons, called receptors TRPV1. And if the nerve cells that sense itching contain TRPV1 receptors that are sensitive to pain factors, how can they be considered nerve cells dedicated to itching?

Alan Basbaum, a pain researcher at the University of California, San Francisco, found that despite TRPV1's reputation as a pain receptor, it also plays a vital role in histamine-induced itch, indicating that TRP receptors are not limited to detecting painful stimuli. The histamine receptor appears to work together with TRPV1 to help neurons transmit an electrical nerve impulse known as an action potential. But other itch factors, besides histamine, complicate the picture, since they do not act through TRPV1.

Bautista, who devoted her career to the study of TRP receptors, was at the time looking for the molecules that transmit itch signals that do not originate from histamine. Bessbaum's discovery that TRPV1 receptors play a role in the itch sensation triggered by histamine gave her a clue to her own hypothesis: that other TRP-like receptors may be involved in other types of itch. She focused on another pain-sensing receptor, TRPA1, which recognizes inflammatory chemicals and mustard oil, and found it to be essential in chloroquine-induced itching. Within an hour of presenting her discovery at a conference held in 2009, Bautista received a phone call from Dong and the two immediately agreed to collaborate. In their joint study, Dong and Autista demonstrated that TRPA1 and MrgprA3 work together to trigger a neural response to the presence of chloroquine. "This discovery confirmed the assumption of the existence of different types of nerve cells that play a role in different types of itching," says Bautista. This discovery also paved the way for the development of new treatment methods for itching. "TRPA1 receptors are considered a very attractive target for the development of treatments because they play an extremely important role in such a wide variety of inflammatory conditions, including itching. If we can curb the effect of TRPA1 [in the human body], it will be of great therapeutic value."

At this point, the many studies conducted on the subject were enough to prove that pain-sensing receptors are also involved in itch detection. But a solution has not yet been found to the question that troubled the researchers: are there unique and dedicated sensory cells for transmitting the itch sensation or are pain sensing cells capable of somehow transmitting both types of stimuli? Dong tried to solve the mystery in a study he conducted in 2013. His research team created genetically engineered mice in which the nerve cells thought to be dedicated to itch sensing, the cells containing the recently discovered itch receptor MrgprA3, were selectively killed. In the absence of these cells, the mice lost the ability to feel itch, while their sense of pain was not impaired.

But Dong still had to prove that the itch sensors are indeed intended to sense itch only and do not also feel pain. He was able to exploit the genetics of the mice to create genetically engineered mice in which all of their neurons lacked the TRPV1 receptor, except for those that were thought to be neurons dedicated to itch sensing. When the researchers activated the TRPV1 receptors using capsaicin, a normally painful stimulus, the mice did not exhibit a sensation of pain, but only a sensation of itching. The experiment confirmed the hypothesis regarding the existence of nerve cells dedicated to itching and at the same time proved that some of the itch receptors are also used in the pain sensing nerves. And what is the explanation for that? Well, "nature uses the same molecules for both sensations," says Dong.

These discoveries were all made in studies dealing with sensory nerves innervating the skin. In fact, the latest research on the subject shows that the skin cells themselves take part in creating itching, by releasing itch-stimulating substances that activate the itch nerves. The complex neural pathway associated with itching also reaches the spinal cord, where researchers recently discovered nerve cells and signaling molecules unique to itching. Scientists also use brain imaging to better understand how the neural activity causes the unique - and so annoying - itching sensation.

And as for Bravel, towards the end of 2013 she was finally freed from the excruciating chronic itching after she turned to another doctor, the tenth in number, a renowned dermatologist who treats patients suffering from persistent itching for which no explanation has been found. He conducted a comprehensive allergy test on her, which showed that Bravel was allergic to a preservative found in various body care and cleaning products. "Everything I used contained this stuff," Brawell says. The moment she ditched those products and started using products from a doctor-approved list, the rash—and accompanying itching—disappeared.

Burwell's case shows how incomprehensible the itch phenomenon is even to medical practitioners: a simple test was enough to provide an easy solution to the distressing problem, but the solution was only found after three years of continuous suffering. Burwell's case also highlights how important it is to identify the underlying factors - and at the same time, clarifies why the complex molecular processes underlying this simple feeling are still shrouded in mystery.