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What is itching?

What is itching?


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What exactly at the molecular level is itching? What physiological function does itching serve, if any? I cant remember the reference but a PLCb3 null mice lost the itch phenotype, so presumably it is mediated by the Gq-PLCbeta pathway through a cell surface GPCR. Since a physical action of scratching relieves it, could it be a case of a mechanosensitive channel at work?


Like all tough questions, this one has no well understood answer. Itching "is one of the most poorly understood sensations."

The obvious facts: The urge to scratch part of your skin is the result of stimulus of the skin which causes some of the nerves to register an irritation (you can get an itch in internal organs too - which sounds excruciating).

Biochemically, following the effects of poison Ivy oils, the cathechols break down to orthoquinones and may stimulate local mast cells to release histimine. So in this case you can see that itching, like many irritations are linked to the immune system which is highly variable from one individual to another, as such it is still a bit of a black box.
The histamine pathway is well studied and histamine stimulates an ion channel protein in nerve cells called TRPV1, which is also known as the capsaicin receptor, which means it is also related to sensing heat. This explains why itching can be relieved (temporarily) by exposing the skin to water that is as hot as the patient can stand without burning them. This is one of the ways pain and itching are highly intertwined.

Still, not all itching is stimulated by histamine release; that isn't the whole story. Antihistamine allergy pills don't help itching. Other nerve channel proteins can be activated to stimulate itching. One example found in an itchy mutant strain of mice is TRPA1, and maybe the G protein coupled receptor, Gastrin Releasing Protein Receptor (GRPR). Its hard to imagine that there will not be more mechanisms discovered later.

Mediated both by immune systems and nerve cells, which literally have a mind of their own and whose signal processing is highly individualized and sensitive to local conditions in the body make itching a fairly mysterious phenomenon. Its also likely that itching can be entirely initiated as a mental condition (Pruritus), so it is not entirely a biochemical phenomenon, which only serves to illustrate the point I guess.


Itching

The Into the Woods director, it soon becomes clear, is itching to get something off his chest.

It was like witnessing the last two weeks of the life of a blind and toothless dog you knew the vet was just itching to destroy.

Itching for the erotic details of Jess and Nick's New Girl dalliance?

And of course, as schools open up again across the country, many high schoolers are itching with misgivings of their own.

American congressmen itching for a fight declared they would no longer eat French fries, only “freedom fries.”

My late distemper of heat and itching being come upon me again, so that I must think of sweating again as I did before.

In hay fever, the itching and redness of the eyes, nose, and throat are controlled from a sensitive point in the naso-pharynx.

I gravely placed a gold piece in his itching palm, asking, "What did they write on the walls?"

Itching and reddening of the skin commenced within twenty-four hours.

An itching red spot about the size of a dime was noticed in thirty-six hours, and it steadily increased in size.


Solved! The Mystery of the Maddening Itch

O.K., so it doesn’t quite rank up there with unraveling the cause of Alzheimer’s or Parkinson’s disease. But with mosquito and poison-ivy season on the way, plenty of folks would be grateful for an answer to a more mundane question: What is the neurological basis of the pruritic response? Or in plain English: Why do we itch?

At least part of that mystery has now been solved by scientists at one of the less celebrated units of the National Institutes of Health. Writing in Science, molecular biologists working at the National Institute of Dental and Craniofacial Research report that a molecule known as neuropeptide natriuretic polypeptide b (Nppb) that is released by nerve cells far from the actual itch site triggers an electrochemical cascade that ultimately tells the brain it’s time to get scratching.

“This is an important breakthrough,” says Sarah E. Ross, a neurobiologist at the University of Pittsburgh. It was also, says the report’s senior author, Mark Hoon, “really fun work. It was like a roller coaster of discovery.”

That may sound a little over the top when the subject is itching, but chronic itch caused by dry skin, psoriasis, diabetes or even liver disease can be maddening, and the cause has long been a true medical mystery. “The classical view,” says Hoon, “was that a single class of nerve cells detected both itch and pain.” According to this theory, the type and intensity of the stimulus told the cells which sensory message to send up to the brain. The nervous system would then respond accordingly.

At one level, the theory is correct: pain and itch, as well as heat, are all transmitted by a class of nerve cells known as TRPV1-expressing neurons. When scientists use genetic engineering to create mice that don’t have these cells, the animals don’t feel any of those three sensations.

But over the past five or 10 years, says Hoon, research in his own group, and also what he calls “some beautiful work by others,” has shown that at a deeper level, the one-neuron-fits-all hypothesis is wrong. Evolution has evidently provided us with a subset of TRPV1-expressing cells, and it’s the ones in that specialized group that do the actual work of making us itch.

What makes these cells special, say Hoon and his co-author, Santosh Mishra, is that they, unlike their pain-sensing cousins, produce Nppb. When the skin is stimulated by a feather or a mosquito bite or a chicken-pox lesion or a drop of urushiol (the itch-inducing oil in poison ivy), a signal zips up to the other end the nerve cell where it triggers the release of Nppb molecules. The molecules leap across a gap, or synapse, to an adjacent nerve cell that carries the signal up the spinal cord toward the brain. All nerve signals travel this way, and all require neurotransmitting chemicals to vault the synaptic gap. But itching needs the particular assistance of Nppb to do that job.

The Nppb, molecule was actually first identified in an entirely different part of the body. “It’s released by the heart,” says Hoon, “to control blood sodium and blood pressure. It’s a cornerstone of biology that a lot of these neurotransmitters are used in different parts of the body for different purposes.”

When they found this heart peptide in some TRPV1 neurons as well, Hoon and Mishra engineered mice that lacked that variation of the neuron. The result: the animals could feel pain and heat just fine but were quite itchless. “The answer just fell into place,” says Hoon. “Sometimes in science you have an idea of how something works, but you just hit a brick wall. This time, that wasn’t the case.”

Identifying the role of the Nppb molecule doesn’t necessarily mean a cure for itching is at hand quite yet. Since Nppb operates not at the skin, but deep inside the body, you’d want to neutralize it with a treatment patients could take orally. “But it also regulates blood pressure, so that wouldn’t be good,” Hoon says. In severe cases, he says, you might consider injecting an Nppb blocker directly into the spinal cord. That too, however, he says with some understatement, “is not a trivial thing to do.”

Even before a safe delivery system for an Nppb blocker is developed, scientists are already pondering the next great question: Why does an itch go away when we scratch? Evolutionarily, the phenomenon makes sense. An itch often suggests the presence of a pest like a mosquito or lice, and a vigorous scratch will kill or disperse them. But what is the neural mechanism that leads to the feeling of relief?

“That’s an excellent question,” says Hoon. “We really don’t know.” A leading hypothesis argues that there may be yet another specialized set of nerve cells that responds to scratching by sending a “stop” signal up to the spinal cord. “We’re investigating this idea,” says Ross, “and hope to submit a paper soon.” When they do, the riddle of the itch will have moved closer still toward being solved at last.


Diana Bautista is a professor in the Department of Molecular and Cellular Biology at the University of California, Berkeley in Berkeley, California.

IRA FLATOW: This is Science Friday. I’m Ira Flatow. The pandemic has us feeling a lot of things, but what about itchy? Now here’s a situation that has happened to me recently. I headed into the drugstore so I put on my mask, I went inside. But pretty soon my face started to it’s right between my nose and my cheek about right there, right under my mask.

So what was I supposed to do? I didn’t want to touch my face or take off my mask to scratch it. That would kind of defeat the point of wearing one, right? It’s so difficult to resist that itchy feeling. But I suffered through it till I could get back into my car and safely scratch. The things we do to keep ourselves and others safe, right?

Well, how many times has this happened to you over the last several months? And wouldn’t it be nice if we could just suppress that itchy feeling? Maybe there’s something we could learn from neuroscience to keep us from pulling off our masks to scratch that itch. Well, we’re going to talk to an expert here to help explain the science behind our itchy pandemic experiences. And to answer all things itch is our expert, Dr. Diana Bautista, Professor in the Department of Molecular and Cellular Biology, University of California at Berkeley. Welcome to Science Friday.

DIANA BAUTISTA: Thank you. I’m excited to be here.

IRA FLATOW: And we want everyone listening to know this interview is being recorded in front of a live Zoom audience because, well, we miss having you being a part of our show. So this is our way of bringing you into our conversation. And if you didn’t get to join us this time, don’t worry about it. Keep an eye out for announcements of future Zoom tapings so you can participate in our social media or on our website at ScienceFriday.com/events. Let’s begin. Dr. Bautista, can you relate to the itchy encounter I had? I’m sure it’s happened to you, right?

DIANA BAUTISTA: Oh it happens to me many times a day. We are by nature, very itchy animals, human beings. And even just the mention of the word itch, I have to apologize to everyone, you’re going to be scratching a lot during this interview. And the idea that you can’t touch your face, which we’re being told all the time these days due to COVID is just enough to make you obsess and think about it constantly.

IRA FLATOW: You know I’ve always wondered why is it that there are some things that make you itch when they touch your body. Maybe it’s wool, something like that. And then you have cloth, something that does not make you itch. Do we know why that is?

DIANA BAUTISTA: We know that it varies a lot from person to person. Some people love cashmere and other people find it incredibly itchy. And that touch evoked itch is also known as mechanical itch. And it actually represents one of the great mysteries in biology. We don’t really understand how something like a gentle touch could be innocuous in some cases and really itchy in another.

IRA FLATOW: Is there a relationship between itch and pain? I’ve heard before that those systems are connected in some way.

DIANA BAUTISTA: Yeah, there is a very intimate interaction between our itch neurons and our pain neurons and how we experience these sensations. And for a long time, it was thought that itch is a subset of pain or a mild pain. But now we know that it’s its own sensation and there are unique free nerve endings in our skin that mediate itch sensations and send signals from your skin to your brain to trigger that sensation of itch, to trigger that negative emotion you have to an itchy sensation and to drive scratching.

IRA FLATOW: When you say that there are signals sent to our brain, is there in each center in my brain someplace?

DIANA BAUTISTA: Definitely, when you experience itch there are several regions of the brain that become activated. Our cortical regions that help you identify where that itch is located, you activate the motor system to trigger scratching behaviors, and then there’s the emotional component as well.

IRA FLATOW: Wow, so if I scratch are their endorphins, sort of pleasure things released in our brain at the same time saying, oh, that feels good.

DIANA BAUTISTA: Yeah. Scratching is quite complex and interesting to neuroscientists because scratching helps you and makes you feel better in many ways. There’s a very local effect of scratching, where applying scratching or any type of pain, like hot, really hot water or icy, an icy compress, anything that causes pain can literally block that itch signal from reaching the brain or decrease the intensity of the itch sensation. So you get this sort of immediate relief from that scratching.

But there’s a secondary effect. When you scratch, brain regions that are associated with reward and also addiction release dopamine and serotonin gets released and you get this big reward from scratching as well. And that can lead to a really horrible itch-scratch cycle where it’s very hard to stop. And probably people have done this when they’ve scratched their itchy mosquito bite until it bleeds. That’s because of that reward.

IRA FLATOW: We have our first Zoom question from Shiro Tanaka, who says, how is the itchy sensation defined dermatologically? Is it an inflammation?

DIANA BAUTISTA: Yes, so acute itch is very different from chronic itch. An acute itch, you activate these itch specific neurons that send an electrical signal to the brain to trigger the sensation and then to trigger scratching behaviors. And it’s very short term. With something like a mosquito bite that’s a little bit longer, your nervous system actually releases compounds and regulates the vasculature to allow immune cells to come in. And that’s really important in the case of, for example, insects that could burrow into your skin that carry disease vectors or parasitic worms. And that immune system comes in. The scratching removes the insect. The immune system gets rid of infected cells. But then the system goes crazy under chronic itch conditions.

IRA FLATOW: Tell me when a chronic itch condition is.

DIANA BAUTISTA: Yeah chronic itch refers to a variety of different disorders and dysfunctions that lead to itch that really can’t be treated by antihistamines and there are very poor therapeutics. And it’s itch that is really long term. So if you imagine the worst itch you ever experienced, and imagined what your life would be like if that itch were to spread over extended parts of your body and were present for every second of every day. And chronic itch has a decreased quality of life similar to the very worst chronic pain conditions.

IRA FLATOW: Are there treatments for these kinds of things?

DIANA BAUTISTA: There are a lot of clinical trials going on right now due to the big boom in itch research over the last five years but right now corticosteroids are often the first line that are prescribed. But they’re really not super effective. And even antihistamines for some forms of allergic itch don’t really work so there’s a big therapeutic need out there.

IRA FLATOW: I remember doctors used to tell kids start to scratch their chickenpox. I mean it’s sort of counterintuitive to your own mind. But it’s bad for you.

DIANA BAUTISTA: Yeah I think short term, acute itch serves as an important warning system, right? We feel itchy when we get a mosquito bite. Mosquitoes carry malaria. Learning to associate that itch with a mosquito helps you develop protective behaviors like putting on DEET or going into the tent when you’re camping when you’re surrounded by mosquitoes or scratching, swatting away. And those are good things.

But under chronic itch conditions, the constant scratching causes damage to the skin and makes the itch worse. And so it’s really counterintuitive. But anybody who’s had a kid who has had eczema knows it’s really hard to not scratch that chronic itch. And it’s called this really vicious itch-scratch cycle that’s really difficult to stop.

IRA FLATOW: That’s a good segue to our next listener, Lisa Hale, has a question about mosquito bites. Hi, go ahead.

LISA HALE: Hi. I was wondering, are some people are more allergic? If they are, do they tend to itch more than like say someone who isn’t?

DIANA BAUTISTA: Yes, so there’s a lot of variation. Some people don’t have an allergic reaction at all or notice when they have mosquito bites. Other people are unfortunate like myself, who suffered from eczema as a kid. And now I’m super sensitive to bug bites and noseeums and mosquitoes. And I have a very large allergic reaction that occurs. And the itch can persist for several days. So there’s a great variation depending on who you are and what your biology is.

IRA FLATOW: Let’s go back to my drugstore visit for a second. It was so hard to fight the urge to scratch, I almost couldn’t do it. Are there any tricks to overriding these? Can you think about something, you know, whatever, because I always wondered one of the things I’ve always wondered about why I could never be an astronaut besides a lot of other reasons, is that if I had the helmet in the spacesuit on and I had to scratch my nose or whatever, that would drive me crazy.

DIANA BAUTISTA: Yes, it definitely drives me crazy. And so when I go to the pharmacy or go grocery shopping, I do have a period in my car where I sit there and I touch my face and I scratch and then I actively think, because we can suppress that strong desire to scratch through– we have control over our motor system. It’s sometimes hard to exert that control, but we can do it.

And so I scratch, I get it out of my system and I actively think, OK, don’t touch your face. Don’t touch your mask. Don’t scratch. And I think that distraction is a big part of it. And actually children with eczema, one of the most effective therapies to get them to stop scratching is through playing video games, probably educational video games are encouraged to get their minds off of their itchiness. And that’s what I suggest you do at the pharmacy.

IRA FLATOW: So you pre-scratch yourself.

IRA FLATOW: You give yourself sort of a pep talk before you go in there and say, I’m going to get it out of my system. Now listen, system, I’m scratching now. I’m getting it out of my system. And it listens.

IRA FLATOW: Yes. Actively fighting that urge. And one thing people don’t realize is how much we touch our face. Our face, because most people primarily use their visual system to navigate the world. We have a lot of enervation, a lot of these free nerve endings in our face that makes it super sensitive, that allows us to be very responsive if a bug lands there or if we get something harmful in our eye. And so we’re super sensitive. And we touch our face hundreds and hundreds of times a day without even realizing it.

IRA FLATOW: I’m doing it now without thinking.

DIANA BAUTISTA: Yeah. Definitely.

IRA FLATOW: Well that brings me to a question I hadn’t thought about until this very moment. And that is why when we touch our faces or scratch your face, it feels like a sensation of scratching but on our soles of our feet, it feels like it’s tickling.

IRA FLATOW: I mean have you ever thought about that? Is that a whole different– that’s a whole different subject.

DIANA BAUTISTA: Yeah and it’s a fascinating mystery in sensory biology. We know a lot about the senses, but our sense of touch that spans gentle, pleasant touching to itchiness to tickle to pain, is one of the least understood senses, which is really surprising to most people.

IRA FLATOW: We’re all familiar, of course with the experience of an itchy bug bite that you just can’t find any relief from. And there are other times you scratch an itch and the feeling goes away. Why are we able to satisfy an itch in some cases but not in other cases?

DIANA BAUTISTA: The itch relief you get from that temporary pain of scratching or putting on really hot water on your mosquito bite is very temporary and it’s not complete. So you get partial relief, but it’s really not enough. When you have chronic itch, that is really constant and the neurons that innervate the skin, that send these signals become hyperactive, as well as the brain regions that are processing these signals. The system becomes primed so that it’s very difficult to turn off.

And scratching as hard as you can, which normally would hurt, if you scratch an area of your body that doesn’t have that itch, is not providing relief. But you’re still triggering some of those reward centers without getting the actual relief of itchy sensations. And that drives this constant damage to the skin and more itch. And that’s why it’s a cycle that’s really difficult to break.

IRA FLATOW: I’m Ira Flatow. This is Science Friday from WNYC Studios. Some people have this talent, I call it a talent. I remember seeing it in the Odd Couple movie, where they’re sitting in the restaurant and one of the characters, can’t remember which one, Felix, starts doing this, [GURGLING NOISE] starts making a noise inside his mouth. And his roommate says, what are you doing? He says, I’m itching the inside of my ear. Do you know what I’m talking about?

DIANA BAUTISTA: I do. I know exactly what you’re talking about. And we do experience itch in the back of our throat. Sometimes if you eat something that you’re allergic to, people with severe allergies especially, you can feel itch inside your ears, in the back of your throat, and inside your nose. And the same types of neurons that innervate our skin that respond to different chemical itch compounds can be triggered actually internally. But little is known about those.

IRA FLATOW: So it’s very embarrassing. I do it. I do it. And when I saw that in the movie, I said, gee, I’m not the only one who does that. Moving on, I’ve seen cats and dogs scratch themselves. We all have. How prevalent is then itchiness in the animal kingdom? Do all animals scratch an itch?

DIANA BAUTISTA: Yeah, I think people don’t realize that itch is really a highly conserved process and scratching across the entire animal kingdom, because it is really an important protective system that we’ve evolved to avoid harm. And it’s not limited to cats and dogs and humans. Even fish can experience a itch type sensation. They get infected by parasites just like we do.

Of course, they can’t scratch themselves. So what they do is they’ll rub against coral to try to get rid of that and get some relief. Or they’ll actually, some fish will go to cleaning stations in the ocean where there are small fish that come in and actually bite them and remove those parasites. Even insects can be infected. So even flies can be infected with mites. And they also have behaviors that look a lot like scratching, where they actually can rub and remove mites from their body.

IRA FLATOW: OK, you certainly do know a lot about itching. But there’s got to be some stuff you still want to know about. What do you still want to know about?

DIANA BAUTISTA: One of the big questions that we’re interested in is understanding mechanical itch? What is it about that itchy sweater that gets you or that itchy mask? We really don’t know. We know a lot more about chemical itch. The other big question that really I think, is shocking that we don’t know more about, our switch is very quick and in some cases click to turn on and long lasting, changes in normal sensitivity. So we for example, when you have chronic itch, a gentle touch that’s normally pleasant or innocuous, becomes itchy.

But if you have chronic pain, that gentle touch becomes painful. How do these normal sensations that we just take for granted really switch and it could be really debilitating, where if you constantly feel the itch from the weight of your clothes or chronic pain from a gentle touch or caress. And we really don’t know how these switches occur and why we’re seeing these chronic conditions at really crazy high rates across the world population. These are normal protective systems that warn us against burning ourself or avoiding toxic plants, that now are just turned on all of the time.

DIANA BAUTISTA: Well, you have driven me to try the Diana Bautista method of talking myself out of scratch– I so want to scratch this part of my shoulder now that you’ve talked about it. But I’m not going to do it. It doesn’t itch. It doesn’t itch. It doesn’t itch. Thank you, Diana. It’s been a great conversation.


When you have an itch, what is happening under your skin?

The average human body is covered by about 20 square feet (2 square meters) of skin. Skin is the only organ that is constantly exposed to potential irritation. And, with so many things coming into contact with your skin daily, you're bound to get an itch or two. Serious itching can be caused by allergies, disease, emotions and infections, but let's take a look at what causes the common itches that aggravate you everyday.

Itching, also known as pruritus, starts with some kind of external stimuli, including bugs, dust, clothing fibers and hair. Like tickling, itching is a built-in defense mechanism that alerts your body to the potential of being harmed. In this case, it might be the potential of being bit by a bug.

When the stimuli lands on your skin, it may not bother you at first, but soon it will begin to rub back and forth across your skin. Once the hair or dust scratches your skin's surface layer, receptors in the dermis of the skin will become irritated. In a split second, these receptors send a signal through fibers in the skin to your spinal cord and then up to the cerebral cortex in your brain.

The same fibers that send itching signals are also used to send pain signals to the brain, which once led some scientists to believe that itching was a form of light pain. That notion has since been dispelled by research, which showed that pain and itching elicit opposite responses. Pain causes us to withdraw and itching causes us to scratch.

As soon as we feel an itch, our first natural response is to scratch the spot of the itch with our fingernails. The reason for this response is simple -- we want to remove the irritant as soon as possible. Once you've scratched the area of irritation, you are likely to feel some relief. When your brain realizes that you've scratched away the irritant, the signal being sent to your brain that you have an itch is interrupted and therefore no longer recognized by the brain.

Even if you don't remove the irritant, scratching will at least cause pain and divert your attention away from the itching. The irritant that caused the itching is very small, maybe only a few microns in length, so it disturbs only a few nerve endings. When you use your fingernail to scratch the spot where the irritant is, you not only remove the irritant but you irritate a lot more nerve endings than the irritant.


The Mechanisms and Perception of Itch

When we feel an itch, we scratch it without thinking twice. But what causes itch in the first place? Why do we even have it? Our innate reaction to everyday itch is to scratch it, but in some skin diseases that cause chronic itch, scratching exacerbates the problem. Dr. Robert LaMotte, Professor of Anesthesiology and of Neurobiology at the Yale School of Medicine, conducts experiments on the perception and biological mechanisms of itch, using psychophysical and electrophysiological methods to measure the sensations of itch and responses of itch mediating sensory neurons.

The Biology Behind Itch

“Nociceptive” sensory neurons with small diameter nerve fibers are responsive to nox¬ious stimuli. A subset of nociceptive nerve fibers that terminate in the skin, respond to one or more chemicals that make us itch. These neurons are termed “pruriceptive” (from the latin word, prurere, “to itch”) whereas nociceptive neurons that do not respond to itchy chemicals are called “nociceptive specific.” Both types of neurons project to pathways in the central nervous system. So how does the brain decode itch from pain? LaMotte explained that the current thinking in the field is that activity in nociceptive specific neurons is interpreted by the brain as “pain,” whereas activity that occurs solely in the pruriceptive population is felt as “itch.”

A diagram of a neuron, the cell that transmits signals from the skin to the central nervous system. Image courtesy of Carleton University, Canada.

More than a decade ago, scientists in Germany found that histamine, a substance usually released during allergic reactions and causes itch, triggered activity in a specific type of nerve fiber terminating in the skin in humans. Most neurons that respond to histamine also respond to other types of stimuli, such as noxious heat, mechanical stimulation, or to capsaicin, which produces burning and stinging pain when injected into the skin.

Since the discovery of histamine’s connection to itch, research has elucidated a wide range of nociceptors, some nociceptive specific and others pruriceptive. Certain nociceptors respond to capsaicin and histamine others respond to noxious heat and capsaicin but not histamine, and still others respond irregularly to mechanical stimuli, heat and histamine and to other itchy chemicals such as certain proteases. For example, one type of protease is contained in the hairs (spicules) of a tropical legume called cowhage (Mucuna pruriens). When these spicules fall off the pods of the plant their tips can stick into the outer layer of skin causing a prickly itch but without the release or presence of histamine. Because most types of clinically important itch are not relieved by anti-histamines, cowhage spicules have been useful in experiments that have identified a mechanosensitive, histamine independent pruriceptive neuronal pathway. Activity in these mechanosensitive neurons may explain why when patients with atopic eczema, a skin disease with chronic itching, put on wool sweaters, the mechanical rubbing of the wool against the skin causes itching. “We are trying to figure out how all the signals get sorted out in the central nervous system,” says LaMotte. “The goal is to identify the sensory neurons and pathways that mediate pain and itch, as they are very diverse and differ in many properties.”

Currently, there is no proven hypothesis on the functional basis of scratching the kind of transient itch we experience every day. One proposed idea suggests that since our skin serves a function of keeping fluids in and external irritants out, itchiness directs our attention to that area of our body so we can scratch and eliminate an irritant or parasite. “Parasites, though, can enter our body very quickly,” points out LaMotte, “So the chances of eliminating them by scratching are not very plausible.”

LaMotte proposes another possibility. Nerve endings are activated when our skin barrier is breached and a chemical irritant (for example from microorganisms living on the skin, activate pruriceptive nerve endings thereby resulting in itch and site-directed scratching. The scratching produces a minor “injury” that may trigger an inflammatory response that hastens the repair of the breach in the skin barrier.

A diagram depicting mast cells releasing histamine upon contact with an allergen, which causes itch and allergic reactions in the human body. Courtesy of MedlinePlus.

Skin Conditions with Chronic Itch

The skin condition eczema is the number one cause of itch. Over 18 million Americans suffer from the chronic, or atopic, form of eczema, and 20 percent of children in the Western hemisphere have chronic eczema. While most patients have a mild form of the condition, which is often treated with a topical steroid or moisturizer, around 10 percent of eczema patients suffer from severe itching.

What we commonly associate with itch, such as an insect bite, is merely temporary and bothersome. Most just react by scratching the itch, maybe even without thinking. The chronic itch of eczema, however, is a perpetual, irritating sensory perception that often results in much suffering. It induces a great urge to scratch, but scratching further damages the protective upper layers of the skin barrier. Damaged skin, stripped of its protective properties, causes nerve fibers just below the surface to be disturbed and overactivated, magnifying an even greater sensation of itch. Thus, scratching actually intensifies the perception of itch, thereby creating a painful and maddening itch-scratch cycle.

Itch in the LaMotte Lab

“Our long range goal is to identify the functional properties of different types of sensory neurons, specifically those mediating pain or itch,” explains LaMotte. “We pick a chemical stimulus that can produce itch in humans, ask human subjects to judge the magnitude of different qualities of sensations, like itch, pricking/stinging and burning, and apply the same stimuli to an animal model to analyze the responses of different types of sensory neurons and pathways.”

In his experiments, LaMotte employed the mouse as his model organism to investigate behavioral responses to itch and pain sensations. Steve Shimada, in the LaMotte lab, wanted to find out whether histamine (itchy to humans) or capsaicin (painful to humans) would evoke different behaviors when injected into the cheek of the mouse. It turned out that mice scratched the cheek with the hindlimb in response to histamine but wiped the cheek with the forelimb in response to capsaicin. A parallel dichotomy of behaviors occurred if the same chemicals were applied to the calf of the hindlimb. But in this case, histamine evoked more biting than licking whereas the reverse was true in response to capsaicin. LaMotte said “we concluded that the mouse model demonstrated a behavioral differentiation between chemicals that elicit itch and those that evoke pain.

Electrophysiology is then used to find the sensory neurons in the mouse that are transmitting the itch and pain signals. As LaMotte describes, “We record the nerve impulses activated by a particular chemical, which shows us which neurons are involved and whether this activity parallels the sensory behavior in mouse and in humans.” In collaboration with Chao Ma, a new physiological preparation was developed that allows the cell bodies of sensory neurons mediating pain and itch to be visualized in vivo. “The advantage of this approach is that individual neurons can be selected for optical imaging of cellular events or for electrophysiological recording,” LaMotte stated.

Ultimately, LaMotte says his goal is to get to know the cellular and molecular mechanisms that are special to each particular type of neuron. If specific neurons activated by itch stimuli are isolated, a targeted, sensory-specific drug might be developed to inhibit the transmission of the “itch.”

Tightly packed skin cells help create the natural barrier of the skin, while ingress of chemical solvents and water causes inflammation Keratinocytes become less tightly held together.

Future Research for Itch

While current research focuses on periph¬eral sensory neurons, LaMotte hopes to identify cellular mechanisms specific to unique neurons and corresponding sensations. From a broader viewpoint, however, LaMotte says he strives to find out how sensations such as itch and pain are separately decoded in the central nervous system. For this, the mode of communication between distinct, unrelated nociceptors must be elucidated to show how sensory signals are deciphered. Once the neural pathways are identified, understanding of the mechanisms and perception of itch may pave way for potential future treatments.

About the Author
Jenny Mei is a sophomore in Berkeley College majoring in Molecular, Cellular, and Develop¬mental Biology. She is the Advertising Manager for Yale Scientific Magazine.

Acknowledgements
Jenny would like to thank Dr. LaMotte sincerely for his generous time and support, as well as an enlightening and intriguing discussion about his research involving the sensation of itch.

Further Reading
Chen, IngFei. “Digging Deeper to Understand Itch.” New York Times 25 April 2008: A11.
LaMotte RH, Shimada SG, Green BG, Zelterman D. “Pruritic and nociceptive sensations and dysesthesias from a spicule of cowhage.” J Neurophysiology. 101.3(2009):1430-43.
Shimada SG, LaMotte RH. Behavioral differentiation between itch and pain in mouse. Pain 139 (3), 681-687, 2008 PMID: 18789837.
Johanek LM, Meyer RA, Hartke T, Hobelmann G, Maine D, LaMotte RH, Ringkamp M. “Psychophysical and physiological evidence for separate neural pathways mediating histaminergic and non-histaminergic itch.” J Neuroscience. 27.28(2007):7490-7.
LaMotte RH, Shimada SG, Green BG, Zelterman D. “Pruritic and nociceptive sensations and dysesthesias from a spicule of cowhage.” J Neurophysiology. 101.3(2009):1430-43. ion


At first glance, itch and pain seem to be related

The definition still accepted by most doctors and researchers today was put forth some 350 years ago by a German physician named Samuel Hafenreffer. He wrote in somewhat circular manner than an itch is any “unpleasant sensation that elicits the desire or reflex to scratch”. If you scratch, then the sensation that provoked it is by definition an itch. It’s a definition that may be reliable, but it’s probably not all that useful.

At first glance, itch and pain seem to be related. The skin is studded with an array of nerve endings called nociceptors whose job is to relay information about the presence of potentially damaging stimuli to the spinal cord and brain. A weak assault on those neurons results in an itch, while a fully fledged attack results in pain.

That’s according to the “intensity theory”. But there’s an alternative, the “specificity theory”, which holds that some neurons are responsible for pain, while a different set cares about itch, which is more formally known as “pruritus”. Or it could be that there’s a single set of neurons responsible for nociception, but that they can somehow tell the difference between stimuli that are itchy and those that hurt.

Obsessive scratching

That itching can arise for so many different reasons doesn’t help. To start with, there’s acute itch, the type most of us are familiar with, which could arise from something as simple as an insect bite. Then there is the more chronic, pathological type of itch that could be associated with dry skin, eczema, psoriasis, or other skin diseases. Brain tumours, multiple sclerosis, chronic liver disease, lymphoma, Aids, and hyperthyroidism have all been associated with chronic itch, as have diseased neurons.

Then there are the psychological and cognitive factors, but not all are as creepy as delusory parasitosis. An obsessive need to scratch can be a manifestation of obsessive-compulsive disorder in these cases, persistent scratching can damage the skin and only serves to exacerbate the problem.

The pain from a scratch is very different from one we might feel when we put a finger in a naked flame (Credit: iStock)

That the itch sensation can be reduced by the application of painful stimuli only makes it an even more curious phenomenon. Scratching is a relatively minor form of pain, but the light pain we experience raking our nails across our skin does seem to help, as does the application of cold, or heat, capsaicin (the chemical that gives peppers their heat), or even a few electrical zaps. This means, paradoxically, that analgesics, which are meant to reduce pain, can actually enhance itch.

The confusion between pain and itch notwithstanding, there’s a fairly straightforward difference between the two. When something hurts, our body responds with its withdrawal reflex. Put your hand near a candle’s flame and you'll experience the overwhelming desire to pull it back.

But the scratching reflex brings attention towards, rather than away, from the affected skin. That actually makes good sense, and points to one possible evolutionary origin for the scratching reflex: closer inspection and a quick scratch is more effective at removing a crawling insect than would the withdrawal reflex. Scratching is a good way to remove not just insects and parasites, but also bits of plants and any other unwanted material hitching a ride on your skin or in your hair.


Eczema

A rash by any other name is still a rash. The terms &ldquoeczema&rdquo or &ldquodermatitis&rdquo are very broad and can mean a whole family of skin conditions, ranging from dandruff, to contact dermatitis to atopic dermatitis. This can lead to many a confused client and skin care professional. In dermatology and skin care, the word &ldquoeczema&rdquo typically refers to atopic dermatitis (AD), a chronic inflammatory skin disease. It causes dry, itchy, irritated skin that requires daily care. Genetic defects in eczema result in abnormal skin cell differentiation. During differentiation, keratinocytes move from the basal cell layer of the epidermis through the granular layer to a group of flattened dead cells in the stratum corneum. This process of epidermal differentiation, or keratinization, involves a variety of proteins responsible for different functions at each stage.

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One of these proteins, filaggrin, plays a major role in epidermal homeostasis it has two main functions. First, it stacks the keratin filaments into dense bundles, allowing for easy desquamation. Imagine how much easier it is to move flattened boxes than propped-open boxes. It is then converted into the skin&rsquos natural moisturizing factor (NMF) along with other byproducts. So if filaggrin does not work very well, it can have adverse effects, not only on the process of epidermal differentiation, but also on the skin&rsquos natural moisture levels and protective lipid barrier. This seems to be the biological basis of dry skin.

In the past five years, researchers have established the link between filaggrin mutations and developing ichthyosis vulgaris4, atopic eczema5 and, most recently, peanut allergies.6 Ichthyosis is another skin disease characterized by very dry skin. The word itself is Greek for &ldquofish,&rdquo suggesting the scaly nature of the lesions. Indeed, scientists are getting closer to understanding the genetic connection between allergic diseases, bringing hope for a future therapy not only for eczema clients, but also for those with allergies and ichthyosis.

There&rsquos another type of eczema that shows up as the same itchy rash, but does not involve allergic responses. This is known as nonatopic eczema, and it affects millions of adults. Although most&mdash
about 90%&mdashdevelop atopic dermatitis before age 5, nonatopic dermatitis develops in adolescence or adulthood, typically by age 15.7, 8 These people don&rsquot have heightened allergic responses or specific allergies, but still get dry, itchy skin. Keep in mind that even if a client is classified as atopic or nonatopic, the end result is the same itchy patch of skin, which must be cared for in the same manner.


Swimmer's Itch FAQs

Swimmer&rsquos itch, also called cercarial dermatitis, appears as a skin rash caused by an allergic reaction to certain microscopic parasites that infect some birds and mammals. These parasites are released from infected snails into fresh and salt water (such as lakes, ponds, and oceans). While the parasite&rsquos preferred host is the specific bird or mammal, if the parasite comes into contact with a swimmer, it burrows into the skin causing an allergic reaction and rash. Swimmer&rsquos itch is found throughout the world and is more frequent during summer months.

How does water become infested with the parasite?

The adult parasite lives in the blood of infected animals such as ducks, geese, gulls, swans, and certain mammals such as muskrats and raccoons. The parasites produce eggs that are passed in the feces of infected birds or mammals.

If the eggs land in or are washed into the water, the eggs hatch, releasing small, free-swimming microscopic larvae. These larvae swim in the water in search of a certain species of aquatic snail.

If the larvae find one of these snails, they infect the snail, multiply and undergo further development. Infected snails release a different type of microscopic larvae (or cercariae, hence the name cercarial dermatitis) into the water. This larval form then swims about searching for a suitable host (bird, muskrat) to continue the lifecycle. Although humans are not suitable hosts, the microscopic larvae burrow into the swimmer&rsquos skin, and may cause an allergic reaction and rash. Because these larvae cannot develop inside a human, they soon die.

What are the signs and symptoms of swimmer&rsquos itch?

Symptoms of swimmer&rsquos itch may include:

  • tingling, burning, or itching of the skin
  • small reddish pimples
  • small blisters

Within minutes to days after swimming in contaminated water, you may experience tingling, burning, or itching of the skin. Small reddish pimples appear within twelve hours. Pimples may develop into small blisters. Scratching the areas may result in secondary bacterial infections. Itching may last up to a week or more, but will gradually go away.

Because swimmer&rsquos itch is caused by an allergic reaction to infection, the more often you swim or wade in contaminated water, the more likely you are to develop more serious symptoms. The greater the number of exposures to contaminated water, the more intense and immediate symptoms of swimmer&rsquos itch will be.

Be aware that swimmer&rsquos itch is not the only rash that may occur after swimming in fresh or salt water.

Do I need to see my health care provider for treatment?

Most cases of swimmer&rsquos itch do not require medical attention. If you have a rash, you may try the following for relief:

  • Use corticosteroid cream
  • Apply cool compresses to the affected areas
  • Bathe in Epsom salts or baking soda
  • Soak in colloidal oatmeal baths
  • Apply baking soda paste to the rash (made by stirring water into baking soda until it reaches a paste-like consistency)
  • Use an anti-itch lotion

Though difficult, try not to scratch. Scratching may cause the rash to become infected. If itching is severe, your health care provider may suggest prescription-strength lotions or creams to lessen your symptoms.

Can swimmer&rsquos itch be spread from person-to-person?

Swimmer&rsquos itch is not contagious and cannot be spread from one person to another.

Who is at risk for swimmer&rsquos itch?

Anyone who swims or wades in infested water may be at risk. Larvae are more likely to be present in shallow water by the shoreline. Children are most often affected because they tend to swim, wade, and play in the shallow water more than adults. Also, they are less likely to towel dry themselves when leaving the water.

Once an outbreak of swimmer&rsquos itch has occurred in water, will the water always be unsafe?

No. Many factors must be present for swimmer&rsquos itch to become a problem in water. Since these factors change (sometimes within a swim season), swimmer&rsquos itch will not always be a problem. However, there is no way to know how long water may be unsafe. Larvae generally survive for 24 hours once they are released from the snail. However, an infected snail will continue to produce cercariae throughout the remainder of its life. For future snails to become infected, migratory birds or mammals in the area must also be infected so the lifecycle can continue.

Is it safe to swim in my swimming pool?

Yes. As long as your swimming pool is well maintained and chlorinated, there is no risk of swimmer&rsquos itch. The appropriate snails must be present in order for swimmer&rsquos itch to occur.

What can be done to reduce the risk of swimmer&rsquos itch?

To reduce the likelihood of developing swimmer&rsquos itch

  • Do not swim in areas where swimmer&rsquos itch is a known problem or where signs have been posted warning of unsafe water.
  • Do not swim near or wade in marshy areas where snails are commonly found.
  • Towel dry or shower immediately after leaving the water.
  • Do not attract birds (e.g., by feeding them) to areas where people are swimming.
  • Encourage health officials to post signs on shorelines where swimmer&rsquos itch is a current problem.

This information is not meant to be used for self-diagnosis or as a substitute for consultation with a health care provider. If you have any questions about the parasites described above or think that you may have a parasitic infection, consult a health care provider.


MRGPRX4 is a bile acid receptor for human cholestatic itch

Patients with liver diseases often suffer from chronic itch, yet the pruritogen(s) and receptor(s) remain largely elusive. Here, we identify bile acids as natural ligands for MRGPRX4. MRGPRX4 is expressed in human dorsal root ganglion (hDRG) neurons and co-expresses with itch receptor HRH1. Bile acids elicited Ca 2+ responses in cultured hDRG neurons, and bile acids or a MRGPRX4 specific agonist induced itch in human subjects. However, a specific agonist for another bile acid receptor TGR5 failed to induce itch in human subjects and we find that human TGR5 is not expressed in hDRG neurons. Finally, we show positive correlation between cholestatic itch and plasma bile acids level in itchy patients and the elevated bile acids is sufficient to activate MRGPRX4. Taken together, our data strongly suggest that MRGPRX4 is a novel bile acid receptor that likely underlies cholestatic itch in human, providing a promising new drug target for anti-itch therapies.

Keywords: MRGPRX4 bile acids cholestasis chronic itch human neuroscience orphan GPCR.

Conflict of interest statement

HY, TZ, SL, QW, OJ, ZW, ZZ, YS, LP, RH, YY, JS, XW, HX, ZZ, PZ, XL, WL, YL No competing interests declared

Figures

Figure 1.. MRGPRX4 is activated by bile…

Figure 1.. MRGPRX4 is activated by bile extract.

( a ) Flow chart for the…

Figure 1—figure supplement 1.. Construct design and…

Figure 1—figure supplement 1.. Construct design and surface expression of candidate GPCRs in HEK293T cells.

Figure 2.. Identification of the active components…

Figure 2.. Identification of the active components in bile extract that activate MRGPRX4.

Figure 2—figure supplement 1.. 1 H-NMR analysis…

Figure 2—figure supplement 1.. 1 H-NMR analysis of bile acids in fractions F1, F2, F3,…

Figure 3.. Functional characterization and molecular profiling…

Figure 3.. Functional characterization and molecular profiling of bile acids as ligands for MRGPRX4.

Figure 3—figure supplement 1.. Human MRGPRX4, but…

Figure 3—figure supplement 1.. Human MRGPRX4, but not human MRGPRX1-3 or mouse and rat Mrgpr…

Figure 4.. MRGPRX4 is expressed in a…

Figure 4.. MRGPRX4 is expressed in a subset of hDRG neurons.

Figure 4—figure supplement 1.. The anti-MRGPRX4 antibody…

Figure 4—figure supplement 1.. The anti-MRGPRX4 antibody has high specificity.

HEK293T cells were transiently transfected…

Figure 5.. MRGPRX4 mediates bile acids induced…

Figure 5.. MRGPRX4 mediates bile acids induced activation of DRG neurons.

Figure 5—figure supplement 1.. Expressing MRGPRX4 in…

Figure 5—figure supplement 1.. Expressing MRGPRX4 in cultured rat DRG neurons renders the cells responsive…

Figure 5—figure supplement 2.. Cultured human DRG…

Figure 5—figure supplement 2.. Cultured human DRG neurons respond to various chemicals.

Figure 6.. Bile acids and MRGPRX4 specific…

Figure 6.. Bile acids and MRGPRX4 specific agonist induce histamine-independent itch in human.

Figure 7.. TGR5 does not serve as…

Figure 7.. TGR5 does not serve as an itch receptor in human.

Figure 7—figure supplement 1.. Expression of TGR5…

Figure 7—figure supplement 1.. Expression of TGR5 in mouse and monkey DRG.

Figure 8.. Elevated bile acids are correlated…

Figure 8.. Elevated bile acids are correlated with the occurrence of itch among patients with…

Figure 8—figure supplement 1.. Quantification of bile…

Figure 8—figure supplement 1.. Quantification of bile acids in human plasma.

Figure 9.. Bilirubin potentiates the activation of…

Figure 9.. Bilirubin potentiates the activation of MRGPRX4 by bile acids and may contribute to…

Figure 10.. Proposed model depicting the mechanism…

Figure 10.. Proposed model depicting the mechanism underlying itch in patients with liver diseases.

Author response image 1.. Representative large-scale RNAscope…

Author response image 1.. Representative large-scale RNAscope images of human DRG.



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