Does using a tickle to tickle an itch make it itch more?

The crosstalk master Mr. Ma Sanli has a famous piece called "Scratch". The content of this crosstalk is: There is a fat man who has a problem. He likes to take a bath. Otherwise, his body will itch and he can't sleep! One day, he met a master selling a secret recipe handed down from his ancestors on the street. He claimed that the secret recipe handed down from his ancestors was specifically for treating skin itching and was absolutely effective. So this man bought a package and took it home. One night, he didn't take a bath, and his body was itchy and uncomfortable... He remembered the secret recipe he just bought, so he opened the paper package and saw a tin foil package inside. He opened the tin foil package inside and saw a red paper package. He opened the red paper package and saw a white paper package. He opened the white paper package and saw another yellow paper package... The more he scratched, the more anxious he became, and the more anxious he became, the more itchy his body became - "This secret recipe, what the hell is this secret recipe?!" He opened the last blue paper package, and inside was a small piece of paper. He opened the paper and saw two words on it - "Scratch"!

Regarding the love-hate relationship between "itch" and "scratch", today we will analyze it in two scenarios: one is "tickling", and the other is "itch scratching".

"Tickling" means that tickling the "itchy spots" on the body will make people laugh.

"Scratch the itch" means that if you feel itchy anywhere on your body, you can scratch it to relieve the itch.

1. Where does the “itch” come from?

Some people often experience unbearable itching of the skin, which may be caused by pruritus. Pruritus refers to a common skin disease in which the skin itches without primary skin lesions. Patients may experience a burning sensation or a feeling of ants crawling on the skin. According to the scope and location of the itching, pruritus is generally divided into two categories: systemic and localized.

(1) Generalized pruritus is often a concomitant or first symptom of many systemic diseases, such as uremia, biliary cirrhosis, hyperthyroidism or hypothyroidism, diabetes, malignant tumors, and neuropsychiatric pruritus. The external causes of generalized pruritus are related to environmental factors (including humidity, season, biological or chemical stimulation in the working environment), topical medications, the use of highly alkaline soaps, and dry skin caused by decreased secretion of the sebaceous glands and sweat glands of the patient's skin.

(2) The causes of localized pruritus are sometimes the same as those of systemic pruritus, such as diabetes. Anal pruritus is often related to pinworm disease, hemorrhoids, anal fistula, etc. Vulvar pruritus is often related to leucorrhea, trichomoniasis, fungal diseases, gonorrhea and cervical cancer. Scrotal pruritus is often related to high local skin temperature, sweating, friction, and fungal infection.

The above is just an introduction to the feeling and surface phenomenon of itching. So, from a deeper level, where does the itching come from? The answer is two ways: chemical itching and mechanical itching.

Chemical itch is caused by the release of chemical mediators such as histamine, substance P, kinins and proteases. For example, the main reason for histamine-induced itch is that this substance causes certain damage to the patient's local tissue during the release process, and may even be accompanied by inflammation and allergic reactions, which leads to itching on the local skin. The itching caused by mosquito bites is mainly related to the production of antibodies and the release of histamine in the body caused by the mosquito body fluids. Antihistamines can inhibit this type of itching. Mechanical itch is often a stress response caused by touch, such as fine hair fibers or crawling insects that lightly touch the skin and cause itching. In fact, the cause of itching is more of a coupling effect of chemistry and mechanics. The former has been widely studied, while the conduction mechanism of the latter is largely unknown.

Next, we will focus on the biomechanical issues of mechanical itch.

2. Why does scratching make you feel itchy?

Some parts of our bodies are particularly ticklish, and even the slightest touch can cause an itch and induce laughter. Why is this so?

Darwin, a British biologist and founder of the theory of evolution, studied the issue of tickling.

Why did such a strange behavior as tickling evolve? According to the theory of evolution, if it did not have the significance of being beneficial to survival, it would not exist in our ancestors and be inherited.

It can be inferred that tickling may have evolved as a way for humans to protect themselves during evolution. You will find that the areas with ticklish spots on the body are actually very vulnerable areas. When tickled, people curl up into a ball and lie on the ground to protect themselves. This is a conditioned reflex. The tickling reflex is like an alarm for the skin. It feels like a hundred spiders crawling on your neck. The instinctive reaction is to hide quickly. This is why tickling causes involuntary twitching and shaking, because it may be that the brain thinks something is crawling on our skin.

Let's get to the bottom of this. Why does scratching make us itch? How does the brain perceive the itch caused by touch through what neural circuits?

Itch is a black box that only a few neuroscientists and dermatologists are interested in. The scientific mechanism of itch is considered a complex and colorful Rubik's cube.

Dr. Rose Hill, a neuroscientist at the Scripps Research Institute, a nonprofit private academic research institution in California, said that the mechanism of itch-induced sensation by touch is one of the " last unknown areas of sensory biology " , while Robert Provine, a neuroscientist at the University of Maryland in Baltimore, said that " tickling is one of the broadest and most profound research topics in science " . It can be seen that even the tickling phenomenon that has become commonplace in daily life is not a simple problem.

Scientists at the Scripps Research Institute discovered through experiments on " tickling " mice that the key sensor used by sensory neurons to detect mechanical stimulation to cause itching is the force receptor on the cell membrane - the piezoelectric protein Piezo1. Piezo1 is a propeller-shaped ion channel that is embedded in the cell membrane in a variety of cell types. Piezo1 can be activated by biomechanical behaviors such as shear stress, stretching, poking, and matrix displacement, thereby achieving mechanical transduction . When there is a "pull" of force on the cell surface, the ion channel is activated, allowing a series of ions to enter the cell, producing a subsequent itch response (Figure 1).

Figure 1 Schematic diagram of the mechanism by which cells sense "tickling" and transmit "itching". (A) Activation mechanism of Piezo1 channel. The leaves of the Piezo1 channel undergo a lever-like flattening movement when mechanical stress is applied, thereby opening its central pore and allowing the influx of positive charges. (B) Piezo1 lever-type mechanotransduction model. The highly curved Piezo1 leaves act as mechanical receptors, directly sensing the curvature and tension of the cell membrane. The function of the long lever is to transmit mechanical stimuli from the leaves to the ion conduction module.

A little more words. Mechanotransduction refers to the process by which cells receive external physical and mechanical signals through mechanoreceptors, and the cytoskeleton system generates corresponding internal physical and mechanical systems and signal transmission systems. It plays an important role in regulating many basic physiological processes at the cellular level, including touch, pain, proprioception, skeletal balance, and blood pressure. In general, the mechanotransduction process relies on mechanosensitive ion channels (mechanotransducers) to initiate depolarization of excitable cell membranes or trigger calcium signals in non-excitable cells. This activates a series of downstream signaling pathways, leading to the regulation of specific cellular and physiological responses.

It can be said that when scientists " tickled " the cells of mice , it was Piezo1 on the cell membrane that sensed the force of tickling and reported it to the nerve cells to produce an itch, so the piezoelectric protein Piezo1 is the " switch " on the cell that senses itch . The itch changes with the activity of Piezo1. This new discovery not only solves a long-standing mystery for the complex itch mechanism, but will also help to bring treatments for chronic itch caused by certain diseases, and open the door to new drug development for better treatment of diseases such as eczema and psoriasis that cause long-term itching.

This breakthrough discovery of the piezoelectric protein Piezo1 has greatly advanced people's understanding of the physiological significance of mechanotransduction and the molecular mechanism of the force that senses the movement of ions across membranes. By " tickling " cells , scientists have discovered the biomechanical mechanism of " tickling ". Due to this major contribution, Professor Ardem Patapoutian of the Scripps Research Institute in the United States and Professor David Julius of the University of California, San Francisco, USA, jointly won the 2021 Nobel Prize in Physiology or Medicine .

Ask some interesting questions.

(1) Why does tickling make us laugh?

Tickling has more implications than you might think. “It’s involved in everything from physical defense to neural programs for playfulness to the formation of a sense of self and other,” says Robert Provine, a neuroscientist at the University of Maryland in Baltimore.

For our ancestors, play was an important part of learning and progress, which was essential for survival. "Tickling is the most primitive form of stimulation," and friends often tickle and tease each other. Tickling shows closeness between friends. This tells us that tickling is a social behavior.

(2) Why can’t we scratch ourselves?

It's the same reason we can't scare ourselves. When we want to tickle ourselves, our brain has already planned it out and foreseen the result of the action, so the stimulation to ourselves is greatly reduced. The brain knows what we want to do to ourselves next, and our brain shuts down the entire tickling reflex. Therefore, when it comes to tickling, only other people can do it.

However, there is a special group of people who can tickle themselves without others, and that is people with schizophrenia. The brains of people with schizophrenia cannot produce predictable behavior. Researching "tickling" may seem a bit unconventional, unprofessional, and a waste of time, but scientific research is ultimately serious and has practical uses. Scientists use what they have learned from tickling research to help develop new treatments for mental illness.

(3) Is tickling just a playful thing?

Human tickling is not a simple matter, and emotional and psychological factors often play a role. Some people find tickling pleasurable, while others find it painful; sometimes tickling has erotic connotations, and sometimes it is used as a form of torture. Humans have been obsessed with tickling for thousands of years, and in ancient times there was even a punishment called "laughing punishment" that would make people die of laughter.

3. Why does “itch” make you scratch?

Everyone has this kind of daily experience: suddenly and inexplicably you feel an itch on your body, and you feel better after a few good scratches. The pain of the itch is replaced by the pleasure of scratching, and you feel happy. Therefore, the American poet Ogden Nash (1902-1971) wrote: happiness is to have a scratch for every itch .

Why can scratching solve the problem of itching? Scientists are restless again.

Research from Washington University in St. Louis, USA, found that scratching prevents nerve endings from sending itch signals to the spinal cord, while causing local swelling and pain. The pain caused by scratching the skin is transmitted to the brain through nerve cells in the spinal cord, interfering with the itch signal and temporarily suppressing the itch sensation, that is, the "pain" masks the "itch" (Figure 2).

Figure 2 Schematic diagram of the sensory neural circuits of pain and itch. The red lines represent pain-related neurons, and the blue lines represent itch-related neurons.

Basically, itch, like pain, is a signal that the body feels something is wrong and sends feedback to the brain. Itch and pain are transmitted by the same nerves (Figure 2). Itch hormones and other substances activate the itch receptors under the skin, which transmit itch signals to the brain through the blue neural pathways. Stimuli such as scratching and heating activate the pain receptors under the skin, which transmit pain signals to the brain through the red intermediate neurons. The key point that "itch scratching" can achieve "scratching to stop itching" appears at the intersection of the red and blue pathways in Figure 2. Itch receptors intensify the itch, while pain receptors inhibit the itch . Here, the two "meet on a narrow road and the brave one wins", and the pain is like "Cheng Yaojin who suddenly appears halfway through the road", which hinders the transmission of the itch to the brain, so the "itch-stopping" effect is achieved .

However, don’t be too happy! Scratching an itch makes you feel good; scratching it for a while makes you feel good; scratching it all the time makes you feel good all the time; it’s not that simple. Scratching an “itch that is hard to explain” is just wishful thinking!

Minor itch can be relieved by scratching a few times, and it will not affect the body. However, itching caused by diseases is not easy to deal with, and even taking medicine is not effective. If you scratch it without thinking, although it can help relieve the itch, scratching can only solve the "immediate" problem. If you use too much force and too many times, the skin may be further irritated, which will aggravate the itching, and may even cause skin damage or even infection.

Why does scratching sometimes not relieve the itching, but makes it itch worse? How did the pain and itching mentioned above become a vicious cycle? Scientists are getting impatient again!

Further research by scientists has found that the principle of the vicious cycle between pain and itch is: when the brain feels pain due to scratching caused by itching, the brain will immediately respond by causing the body to produce a neurotransmitter called serotonin to control the pain. However, while these serotonins inhibit pain, they also activate the "gastrin-releasing protein receptor" (GRPR) neurons, making the itching more intense. The strong itching will trigger a new round of scratching and pain, and then the vicious cycle will repeat itself.

Based on the current discoveries, scientists hope to use drugs or some kind of stimulant to mimic the activity of spinal thalamic tract nerve cells and solve people's "unspeakable itch."

From the above interpretation, we can see that "tickling" can be divided into two types: light touch and hard scratching. Light force and gentle movements will produce "itching"; strong force and vigorous movements will relieve "itching". This is both right and wrong. It depends on who is being tickled. If you don't believe it, try it! In any case, force plays a vital role in external stimulation in "tickling" and "itch scratching" .

Inspired by the Nobel Prize for tickling cells, I scratched my head and tickled myself, but ended up scratching my hair until it was completely bald, but I still didn’t win any prize!