On October 4, 2021, the Nobel Prize Conference held at the Caroline Medical School in Sweden announced that the 2021 Nobel Prize in Physiology and Medicine will be awarded to David Julius and Ardem Patapoutian of the United States. These is recognition of their outstanding contributions in the field of “discovering temperature and tactile receptors”. The two winners will share the prize of 10 million Swedish kronor.
For thousands of years, humans have been trying to explore the origin of consciousness and have also been trying to control our bodies. With the advancement of anatomy, we have learned the magical role of neurons in sensory conduction. But the neurons that feel the world at all times, how do you distinguish between sweet, sour, bitter, spicy, and salty, and cold, hot, and warm? What determines the difference in neuron function?
For a long time, scientists have speculated that the different responses of nerve cells to different stimuli are likely to depend on ion channel receptors on the cell membrane. Ion channel receptors are like doors and windows on houses. Its opening and closing affect the in and out of ions inside and outside the cell, and the different selectivity of cations and anions will affect the change of cell membrane potential. The normal cell membrane maintains a positive and negative potential difference between the outside and the inside. If a large amount of cations flows in or anions flows out, it will cause the depolarization of the cell membrane (the resting potential changes in the direction of decreasing the negative value in the membrane). When a certain level is reached, action potentials (also called nerve impulses) will also be induced. This action potential can be conducted between nerve cells without attenuation, just like the conduction of an electric current in a non-impedance wire, and eventually reach the cerebral cortex to produce different feelings.
As we all know, eating chili will feel hot because it contains capsaicin, but how does capsaicin activate the function of nerve cells that cause this feeling? This has always been a mystery. In the late 1990s, David Julius of the University of California, San Francisco, was working on such an interesting subject: How does capsaicin cause the burning sensation when we come into contact with peppers? Julius, who is good at receptor cloning, began to become interested in the molecular mechanisms of somatic perception and pain. Using pepper as the starting point, after experiencing many difficulties, he finally successfully cloned the capsaicin-specific receptor-vanilloid receptor type 1 (TRPV1) in 1997, and unexpectedly discovered that the receptor can be activated to temperatures above 43°C. This great discovery, for the first time presents the signal transduction effect of ion channel receptors between physical and chemical stimuli, that is, the stimulation of natural chemical substances such as capsaicin and physical stimuli such as temperature can be uniformly converted into electrical signals through the TRPV1 channel on the cell membrane. From the molecular level, it shows us the most basic source of somatosensory cognition and renews our cognition of somatosensory.
When the capsaicin receptor TRPV1 was first discovered, people were quite excited about the protein receptor that can convert chemical and physical signals into electrical signals. But at the same time, people were surprised to find that spicy is not a sense of taste, but a sense of pain. The reason is that TRPV1 receptors are specifically expressed in nociceptive neurons (afferent neurons that specifically recognize nociceptive stimuli) and are widely distributed in various tissues and organs of the body. When stimulated by hot pepper or high temperature, the TRPV1 receptor is immediately activated to generate electrical signals, which are uploaded to the brain along the nociceptive afferent nervous system. And because the brain’s interpretation of nociceptive afferent nerve signals is unified as the stimulus of “pain”, the sensation of spiciness is scientifically defined as the sensation of pain (of course, spiciness is different from ordinary pain due to its thermal properties). It is not difficult to explain why in addition to our mouth, our eyes and skin also have a tingling sensation.
How to solve spicy food scientifically?
The first is to break the bond between capsaicin and TRPV1 receptor, such as drinking high-fat foods or beverages (milk, soy milk, ice cream, etc.) to dissolve capsaicin bound to the receptor.
The second method is to interfere with the brain’s perception of spicy. For example, sucrose and vanillin have a good anti-spicy effect. The reasons for vanillin to relieve spicy are more complicated. On the one hand, sucrose relieves spicy because the stimulation of sweet and spicy acts on different receptor cells in the mouth, and the interaction between receptor cells interferes with the production of brain consciousness. On the other hand, The brain releases analgesic substances after receiving the sweet stimulus, thereby alleviating the spicy pain.
Another interesting study found that pinching the nostrils can inhibit 50% of the spicy feeling. The reason is that the nostrils are closed and the surface temperature of the tongue will decrease, and the decrease in temperature will reduce the possibility of TRPV1 activation. (Next time it’s so spicy, maybe you can try to pinch your nose for the first time?)
In addition to the flavoring agent on the table, people have always used chili as an analgesic. But it wasn’t until TRPV1 was discovered that the analgesic mystery of pepper came to the surface: when TRPV1’s ion channel properties are continuously activated, cations will continue to flood into the cell, and excessive calcium ions can produce cytotoxicity. Cells will shut down the TRPV1 channel feedback due to their own protection, and desensitize nociceptive neurons to capsaicin and other nociceptive stimuli, reducing the production of pain signals, thereby inhibiting pain perception.
After grasping the relationship between TRPV1 receptor and analgesia, scientists regarded it as a new and important drug target for the treatment of a variety of chronic pain. Large pharmaceutical companies have entered the game to block the brain’s perception of pain by simulating and enhancing the activation of capsaicin on the TRPV1 channel, or directly inhibiting the channel function, hoping to develop new and efficient painkillers to supplement the existing The limitations and strong risks of drugs in treatment (opioids have addiction problems, and some anti-inflammatory analgesics have risks of liver and cardiovascular damage). At present, more than a dozen related drugs have undergone clinical trials at various stages, such as the ultra-pure synthetic capsaicin (trans isomer) preparation CNTX-4975 launched by the biopharmaceutical company Centrexion Therapeutics.
“Hot” opens the door to temperature exploration
Why does chili make us feel hot while it hurts us? As mentioned earlier, when the TRPV1 receptor is activated by capsaicin, it can also be activated by physical high temperatures above 43°C. After TRPV1, David Julius and other teams of scientists have successively discovered that a variety of ion channel proteins similar to TRPV1 (which belong to the TRP protein family) are related to temperature perception. For example, the team of Ardem Patapoutian, who also won the Covely Neuroscience Prize, confirmed a type of menthol-sensitive ion channel through the menthol molecule (the main component of peppermint) in 2002 TRPM8, this channel can be activated by harmless low temperature of 8°C~28°C. In 2003, the team discovered a cold sensory channel called TRPA1 that can be activated by mustard, which can be activated by ultra-low temperature (<17°C).
At present, we can basically infer from the molecular level the source of cold, heat and warm feelings: primary sensory neurons express a variety of TRP channel subtypes related to temperature perception, for example, TRPV1 (≥42°C), TRPV2 (≥52°C), TRPM3 (≥40°C) that feel noxious heat; TRPV3 (≥31°C), TRPV4 (≥25°C), TRPM2 (≥35°C), TRPM4/TRPM5 (15-25°C) for feeling non-noxious heat; TRPM8 (≤28°C) for feeling non-noxious cold; Feel the nociceptive cold TRPA1 (≤17°C) and feel the reduced temperature TRPC5 (25-37°C). When the body is in a different temperature environment, specific temperature-sensitive ion channels will be activated to generate electrical signals, which are transmitted to the brain through the nervous system to produce specific temperature perception.
What’s interesting is that the protein receptors that feel the heat and cold are not specializing in their duties, but “multi-tasking”, so that the magical experience of hot pepper and cool peppermint is created. So the question is, does the heat we feel when we eat chili is really related to the increase in physical temperature?
To be sure, the heat of eating chili-like substances is not the result of physical temperature changes, but the result of perception. Everyone may have felt that after being spicy enough, they are more sensitive to the feeling of heat. This is because the TRPV1 channel, which can be activated by capsaicin and physical high temperature (≥42°C) at the same time, has a lower threshold for temperature perception after being activated by capsaicin, that is, a body temperature of less than 42°C can also induce noxious “heat.” At the same time, the dual activation of capsaicin and temperature on the TRPV1 receptor also greatly enhances the excitability of sensory neurons that express the receptor. Therefore, our feelings are “abnormally” magnified, and even a mouthful of the spicy soup at 40°C will have a “fire-breathing” feeling.