At least 16 different types of nerve cells are found in our skin. Together they form the human sense of touch, temperature and pain. But contrary to previous assumptions, one specialized cell type is not responsible for pain and another for touch, cold or heat – rather, the individual nerve cells react to several different environmental stimuli. Our skin sensory system works much more complicatedly and with less division of labor than expected, as researchers report in “Nature Neuroscience”. They also found subtle differences between our sense of pain and that of mice and macaques.
What we know today about the human nervous system has largely been discovered by scientists through animal experiments, the results of which were then confirmed in human cell models or clinical studies. But some findings from animal experiments could never be transferred to the human body. This could be because the animal and human nervous systems are only partially comparable. But how similar are humans and animals actually on a neurological level? And what is going on in the individual nerve cells?
Detailed analysis of the skin’s nerve cells
To find out, a team led by Huasheng Yu from the University of Pennsylvania compared the nervous systems of humans, mice and macaques. The neurobiologists focused on the senses of touch, temperature and pain and used skin samples to analyze which nerve cells were involved. To do this, they compared the RNA found in individual nerve cells for the first time – an indication of the genes active in them and the proteins and receptors present. Based on this, Yu and his colleagues grouped the approximately 1,000 nerve cells examined into different types, with cells with similar gene expression profiles ending up in the same group.
It turned out that the nerve cells in the human skin, which are involved in our sensory system, belong to no fewer than 16 different cell types. There are therefore more subtypes of these sensors than expected. But does that also mean that these 16 nerve cell types each fulfill a different function for the sensory perception of our skin? For example, do some of these cell types sense heat, while others sense pain or touch? In order to test this common assumption, the neurobiologists then analyzed the function of the individual nerve cells by exposing them to various stimuli such as heat, pressure or chemicals. Using a special method called microneurography, they looked at whether individual nerve cells in the skin of human and animal test participants react to the stimuli and send signals to the brain.
One cell type, multiple functions
The tests surprisingly revealed that the nerve cells within a cell type respond not just to individual environmental stimuli, but to multiple triggers. For example, a cell type that responds to gentle, pleasant touch also responded to heat, cold and capsaicin – the chemical responsible for the pain of spicy foods like chilies. The previous assumption was that nerve cells that are “specialized” in pain react to this substance. However, the experiments have now revealed that these nerve cells are not specialists, but rather multifunctional tools: They react not only to the pain of capsaicin, but also to non-painful chemicals such as menthol and cold.
“There is a popular idea that nerve cells are very specific – that one type of nerve cell senses cold, another senses a particular frequency of vibration, and a third responds to pressure, and so on. But we now see that it is much more complicated,” says co-author Saad Nagi from Linköping University. How exactly the nerve cells perceive and process the various stimuli has not yet been completely clarified. For example, the type of cell that responds to gentle touch also senses cold, even though, according to its RNA, no genes are active in it that would ensure the production of cold-sensitive proteins. The researchers conclude that there must be another, previously unknown mechanism for cold sensing in the cells. There could also be other, as yet not understood, mechanisms for other skin irritations.
Human nerves sense pain faster than mice
The comparison with mice and macaques also showed that their skin sensory system is structured similarly to that of humans, but is also different: These animals therefore have a similar number of different nerve cell types in their skin as we do, but their gene expression profile is not always identical to the 16 cell types identified in human skin. The animal nerve cells could therefore also have other functions or combinations of functions, according to the team.
People also have significantly more cells of the type that recognize pain particularly quickly and transmit this signal to the brain. “The fact that pain is signaled at a much higher speed in humans compared to mice is probably just a reflection of body size. In humans, the distances are greater than in mice, and the signals have to be sent to the brain more quickly. Otherwise you would be injured before you could even react,” suspects co-author Håkan Olausson from Linköping University.
In follow-up studies, the neurobiologists now want to look for further similarities, differences and functions of the individual nerve cells of the sense of touch. They also want to test whether the distribution of cell types differs depending on the region of the body, age and gender.
Source: Huasheng Yu (University of Pennsylvania) et al.; Nature Neuroscience, doi: 10.1038/s41593-024-01794-1