Summary: TRPM8 protein is a sensor responsible for chemical and cold sensations. Modulating this sensor, such as applying menthol, is known to help modulate pain sensation. In the new study, researchers have identified a way to modulate this protein, thus countering pain without influencing cold sensation. This discovery may help create effective drugs for chronic pain management.
The problem of chronic pain is increasing globally. Although there are many painkillers, but they all belong to a few groups, like opioids and non-steroidal anti-inflammatory agents (NSAIDs).
NSAIDs are quite effective for moderate-intensity acute pain, but they are not very useful for severe pain or chronic pain. Their long-term use is also associated with many side effects.
Similarly, opioids are good for both acute and chronic pains, but they also fail to help in many chronic pain syndromes. Additionally, they cause addiction and carry the risk of overdose.
Thus, there is definitely a need to find chronic pain specialists in St. Louis with better and safer drugs for chronic pain management. One such emerging approach is drugs acting on TRPM8 (transient receptor potential melastatin 8) receptors. These receptors are both chemical receptors and also help feel cold. Thus, they are sensitive to menthol, leading to a cold sensation. But these receptors also help sense drops in temperature, too.
It is also known that substances that act on these receptors help reduce pain sensation. Thus, for example, menthol is often added to creams and balms. However, researchers are interested in creating oral drugs that could modulate the activity of these sensors and help manage pain.
In the new study done by researchers from Arizona State University’s School of Molecular Sciences and Biodesign Center for Personalized Diagnostics and published in Science Advances, researchers found that these receptors were primarily chemical sensors, but later, they evolved and started sensing cold temperatures.
Why does this understanding matter? The problem is that when we want to regulate pain by modulating TRPM8 sensors, we want to reduce pain sensation, without disturbing the body’s ability to sense cold or temperature.
Researchers have been experimenting with these sensors for a long time. The challenge they have been facing is that drugs that help control pain by acting on TRPM8 sensors also disturb the body’s ability to sense cold, something that is not needed.
Researchers know that the cold sensation caused by menthol and that caused by ice are two different things. So, they want to understand which part of this protein, TRPM8, is responsible for chemical sensation, and which one is for cold sensation so they can selectively modulate the chemical sensing part and thus help those living with chronic pain.
Moreover, early studies suggest that dysregulation in TRPM8 protein plays an important role in chronic pain. That is why those living with chronic pain may even experience pain when they touch metal desks.
There are a few ways to understand the structure of this protein. Researchers have been studying this protein in other mammals and vertebrates. They have been using computational methods to understand how this protein has changed with evolution. In this new study, they made a few interesting discoveries.
In the new study, they could identify the part of the protein that is a chemical sensor and the other part of the protein that is a cold sensor. Further, what surprised researchers is the fact that it seems the chemical sensory part of TRPM8 emerged much before its cold sensing part.
By better understanding the evolution of such chemical sensors like TRPM8, it is possible to develop more effective and safer painkillers. These discoveries will help specifically target the chemical sensing part of the receptor without disturbing thermal sensation and regulation.
Some of the drugs targeting these receptors are already in the advanced testing stage. Thus, it is quite likely that in the near future, we may see the emergence of safer and more effective drugs for managing chronic pain.
Source:
Luu, D. D., Ramesh, N., Kazan, I. C., Shah, K. H., Lahiri, G., Mana, M. D., Ozkan, S. B., & Van Horn, W. D. (2024). Evidence that the cold- and menthol-sensing functions of the human TRPM8 channel evolved separately. Science Advances, 10(25), eadm9228. https://doi.org/10.1126/sciadv.adm9228