New research at Arizona State University explores the evolution and function of the TRPM8 protein, with the goal of developing non-addictive pain medications that avoid the side effects of temperature regulation, potentially revolutionizing the treatment of chronic pain.
The detection of menthol precedes the sensation of cold, indicating distinct activation mechanisms that can be distinguished. This differentiation opens up opportunities for new pain treatments that avoid unwanted thermal side effects.
Millions of people around the globe suffer from chronic pain, and many existing treatments rely on opioids, which have significant risks of addiction and overdose. The development of non-addictive pain relief options could transform the way pain is managed. Recent research focusing on a human protein that controls cold sensations is paving the way for new painkillers. These innovative drugs aim to manage pain without altering body temperature or posing addictive risks.
A new study published June 21 in the journal Advances in science, led by Wade Van Horn, professor at Arizona State University’s School of Molecular Sciences and Biodesign Center for Personalized Diagnostics, has revealed new insights into the key human cold and menthol sensor TRPM8 (transient receptor potential melastat 8 ). Using techniques from many fields such as biochemistry and biophysics, their study revealed that it was a chemical sensor before it became a cold temperature sensor.
The team used the reconstruction of the ancestral sequence to study the ancient TRPM8 protein, providing new avenues for pain relief without the adverse effects seen in previous TRPM8-targeted treatments. This research illustrates how evolutionary biology and modern pharmacology can collaborate to improve the management of chronic pain. Credit: ASU/ Wade Van Horn
“If we can start to understand how to dissociate the chemical sensation of cold from the actual sensation of cold, in theory, we could make drugs without side effects,” said Van Horn, whose research focuses on membrane proteins of involved in human health and disease. “By understanding the evolutionary history of TRPM8, we hope to contribute to the design of better drugs that provide relief without the dangerous side effects associated with current pain relievers.”
The role of TRPM8 in pain
When a person touches a metal table and feels cold, the human body activates TRPM8. For cancer patients receiving certain types of chemotherapy, touching a table can hurt. TRPM8 is also involved in many other types of pain, including chronic neuropathic and inflammatory pain.
By further understanding this specificity of the chemical sensation of cold versus the physical sensation of cold, scientists can target relief without causing the side effects of temperature regulation often seen in TRPM8 clinical trials for pain treatments.
In the research, the team used ancestral sequence reconstruction, a time machine for diverse proteins, to compile the TRPM8 family tree that exists today and then used that information to determine what proteins from long-extinct animals might have looked like.
Research published in Science Advances on June 21, led by Wade Van Horn, professor at Arizona State University’s School of Molecular Sciences and Biodesign Center for Personalized Diagnostics (center) has revealed new insights into the key cold sensor and menthol TRPM8 (transient receptor potential). melastatin 8). Credit: ASU/David Rozul
Using computational methods to reconstruct primate, mammalian and vertebrate TRPM8, the researchers were able to understand how TRPM8 has changed over hundreds of millions of years by comparing the sequences of current proteins to predict the sequences of their ancient ancestors. Furthermore, the combination of laboratory experiments and computational studies enables the researchers to identify critical sites in TRPM8 that allow a clearer understanding of temperature sensitivity, which can be tested in subsequent experiments.
“Comparative analysis of ancestral and human TRPM8 dynamics also supports experimental data and will allow us to identify critical sites in temperature sensing, which we will soon test,” said Banu Ozkan, professor in the Department of Physics at ASU, which was involved in the study.
Advances in ancestral protein studies
The team then expressed these ancestral TRPM8s in human cells and characterized them using various cellular and electrophysiological techniques.
Ion channel in cell membrane, 3D illustration.
“Studies based on ancestral proteins allow us to focus on the larger lineage of interest, such as human TRPM8, to alleviate concerns that arise in drug discovery from species differences, such as in mice and humans,” said the first author. of study, Dustin Luu, a. PhD graduate of ASU’s School of Molecular Sciences and current PhD student at ASU’s Biodesign Center for Personalized Diagnostics.
Luu continued: “We found that surprisingly the sensation of menthol appeared well before the sensation of cold. The difference in appearance and attenuation of these activation modes suggests that they are separate and can be dissociated with further research enabling new pain therapies without the negative side effect on thermal sensitivity and thermal regulation that has plagued clinical trials aimed at TRPM8.
As science continues to unravel the mysteries of our biological mechanisms, studies like these show how evolutionary biology and modern pharmacology can collaborate to address urgent medical needs and improve the quality of life for those who suffer from chronic pain.
Reference: “Evidence that the cold and menthol sensing functions of the human TRPM8 channel evolved separately” by Dustin D. Luu, Nikhil Ramesh, I. Can Kazan, Karan H. Shah, Gourab Lahiri, Miyeko D. Mana, S. Banu Ozkan and Wade D. Van Horn, June 21, 2024, Advances in science.
DOI: 10.1126/sciadv.adm9228