New research at Arizona State University examines the evolution and function of the TRPM8 protein, with the goal of developing non-addictive painkillers that avoid side effects of temperature regulation, potentially revolutionizing the treatment of chronic pain.
The detection of menthol predates the sensation of cold, suggesting separate activation mechanisms that can be distinguished. This differentiation opens up possibilities for new pain treatments that avoid unwanted thermal side effects.
Millions of people around the world suffer from chronic pain, and many existing treatments rely on opioids, which carry significant addiction and overdose risks. Developing non-addictive options for pain relief can transform the way pain is treated. Recent research focused on a human protein that controls cold sensations is paving the way for new painkillers. These innovative medications aim to manage pain without altering body temperature or posing addiction risks.
A new study published June 21 in the journal Scientific progress, led by Wade Van Horn, professor at Arizona State University’s School of Molecular Sciences and Biodesign Center for Personalized Diagnostics, has uncovered new insights into the key human cold and menthol sensor TRPM8 (transient receptor potential melastatin 8). Using techniques from many fields, such as biochemistry and biophysics, their research revealed that it was a chemical sensor before it became a cold temperature sensor.
The team used reconstruction of ancestral sequences to study ancient TRPM8 proteins, offering new opportunities for pain relief without adverse effects seen with previous TRPM8-targeted treatments. This research illustrates how evolutionary biology and modern pharmacology can work together to improve the management of chronic pain. Credit: ASU/Wade Van Horn
“If we can start to understand how to decouple the chemical perception of cold from actual cold perception, we could theoretically make drugs without side effects,” says Van Horn, whose research focuses on membrane proteins 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 painkillers.”
The role of TRPM8 in pain
When a person touches a metal desk and it feels cold, the human body activates TRPM8. For cancer patients taking certain types of chemotherapy drugs, touching a desk can hurt. TRPM8 is also involved in many other types of pain, including chronic neuropathic and inflammatory pain.
By better understanding this specificity of the chemical detection of cold versus the physical detection of cold, scientists can achieve relief without causing the temperature regulation side effects often seen in TRPM8 clinical trials for pain treatments.
In the study, the team used ancestral sequence reconstruction, a time machine for all kinds of proteins, and pieced together the family tree of TRPM8 that exists today. The team then used that information to determine what the 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 uncovered new insights into the key human cold and menthol sensor TRPM8 (transient receptor potential). melastatin 8). Credit: ASU/David Rozul
Using computational methods to revive ancestral primate, mammal 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 match the sequences of their ancient ancestors. to predict. Furthermore, the combination of laboratory experiments and computational studies allows the researchers to identify critical places in TRPM8 that allow a clearer understanding of temperature measurement, which can be tested in subsequent experiments.
“Comparative dynamics analysis of ancestral and human TRPM8 also supports the experimental data and will allow us to identify critical locations in temperature measurement, which we will test soon,” said Banu Ozkan, professor in ASU’s Department of Physics, who 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.
“Ancestral protein-based studies allow us to focus on the lineage of most interest, such as human TRPM8, to alleviate concerns in drug discovery arising from speciation differences, such as in mice and humans,” says first author of the study Dustin Luu, a Doctoral alumnus of the ASU School of Molecular Sciences and current postdoctoral researcher at ASU’s Biodesign Center for Personalized Diagnostics.
Luu continued: “We found that surprisingly, the menthol perception appeared long before the cold perception. The difference in appearance and attenuation of these activation modes suggests that they are separate and can be disentangled with further research that could enable new pain therapies without the adverse side effects in thermal sensing and thermal regulation that have plagued TRPM8-targeted clinical trials.
As science continues to uncover the mysteries of our biological mechanisms, studies like these illustrate how evolutionary biology and modern pharmacology can work together to address urgent medical needs and improve the quality of life for people suffering 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, Scientific progress.
DOI: 10.1126/sciadv.adm9228