The only available treatments for millions of people with chronic pain worldwide frequently involve the use of opioids, which pose the risk of addiction and overdose. Scientists are getting closer to creating painkillers that do not alter body temperature or, perhaps more importantly, carry the risk of addiction using new research that focuses on the human protein that controls cold sensations.
New information about the primary human cold and menthol sensor, transient receptor potential melastatin 8(TRPM8), has been gleaned from research led by Wade Van Horn, an Associate Professor in Arizona State University's School of Molecular Sciences and Biodesign Center for Personalized Diagnostics, and published in Science Advances.
The researchers used techniques from various fields, such as biochemistry and biophysics, to uncover that it functioned initially as a chemical sensor before evolving into a cold temperature sensor.
If we can start to understand how to decouple the chemical sensing of cold from actual cold sensing, in theory, we could make side-effect-free drugs. By understanding the evolutionary history of TRPM8, we hope to contribute to designing better drugs that offer relief without the dangerous side effects associated with current painkillers.”
Van Horn, Associate Professor, School of Molecular Sciences and Biodesign Center for Personalized Diagnostics, Arizona State University
Van Horn’s research focuses on membrane proteins involved in human health and disease.
The human body triggers TRPM8 in response to cold metal desk touches. Touching a desk can be painful for cancer patients receiving certain types of chemotherapy. Numerous other forms of pain, such as inflammatory and chronic neuropathic pain, are also associated with TRPM8.
By gaining more insight into the distinction between chemical and physical cold sensing, researchers can focus on pain relief without inadvertently causing the temperature regulation adverse effects that are frequently observed in TRPM8 clinical trials.
The research team employed ancestral sequence reconstruction - a protein-based time machine. The team used the information gathered to compile the TRPM8 family tree currently in existence to speculate about the possible composition of proteins from long-extinct animals.
By comparing the sequences of current proteins to those of their ancient ancestors, the researchers could comprehend how TRPM8 has evolved over hundreds of millions of years through computational methods to resurrect ancestral primate, mammalian, and vertebrate TRPM8.
Furthermore, the researchers are able to pinpoint crucial locations in TRPM8 that provide a clearer understanding of temperature sensing and can be tested in further experiments using the combination of computational studies and lab experiments.
Comparative dynamics analysis of ancestral and human TRPM8 also supports the experimental data and will allow us to identify critical sites in temperature sensing, which we will be testing soon.”
Banu Ozkan, Professor, Department of Physics, Arizona State University
Subsequently, the group produced these progenitor TRPM8s in human cells and employed diverse cellular and electrophysiological methodologies to describe them.
Ancestral protein-based studies allow us to focus on the lineage of most interest, such as human TRPM8, to alleviate concerns arising in drug discovery from speciation differences, like in mice and humans.”
Dustin Luu, Postdoctoral Fellow, Biodesign Center for Personalized Diagnostics, Arizona State University
Dustin Luu is an ASU School of Molecular Sciences doctoral alumnus.
Luu added, “We discovered that, surprisingly, menthol sensing appeared way before cold sensing. The difference in appearance and attenuation of these activation modes suggest they are separate and can be disentangled with further research enabling new pain therapies without the adverse side effect in thermal sensing and thermal regulation, which has plagued TRPM8-targeted clinical trials.”
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