Researchers discover non-opioid therapeutic for relieving neuropathic pain

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Among the most difficult types of pain to alleviate is neuropathic pain, pain that is usually caused by damage to nerves in various body tissues, including skin, muscle and joints. It can cause patients to suffer feelings like electric shocks, tingling, burning or stabbing. Diabetes, multiple sclerosis, chemotherapy drugs, injuries and amputations have all been associated with neuropathic pain, which is often chronic, sometimes unrelenting and affects millions of people worldwide. Many of the available pain medications are only moderately effective at treating this type of pain and often come with serious side effects, as well as risk of addiction.

Now researchers at UT Austin, The University of Texas at Dallas and the University of Miami have identified a molecule that reduces hypersensitivity in trials in mice by binding to a protein they have shown is involved in neuropathic pain. 

The findings appear in the journal Proceedings of the National Academy of Sciences

We found it to be an effective painkiller, and the effects were rather long-lived. When we tested it on different models, diabetic neuropathy and chemotherapy-induced neuropathy, for example, we found this compound has an incredible beneficial effect."

Stephen Martin, the June and J. Virgil Waggoner Regents Chair in Chemistry at The University of Texas at Austin and co-corresponding author of the paper

The new compound, dubbed FEM-1689, does not engage opioid receptors in the body, making it a possible alternative to existing pain medications linked to addiction. In addition to reducing sensitivity, the compound can help regulate the integrated stress response (ISR), a network of cellular signaling that helps the body respond to injuries and diseases. When well regulated, the ISR restores balance and promotes healing. When it goes awry, the ISR can contribute to diseases such as cancer, diabetes and metabolic disorders.

"It's our goal to make this compound into a drug that can be used to treat chronic pain without the dangers of opioids," Martin said. "Neuropathic pain is often a debilitating condition that can affect people their entire lives, and we need a treatment that is well tolerated and effective."

NuvoNuro Inc., a company co-founded by Martin and other authors on the paper, was recently awarded a grant from the National Institutes of Health HEAL Initiative, which funds research to find scientific solutions to the national opioid crisis, to create a drug based on their findings.

"This work is the culmination of a wonderful five-year collaboration with our colleagues at UT Austin and is a great example of academic drug discovery pushing the field of non-opioid pain therapeutics forward," said Theodore Price, a professor of neuroscience at The University of Texas at Dallas and co-corresponding author of the paper. "Our funding from NIH on this continuing project through our spin-out company, NuvoNuro, has the potential to take us toward clinical development in the next few years, which is extraordinarily exciting."

Muhammad Saad Yousuf, Eric T. David, Stephanie Shiers, Marisol Mancilla Moreno, Jonathan Iketem, Danielle M. Royer, Chelsea D. Garcia, Jennifer Zhang, Veronica M. Hong, Subhaan M. Mian, Ayesha Ahmad and Benedict J. Kolber of The University of Texas at Dallas; James J. Sahn and Hongfen Yang of UT Austin; and Daniel J. Liebl of University of Miami Miller School of Medicine were also authors on the paper.

The research was funded by the National Institutes of Health, Natural Sciences and Engineering Research Council of Canada and the Robert A. Welch Foundation.

Source:
Journal reference:

Muhammad Saad Yousuf, M. S., et al. (2023). Highly specific σ 2 R/TMEM97 ligand FEM-1689 alleviates neuropathic pain and inhibits the integrated stress response. Proceedings of the National Academy of Sciences. doi.org/10.1073/pnas.2306090120.

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