Non-opioid compound has potential to ease chronic nerve pain

Scientists identify FEM-1689 as effective painkiller in animal models

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Scientists at The University of Texas at Austin (UT Austin) have developed a novel non-opioid compound, called FEM-1689, that is able to reduce pain related to nerve damage in animal models.

Neuropathic pain, or pain caused by damage to nerves, is a common symptom of multiple sclerosis (MS) and many other conditions. Researchers think this new compound could be developed as a treatment option to control neuropathic pain — without the addictive properties of other painkillers.

“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,” Stephen Martin, PhD, a professor at UT Austin, said in a press release.

Though researchers had previously shown that FEM-1689 has pain-relieving effects, it wasn’t clear exactly how the compound worked. Now, the scientists have shown it works by modulating the activity of a protein called the sigma 2 receptor, also known as transmembrane protein 97 or TMEM97. Notably, the compound doesn’t interact with opioid receptors.

The findings were published in PNAS, in the study “Highly specific [sigma]2R/TMEM97 ligand FEM-1689 alleviates neuropathic pain and inhibits the integrated stress response.”

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“It’s our goal to make this compound into a drug that can be used to treat chronic pain without the dangers of opioids,” said Martin, a co-author on the study.

In a mouse model, the researchers showed FEM-1689 treatment was able to reduce pain caused by methylglyoxal, a metabolic byproduct thought to contribute to neuropathic pain in diabetes.

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

The scientists also showed pain-sensing nerve cells produce the TMEM97 protein. When mice were engineered to lack this protein, FEM-1689 no longer had pain-relieving effects, demonstrating the therapy’s effects on pain act via this protein.

“We conclude that these findings nominate … TMEM97 as a bonafide target for developing effective treatments for neuropathic pain,” the scientists wrote.

In further cell experiments, the researchers found that FEM-1689 binding to TMEM97 inhibits a cellular signaling pathway called the integrated stress response (ISR), which is triggered by compounds like methylglyoxal that cause neuropathic pain. The team noted further research will be required to understand in detail the molecular effects of modulating TMEM97 with FEM-1689 or other therapeutic candidates.

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The researchers have formed a spin-out company called NuvoNuro, which recently received a grant from the National Institutes of Health (NIH) as part of a program to combat the opioid crisis.

“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, PhD, professor at The University of Texas at Dallas and co-author of the study.

“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,” Price added.