Scientists at three American universities have identified a compound that sharply reduced nerve pain hypersensitivity in mice — without touching the opioid receptors that make existing painkillers so dangerous. The discovery opens a potential new path for treating neuropathic pain, a chronic condition that affects millions of people and resists most available drugs.
At a glance
- Non-opioid compound: FEM-1689 binds selectively to a receptor called σ2R/TMEM97 and does not engage opioid receptors, making addiction a far smaller concern than with current pain medications.
- Nerve pain relief: In mouse models of both diabetic neuropathy and chemotherapy-induced neuropathy, FEM-1689 produced strong, long-lasting reductions in mechanical hypersensitivity — the symptom where even light touch causes severe pain.
- Integrated stress response: The compound worked by inhibiting a cellular signaling network called the integrated stress response in neurons, and the same inhibitory effect was observed in human neurons tested in the lab.
Why neuropathic pain is so hard to treat
Neuropathic pain arises from damage to nerves in the skin, muscles, joints, and other tissues. Diabetes, chemotherapy drugs, multiple sclerosis, injuries, and amputations can all trigger it. The result is often mechanical allodynia — a state where innocuous sensations like a gentle brush against the skin register as acute pain.
Most available painkillers do little for this type of chronic pain. Opioids carry serious risks of dependence and overdose. Anti-seizure drugs and antidepressants used off-label provide partial relief for some patients but leave many others without good options. For people living with diabetic or chemotherapy-induced neuropathy, the pain can persist for years or an entire lifetime.
What the researchers found
The team — from the University of Texas at Austin, UT Dallas, and the University of Miami — focused on the sigma 2 receptor (σ2R), which was identified in 2017 C.E. as the transmembrane protein TMEM97. Earlier work by the group had shown that small molecules binding selectively to σ2R/TMEM97 could produce strong anti-neuropathic pain effects in mice. FEM-1689 is one such molecule, and it showed improved selectivity for the receptor.
To confirm the mechanism, the researchers used mice with the Tmem97 gene knocked out. In those animals, FEM-1689 had no pain-reducing effect — direct evidence that the compound works through that specific target. They also found it inhibited the integrated stress response (ISR) in neurons, a signaling network the body uses to adapt to stressors. Abnormal ISR activity is linked to diabetes, neurodegeneration, and cancer. The same inhibitory effect appeared when the team tested the compound in human neurons in the lab.
“We found it to be an effective painkiller, and the effects were rather long-lived,” said Stephen Martin, a co-corresponding author of the study. “When we tested it on different models, diabetic neuropathy and chemotherapy-induced neuropathy, for example, we found this compound has an incredible beneficial effect.”
A non-opioid path forward
Because FEM-1689 binds selectively to σ2R/TMEM97 and does not engage opioid receptors, it sidesteps the addiction risk that shadows most strong pain medications. That selectivity is exactly what researchers in this space have been looking for. This work is part of a wider wave of public health wins in pain management and disease treatment that are moving medicine away from dependence-forming drugs.
The team’s goal is to develop FEM-1689 into a clinical drug. “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,” Martin said. “It’s our goal to make this compound into a drug that can be used to treat chronic pain without the dangers of opioids.”
The findings were published in the journal PNAS (Proceedings of the National Academy of Sciences). The research adds to a growing set of non-opioid approaches moving through early development — including the FDA’s 2024 C.E. approval of suzetrigine, the first new class of pain drug in over two decades, which works by blocking a specific sodium channel in pain-sensing nerves.
What still needs to happen
All the results so far come from mouse models and lab experiments on human neurons — not from human clinical trials. The path from a promising compound to an approved drug is long, expensive, and often fails. Many molecules that work in mice do not survive the translation to human patients, and it is not yet known whether FEM-1689 is safe or effective in people.
Still, the mechanistic clarity here is notable. Identifying the precise receptor, confirming the knockout-mouse result, and observing the same cellular effect in human neurons gives researchers a solid target to work toward. That kind of early rigor tends to make the development path cleaner, even if it does not guarantee success.
Neuropathic pain affects an estimated one in 10 adults in the U.S. and is among the most undertreated pain conditions in medicine. For the many patients whose pain does not respond to existing drugs, a non-opioid option built on a well-understood mechanism would be a meaningful advance. This research, conducted at three University of Texas system institutions and the University of Miami, puts that possibility on firmer ground.
Read more
For more on this story, see: New Atlas
For more from Good News for Humankind, see:
- FDA approves first non-opioid pain drug in over 20 years
- New bone cancer drug from University of East Anglia shows early promise
- The Good News for Humankind archive on global health
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