Researchers have discovered a non-opioid compound that, in mice, effectively reduced the pain hypersensitivity associated with chronic and often debilitating nerve pain caused by diabetes or chemotherapy drugs. It’s opened the door to developing a drug to treat the condition for which existing painkillers do little.
Diabetes, chemotherapy drugs, multiple sclerosis, injuries and amputations have all been associated with neuropathic pain, usually caused by damage to nerves in various body tissues, including the skin, muscles and joints. Mechanical hypersensitivity – or mechanical allodynia – is a major symptom of neuropathic pain, where innocuous stimuli like light touch cause severe pain.
Many available pain medications aren’t effective in reducing this often-debilitating type of chronic pain. However, researchers at the University of Texas at Austin (UT Austin), in collaboration with UT Dallas and the University of Miami, may have advanced the treatment of neuropathic pain by discovering a molecule that reduces mechanical hypersensitivity in mice.
“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.”
The compound is FEM-1689, which binds to the sigma 2 receptor (σ2R), which was identified in 2017 as transmembrane protein 97 (TMEM97). The researchers had previously found that several small molecules that bind selectively to σ2R/TMEM97 produce strong and long-lasting anti-neuropathic pain effects in mice. FEM-1689, one such small molecule, was found to have improved selectivity for σ2R/TMEM97.
In the current study, the researchers used male and female mice with the Tmem97 gene knocked out and found that the pain-hypersensitivity-reducing effect of the FEM-1689 binding molecule was absent in mice without the gene. They also found that the compound inhibited the integrated stress response (ISR) in the animals’ neurons, a cellular signaling network that helps the body adapt to environmental stressors and pathological conditions and maintain health. Abnormal ISR signaling is associated with a range of diseases, including diabetes and metabolic disorders, neurodegeneration, and cancer. In lab experiments, the same inhibitory effect was seen in human neurons.
The findings suggest that targeting FEM-1689 and, by extension, σ2R/TMEM97 in pain patients could reduce mechanical hypersensitivity by inhibiting the ISR. Importantly, because FEM-1689 selectively binds to σ2R/TMEM97 and does not engage opioid receptors, it’s a potential alternative to existing pain medications linked to addiction.
“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.”
The study was published in the journal PNAS.
Source: UT Austin
