Chronic pain affects more than 50 million people in the U.S.as well as worldwide. For decades treatment options for pain that persists in the absence of inflammation have been limited. Seventy-five percent of these patients, disproportionately women, experience pain that is inadequately managed by current therapeutics.
To address this, scientists at Virginia Tech have found a way to switch it off in female mice by blocking a single pathway using compounds developed at the National Institutes of Health’s National Center for Advancing Translational Sciences.
In a new study neuroscientist Ann Gregus erased well-established pain behaviours by shutting down an enzyme system that produces molecules known to amplify pain signals. This finding could open the door to the first new class of non-opioid chronic pain treatments in years.
This is a potential lifeline for patients whose symptoms defy standard drugs.
“Earlier studies have focused largely on preventing development of pain — so the key finding here is the reversal of an established pain state and associated functional deficits, which more closely mimics the human experience,” explains Gregus.
She adds: “It provides hope for people living with daily, persistent pain that does not respond to conventional treatments.”
A stubborn pain type — and a new target
The study focused on nociplastic pain, a poorly understood category that includes fibromyalgia, chronic low back pain, and some migraines. Unlike pain caused by injury or ongoing inflammation, nociplastic pain arises from changes in how the nervous system processes signals, often leaving no visible damage to treat.
These conditions are resistant to treatments such as nonsteroidal anti-inflammatory drugs (NSAIDs) and are only partially relieved by anticonvulsants and antidepressants. Opioids are a last resort and generally are avoided due to risks of dependence and addiction. While NSAIDs block certain inflammatory pathways, the Gregus lab’s approach targets a different biochemical route that those drugs leave untouched.
“Chronic pain patients are often told pain is all in their heads and they just have to learn how to tolerate it,” Gregus clarifies. “But what we’re showing is that there is a clear biological mechanism — and one we can target.”
Switching off pain after it’s entrenched
To mimic nociplastic pain, the researchers used an immune challenge that activates this receptor and ramps up pain pathways in the spinal cord. Once the mice developed clear pain behaviors, they treated them with highly selective compounds that block parts of the enzyme system.
The results were successful: tissue analysis confirmed that the immune challenge had ramped up production of pain-driving molecules, but upon treatment administration, tactile and cold pain hypersensitivity vanished, and grip strength returned. Administering those molecules alone also reproduced the pain state, confirming their role.
One of the compounds tested is currently in Phase II clinical trials for another disease by Veralox Therapeutics. Because it already has human safety data, it could shorten the path to clinical trials for chronic pain.
The next step is to see whether the same enzyme-blocking strategy works in models that mirror the complexity of human disease: for example, conditions such as chemotherapy-induced peripheral neuropathy, which can linger for years after cancer treatment, and diabetic neuropathy, a leading cause of disability worldwide.
A therapy that could block and reverse the underlying cause — rather than simply mask symptoms — would mark a rare breakthrough in chronic pain care. For Gregus, that potential makes the path forward clear: translate the discovery into a treatment that delivers what patients almost never get — lasting relief.
The research appears in the science journal Pain, titled “12/15-lipoxygenases mediate toll-like receptor 4-dependent nociplastic pain hypersensitivity in female mice.”
