A University of Alberta-led team has identified a new way to treat post-surgical pain in animals and human cells, in a bid to find non-addictive treatments for acute and even chronic pain.
In a recently published paper in the journal Anesthesiology, the researchers report they reduced pain-like behaviour in mice by chemically inhibiting a protein their previous research had identified within neuron cells in the peripheral nervous system.
The peripheral nervous system is a network of nerves that runs through the body carrying messages to and from the central nervous system.
The team also reported reduced sensory neuron excitability when they repeated the process in human sensory neurons in the lab.
"If you inhibit this protein and target it, you can take away the edge of that acute pain," says Bradley Kerr, professor and research director in the Department of Anesthesiology and Pain Medicine, and adjunct professor in the departments of Pharmacology and Physiology. "The next big question is, will it help with chronic pain states?"
The team targeted the protein endoplasmic reticulum oxidoreductin 1 (ERO1), which sends calcium as a fuel source to the mitochondria in the sensory neuron cells. When there's been an injury to the body, like a surgery, the ERO1 protein sends extra calcium to the neurons, making them even more pain sensitive. The researchers used an injectable drug called EN460 to interfere with that process.
"If you're a neuron and your job is to fire signals to your brain about pain and now you're getting fed a lot of calcium and you become hyperexcitable, you're going to start sending 10 or 20 messages instead of two or three, and your brain is going to interpret pain as being amplified and much greater," Kerr explains. "Our idea is that when you inhibit ERO1, you are dialling down the tap, so you're not feeding the mitochondria as much calcium and the energy activity of that cell is going to drop down."
Kerr, who is a specialist in chronic pain, says the effect of the treatment was seen within an hour.
"I've been doing pain research for almost 30 years, and this was pretty remarkable," he says. "These mice were pretty chilled out. The EN460 worked as well as an opioid."
The researchers look for changes in nociceptive reflexes in the mice, which are the immediate responses we all have to stimuli like injury or excessive heat even before the central nervous system (our spinal cord and brain) registers the pain and we say, "Ouch!"
"Our study shows that these very simple sensory neurons that are just detecting stimuli from the outside world and relaying messages are actually really critical in this process of pain," says Kerr. "If you stop the signal right at the source, you can profoundly affect how the pain experience unfolds. And of course, targeting those cells out in the periphery can often be quite a lot easier than it can be to get drugs into the brain."
Kerr brought together a multidisciplinary team of researchers to examine the potential of this treatment from different angles. The main driver behind the work was doctoral student Aislinn Maguire, who has now graduated. The original identification of ERO1 as a key protein came from Thomas Simmen, professor of cell biology. Anna Taylor and Harley Kurata, both associate professors of pharmacology, helped test whether EN460 has addictive properties (they found it doesn't) and whether it could work as an anesthetic at higher doses (it does).
Associates from Texas and West Virginia helped refine the drug and test it in human cells, demonstrating potential for the work to translate to humans.
"This project exemplifies science in 2025. It really was a village that came together," Kerr notes. "I don't think this paper would be in this top-tier prestigious journal without all of these elements that we brought together."
Kerr says the next step is to test it in mice that have chronic pain like that experienced by people with multiple sclerosis. And though the team is a long way from having a clinic-ready product, their ultimate goal is to find less harmful replacements, or at least supplements, for opioids as pain medications.
The research was funded by the Canadian Institutes of Health Research, and some of it was conducted in the Faculty of Medicine & Dentistry's Cell Imaging Facility. All U of A members of the research team are members of the Neuroscience and Mental Health Institute.