Irvine, Calif., Sept. 2, 2026 — Researchers at the University of California, Irvine, have identified a potential biological pathway that could explain why some injuries lead to chronic pain. The study, published in Science Translational Medicine, suggests that long-lasting pain may be preventable by targeting this pathway shortly after an injury occurs, rather than only managing pain after it has become established.
Chronic pain remains a significant challenge in medicine, with millions experiencing persistent pain even after an injury, such as a sprained back or surgical incision, has healed. The exact reasons why some injuries resolve while others progress to a lifelong condition have largely been unknown.
Led by Daniele Piomelli, a Distinguished Professor of anatomy and neurobiology at UCI, the research team used mice to investigate the transition from acute injury pain to chronic pain. Days after a tissue injury was induced in a hind paw, specific cells in the spinal cord, known as oligodendrocytes, began to change their behavior. Normally responsible for maintaining the fatty insulation around nerve fibers (myelin), these cells started reducing the production of this insulating material.
This cellular shift initiated a cascade of events. Adjacent nerve fibers began to lose their structural integrity, prompting neurons to produce amyloid precursor proteins. These proteins then generated beta-amyloid 42, which are sticky protein fragments notoriously associated with the plaques found in the brains of individuals with Alzheimer’s disease. Elevated levels of beta-amyloid appeared in the spinal cord of the mice precisely during the period when their pain transitioned from temporary to lasting.
The connection to amyloid biology was an unexpected discovery. Piomelli stated that the team was not initially searching for this link, but it emerged directly from the data. He noted that the pathway proved to be central to the development of chronic pain, observing, "When we blocked it, the chronic pain simply didn’t develop."
To confirm that beta-amyloid was a driving factor and not merely present, the researchers intervened in several distinct ways. They studied genetically engineered mice that lacked the amyloid precursor protein. They also employed an antibody designed to neutralize beta-amyloid. Furthermore, they used three different drugs and removed a gene that blocks amyloid precursor protein production. In every instance, preventing amyloid production during the crucial early period after injury successfully stopped the mice from developing the lasting hypersensitivity characteristic of chronic pain in this model. Crucially, their initial, acute response to the injury remained unaffected.
The team also pinpointed an upstream activator: an enzyme called N-acylethanolamine acid amidase. This enzyme becomes active in oligodendrocytes following an injury. Mice bred without this specific enzyme in these cells did not experience the rise in beta-amyloid and consequently did not develop chronic pain. This finding was further confirmed in a separate model of nerve injury, indicating that the mechanism is not unique to a single animal model.
Piomelli emphasized the significance of these findings, stating that the research provides a mechanistic explanation for the timing of the transition to chronic pain and offers a clear target for intervention. He highlighted that the goal is to intervene while the process is still reversible, rather than treating pain only after it has become chronic.
If these findings translate to humans, the implications for pain treatment could be substantial. Current pain management strategies primarily address chronic pain once it is already established. This new research suggests a different approach: identifying and treating the specific biological process during a brief post-injury window, potentially preventing chronic pain from developing at all. The study also raises questions about whether chronic pain and neurodegenerative diseases share more biological commonalities than previously thought, noting that the mice developed spinal deposits resembling Alzheimer’s-related plaques months after injury.
The next phase of research, according to Piomelli, will involve determining if this same pathway is active in humans and whether it can be safely targeted. He cautioned that existing drugs for Alzheimer’s or those targeting amyloid should not be used off-label for pain. The research received support from the National Institute on Aging and the National Institute of Diabetes and Digestive and Kidney Diseases.
