Irvine, Calif., Sept. 2, 2026 — Researchers at the University of California, Irvine have identified a biological pathway that may drive the development of chronic pain, drawing an unexpected connection to the amyloid biology long associated with Alzheimer’s disease. The study, published in Science Translational Medicine, indicates that chronic pain might stem from a distinct biological process that initiates shortly after an injury.
Traditionally, the reasons why some injuries lead to lifelong pain while others fully heal have been largely unknown. The UCI research suggests that future treatments might focus on preventing pain from becoming chronic, rather than only managing it once it is established.
Led by Daniele Piomelli, Distinguished Professor of anatomy and neurobiology at UCI, the research team used mice to investigate how an injury triggers a sequence of events in the spinal cord. Days after a hind paw injection, which was designed to simulate tissue injury, certain cells known as oligodendrocytes began to behave abnormally. These cells typically maintain the fatty insulation around nerve fibers, called myelin. However, they started to reduce the production machinery for this insulating material.
This cellular shift led to nearby nerve fibers losing structural integrity. In response, neurons began to produce amyloid precursor proteins, which in turn generated beta-amyloid 42. These protein fragments are notable for forming the plaques found in the brains of individuals affected by Alzheimer’s disease. In the mice studied, an increase in beta-amyloid was observed in the spinal cord precisely during the period when the pain transitioned from a temporary state to a lasting condition.
Professor Piomelli stated that the team was not initially looking for a link to amyloid biology, but that this connection emerged directly from the data. He expressed surprise at the centrality of this pathway, noting that it was not merely present alongside chronic pain. Piomelli added, “When we blocked it, the chronic pain simply didn’t develop.”
To determine if beta-amyloid was directly causing chronic pain or merely present during its onset, the researchers conducted several independent interventions. They utilized genetically engineered mice that lacked the amyloid precursor protein and employed an antibody designed to neutralize beta-amyloid. Other methods included using three chemically distinct drugs or removing a gene that blocks amyloid precursor protein production. In each instance, preventing amyloid production during the crucial early window after injury stopped the mice from developing the lasting, centrally driven hypersensitivity characteristic of chronic pain in this model. Their initial, acute response to the injury remained unaffected.
The research team also identified an upstream cause: an enzyme called N-acylethanolamine acid amidase. This enzyme becomes active in oligodendrocytes following an injury. Mice bred to specifically lack this enzyme in these cells were protected from the increase in beta-amyloid and 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.
According to Piomelli, these findings provide a mechanistic explanation for why the transition to chronic pain occurs when it does and offers a clear approach for intervention. He emphasized that the objective is not just to treat pain after it becomes chronic but to intervene during a phase when the process is still reversible.
If these findings are validated in humans, the implications could be substantial. Nearly all current pain treatments address pain after it has become chronic. This new research points to a different strategy: identifying and treating the biological process during a brief window after an injury, potentially preventing chronic pain from ever taking hold. It also raises intriguing questions about whether chronic pain and neurodegenerative diseases share more biological commonalities than previously thought. Months after injury, the mice in the study developed spinal deposits that resembled Alzheimer’s-related plaques.
Piomelli indicated that the next steps involve investigating whether this same pathway functions in humans and if it can be safely targeted. He also cautioned against using existing Alzheimer’s or amyloid-targeting drugs off-label for pain. The research was supported by grants from the National Institute on Aging and the National Institute of Diabetes and Digestive and Kidney Diseases.
Founded in 1965, UC Irvine is a member of the Association of American Universities and is ranked among the nation’s top public universities. The campus is recognized for its academic achievements, premier research, and innovation, contributing significantly to the local economy as Orange County’s second-largest employer.
