Researchers at the University of California, Irvine have uncovered a potential biological mechanism that may explain why some injuries lead to chronic pain, offering a new direction for preventative treatments. The study, led by Daniele Piomelli, Distinguished Professor of anatomy and neurobiology, points to a connection with the same amyloid biology typically associated with Alzheimer’s disease.
Chronic pain remains a persistent challenge in medicine, often developing even after an initial injury, such as a sprained back or surgical incision, has healed. The reasons behind this transition from temporary discomfort to a lifelong condition have largely been unclear.
The UCI team’s research, published in Science Translational Medicine, suggests that this shift to chronic pain might be driven by a distinct biological process that begins soon after an injury occurs. Their work utilized mice to trace how an injury triggers a series of reactions within the spinal cord.
Days after an injection designed to mimic tissue injury in a hind paw, cells called oligodendrocytes in the spinal cord began to change their behavior. These cells normally maintain the fatty insulation around nerve fibers, known as myelin, but post-injury, they reduced the production of this insulating material. Subsequently, nearby nerve fibers started to lose their structural integrity. In response, neurons began to produce amyloid precursor proteins, which generate beta-amyloid 42, the sticky protein fragments known for forming plaques in Alzheimer's-affected brains. This elevated beta-amyloid appeared in the spinal cord precisely when the pain in the mice was transitioning from acute to a lasting condition.
Piomelli noted the unexpected nature of the discovery, stating, "We were not looking for a connection to amyloid biology; it emerged from following the data." He emphasized the pathway's critical role, adding, "When we blocked it, the chronic pain simply didn't develop."
To confirm that beta-amyloid was a driving factor rather than merely a co-occurring phenomenon, the researchers used several independent interventions. They studied genetically engineered mice that lacked the amyloid precursor protein. They also tested an antibody designed to neutralize beta-amyloid. Further experiments involved the use of three different chemical drugs and the removal of a gene that blocks amyloid precursor protein production. In each instance, preventing amyloid production during the crucial early period after injury successfully stopped the mice from developing the lasting, centrally driven hypersensitivity characteristic of chronic pain. Importantly, their initial, acute response to the injury remained intact.
The team also identified an upstream cause: an enzyme named N-acylethanolamine acid amidase (NAAA). This enzyme becomes active in oligodendrocytes following injury. Mice specifically bred without 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 robust across different injury types.
Piomelli highlighted the practical implications, stating, "This gives us a mechanistic explanation for why the transition to chronic pain happens when it does and a real handle on how to intervene." If these findings are replicated in humans, they could significantly change how pain is treated. Most current pain therapies focus on managing chronic pain after it has already taken hold. This research suggests a new approach: intervening during a brief post-injury window to potentially prevent chronic pain from developing at all. The study also raises questions about possible shared biological mechanisms between chronic pain and neurodegenerative diseases, particularly as the mice developed spinal deposits resembling Alzheimer’s-related plaques months after injury.
The next steps for the research include investigating whether this same pathway is active in humans and if it can be safely targeted for therapeutic purposes. Piomelli cautioned that existing drugs for Alzheimer’s disease or those targeting amyloid should not be used off-label for pain treatment.
The research received support from the National Institute on Aging and the National Institute of Diabetes and Digestive and Kidney Diseases. The University of California, Irvine, a prominent research institution in the city and Orange County's second-largest employer, continues to contribute to local and global scientific advancements, impacting the community through its research and economic presence.
