The causal role of brain circuits in osteoarthritis pain

Osteoarthritis (OA) is a leading cause of chronic pain worldwide, resulting in substantial disability and placing a substantial burden on patients and society. The hallmark symptom of OA is joint pain. Despite extensive research, new treatments for OA pain remain limited, partly owing to a lack of understanding of underlying pain mechanisms. For a long time, OA pain was seen as a reflection of nociceptive activity at the joint level, and the brain has been viewed as a passive recipient of such information. In this Review, we challenge these concepts and discuss how, over time, the activation of peripheral nociceptors leads to adaptations in the brain that dictate the properties and experience of OA pain. These adaptations are further influenced by the inherent properties of the brain. We review general concepts that distinguish pain from nociception, present evidence on the incongruity between joint injury and experience of OA pain, and review brain circuits that are crucial in the perception of OA pain. Finally, we propose a model that integrates nociception, spinal-cord mechanisms, and central nervous system dynamics, each contributing uniquely to pain perception. This framework has the potential to inform the development of personalized treatment strategies.