The glymphatic system in chronic pain: putative mechanisms and prospective therapeutic strategies

Chronic pain represents a widespread and substantial clinical burden, yet existing therapeutic approaches frequently yield suboptimal outcomes, partly due to an incomplete understanding of its underlying pathogenic mechanisms. The glymphatic system, a brain-wide network involved in cerebrospinal fluid circulation and metabolic waste clearance, has been observed to exhibit progressive dysfunction during the development and maintenance of chronic pain. The relationship between chronic pain and glymphatic dysfunction appears multifaceted and complex. This perspective review systematically synthesizes emerging evidence to summarize the potential bidirectional interplay between glymphatic dysfunction and chronic pain pathogenesis, with an emphasis on glymphatic dysfunction as a plausible contributing mediator across diverse pain conditions. We specifically address how neuroinflammation-associated glymphatic dysfunction may contribute to the progression of chronic pain, and conversely, how persistent pain may further amplify neuroinflammation, thereby potentially establishing a self-sustaining vicious cycle. Furthermore, we outline rationales for putative clinical interventions targeting this pathological cascade, with the goal of providing conceptual insights for the development of novel therapeutic strategies for chronic pain. Collectively, this review advances current understanding of the potential links between chronic pain and glymphatic dysfunction and presents an alternative conceptual framework for the future management of chronic pain.