Prostaglandin Signaling and Matrix Dysfunction in Chronic Pain: The Role of Fibrin Persistence and Fibrotic Remodeling

Chronic pain disorders are commonly explained through inflammatory and nociceptive signaling pathways, with therapeutic strategies largely directed toward cytokine suppression and prostaglandin inhibition. Prostaglandins, generated from arachidonic acid via cyclooxygenase pathways, are key mediators of acute inflammatory nociception and remain an important therapeutic target; however, symptomatic improvement does not consistently restore tissue function or prevent progression to stiffness, fibrosis, and persistent movement-related pain. Increasing evidence suggests that chronic pain may involve structural alterations within the tissue microenvironment in addition to biochemical mediators. Persistent fibrin deposition, impaired fibrinolytic activity, microcirculatory compromise, and maladaptive extracellular matrix remodeling have been implicated in the progression of tissue stiffening and altered Mechan transduction. These structural abnormalities may increase interstitial pressure, disrupt tissue compliance, and sustain nociceptor activation, thereby shifting pain from a predominantly inflammatory phenomenon to a mechanically driven pathology. In parallel, prolonged peripheral matrix dysfunction may promote sustained afferent input, neuroimmune activation, and central sensitization, contributing to fatigue and cognitive dysfunction. This review synthesizes current evidence linking prostaglandin-mediated nociceptive pathways with fibrin persistence and extracellular matrix dysregulation in chronic pain and fibrosis, and proposes a matrix-centric framework to guide therapeutic strategies aimed at restoring tissue microarchitecture, microcirculatory health, and long-term functional recovery.