Neuroimmune Interactions in Chronic Pain and Neuroinflammation: Peripheral Nerve Injury, Neuroimmune Mechanisms, and Therapeutic Recovery

The pathogenesis of chronic pain includes persistent neuroimmune interactions that contribute to both peripheral and central pain sensitization. Tissue injury and peripheral nerve injury activate immune and glial pathways through various cytokines, chemokines, complement, damage-associated molecular patterns (DAMPs), and neuroimmune feedback loops involving nociceptors, macrophages, mast cells, microglia, and astrocytes. This review examines the mechanisms by which these interactions contribute to persistent nerve injury, neuroinflammation, and the transition from acute injury to chronic pain. Biomarkers and their molecular targets may improve identification of the different pain mechanisms involved while also supporting immune-based therapeutic strategies, although their clinical utility and consistency remain limited. Current and new immune-based therapies that target cytokine signaling, glial activation, complement pathways, neurotrophic factors, and inflammatory resolution mechanisms have demonstrated promising effects in preclinical studies. Resolution of neuroinflammation also involves immune regulation, cellular reprogramming, and peripheral nerve regeneration. There is a unique role for neuroimmune signaling in chronic pain, and the current literature suggests that targeting persistent inflammatory pathways promotes resolution and nerve repair. Overall, this review aims to highlight the potential approaches for recovery and the role inflammation plays in chronic pain states.