The function of chemokine-driven glial-neuronal interaction in chronic pain

Chronic pain affects hundreds of millions worldwide, yet current treatments—from NSAIDs to opioids—fall short and bring unwanted side effects. Neuroinflammation drives bidirectional glial-neuronal communication, a core mechanism underlying central sensitization in chronic pain, with chemokines serving as key mediators. Most studies to date have zeroed in on isolated pathways or specific anatomical sites, missing the bigger picture. We pull together findings across the neural axis, spanning peripheral sensory ganglia, the spinal dorsal horn, and higher brain centers, then dissect the molecular machinery of chemokine-mediated crosstalk among microglia, astrocytes, and neurons. We trace downstream regulatory cascades through two major axes—CCL2/CCR2 and CX3CL1/CX3CR1—along with their effector branches (ERK-GluN2B, p38 MAPK-NF-κB), map out polarization phenotypes (M1/M2 for microglia, A1/A2 for astrocytes), and detail the functional shifts glia undergo in disease states. By knitting scattered observations into a unified regulatory map of chemokine signaling across the chronic pain neural network, this review addresses the field’s persistent lack of systematic integration.