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Cross-talk between astrocytes and microglia plays an important role in neuroinflammation and central sensitization, but the manner in which glial cells interact remains less well-understood. Herein, we investigated the role of dual immunoglobulin domain-containing cell adhesion molecules (DICAM) in the glial cell interaction during neuroinflammation. DICAM knockout (KO) mice revealed enhanced nociceptive behaviors and glial cell activation of the tibia fracture with a cast immobilization model of complex regional pain syndrome (CRPS). DICAM was selectively secreted in reactive astrocytes, mainly via extracellular vesicles (EVs), and contributed to the regulation of neuroinflammation through the M2 polarization of microglia, which is dependent on the suppression of p38 MAPK signaling. In conclusion, DICAM secreted from reactive astrocytes through EVs was involved in the suppression of microglia activation and subsequent attenuation of neuroinflammation during central sensitization.