CD200/CD200R1 activation alleviates central sensitization in chronic migraine via STAT6.

Abstract

ObjectiveChronic migraine (CM) is characterized by central sensitization (CS), in which microglial activation plays a key role. The neuron-glia communication axis CD200/CD200R1 is a critical immunomodulatory pathway. This study investigated whether and how CD200/CD200R1 signaling modulates CS in a CM model.MethodsA CM mouse model was established by repeated nitroglycerin (NTG) injections. Pain thresholds were assessed. Protein expression in the trigeminal nucleus caudalis (TNC) was analyzed. The role of STAT6 was examined using inhibitor AS1517499.ResultsNTG treatment induced sustained hyperalgesia and downregulated CD200 and CD200R1 expression in the TNC. Administration of the CD200R1 agonist CD200Fc reversed pain hypersensitivity, suppressed the overexpression of CGRP and c-Fos, and reduced pro-inflammatory cytokines. CD200Fc promoted STAT6 phosphorylation and increased expression of anti-inflammatory markers (Arg-1, YM-1, YM-2). Inhibition of STAT6 phosphorylation abolished the therapeutic effects of CD200Fc on pain biomarkers without altering CD200R1 expression.ConclusionOur findings demonstrate that enhancing the CD200/CD200R1 pathway alleviates central sensitization and pain hypersensitivity in CM, likely by promoting an anti-inflammatory microglial phenotype via STAT6 phosphorylation. The CD200/CD200R1/STAT6 axis represents a novel therapeutic target for chronic migraine.