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Peer-reviewedCC BY-NC 4.0Molecular Pain

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

  • ZiChao Li1
  • Dan Li2
  • ZhenZhen Fan1
  • HongBin Cai1
  • ZhaoMing Ge1
  1. 1Department of Neurology, Lanzhou University Second Hospital, Lanzhou, Gansu, China
  2. 2Foot-and-Mouth Disease and Emerging Diseases Team, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu, China
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Abstract

Objective: Chronic 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.

Methods: A 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.

Results: NTG 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.

Conclusion: Our 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.

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Cite

BibTeXRIS
BibTeX
@article{li2026cd200cd200r1,
  title = {{CD200/CD200R1 activation alleviates central sensitization in chronic migraine via STAT6}},
  author = {ZiChao Li and Dan Li and ZhenZhen Fan and HongBin Cai and ZhaoMing Ge},
  journal = {Molecular Pain},
  year = {2026},
  month = sep,
  doi = {10.1177/17448069261491583},
  url = {https://doi.org/10.1177/17448069261491583},
  note = {CC BY-NC 4.0},
}
RIS
TY  - JOUR
TI  - CD200/CD200R1 activation alleviates central sensitization in chronic migraine via STAT6
AU  - ZiChao Li
AU  - Dan Li
AU  - ZhenZhen Fan
AU  - HongBin Cai
AU  - ZhaoMing Ge
PY  - 2026
DA  - 2026/09/21
JO  - Molecular Pain
DO  - 10.1177/17448069261491583
UR  - https://doi.org/10.1177/17448069261491583
AB  - Objective: Chronic 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.  Methods: A 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.  Results: NTG 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.  Conclusion: Our 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.
SN  - 1744-8069
ER  -