Chemokine CCL2 Mediates Neuroglial Crosstalk and Drives Chronic Pain Pathogenesis.
10.1007/s12264-025-01519-9
- Author:
Junyu LU
1
;
Yunxin SHI
1
;
Yongkang LI
1
;
Ziyi NIU
1
;
Shengxi WU
1
;
Ceng LUO
2
;
Rou-Gang XIE
3
Author Information
1. Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China.
2. Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China. luoceng@fmmu.edu.cn.
3. Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China. rgxie@fmmu.edu.cn.
- Publication Type:Review
- Keywords:
Central sensitization;
Chronic pain;
Peripheral sensitization;
The C–C motif chemokine ligand 2 (CCL2);
The C–C motif chemokine receptor 2 (CCR2)
- MeSH:
Humans;
Chronic Pain/physiopathology*;
Animals;
Neuroglia/metabolism*;
Chemokine CCL2/metabolism*;
Receptors, CCR2/metabolism*
- From:
Neuroscience Bulletin
2025;41(12):2296-2321
- CountryChina
- Language:English
-
Abstract:
Chronic pain, frequently comorbid with neuropsychiatric disorders, significantly impairs patients' quality of life and functional capacity. Accumulating evidence implicates the chemokine CCL2 and its receptor CCR2 as key players in chronic pain pathogenesis. This review examines the regulatory mechanisms of the CCL2/CCR2 axis in chronic pain processing at three hierarchical levels: (1) Peripheral Sensitization: CCL2/CCR2 modulates TRPV1, Nav1.8, and HCN2 channels to increase neuronal excitability and CGRP signaling and calcium-dependent exocytosis in peripheral nociceptors to transmit pain. (2) Spinal Cord Central Sensitization: CCL2/CCR2 contributes to NMDAR-dependent plasticity, glial activation, GABAergic disinhibition, and opioid receptor desensitization. (3) Supraspinal Central Networks: CCL2/CCR2 signaling axis mediates the comorbidity mechanisms of pain with anxiety and cognitive impairment within brain regions, including the ACC, CeA, NAc, and hippocampus, and it also increases pain sensitization through the descending facilitation system. Current CCL2/CCR2-targeted therapeutic strategies and their development status are discussed, highlighting novel avenues for chronic pain management.
