Junyu Lu1,2,3 · Yunxin Shi1,2,4 · Yongkang Li1,2,3 · Ziyi Niu1,2 · Shengxi Wu1,2 · Ceng Luo1,2  · Rou‑Gang Xie1,2

1 Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi’an 710032, China 

2 The Shaanxi Province Key Laboratory of Brain Function Analysis and Modulation, Xi’an 710032, China 

3 The First Regiment, School of Basic Medicine, Fourth Military Medical University, Xi’an 710032, China 

4 School of Medicine, Tongji University, Shanghai 200092, China

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.

Keywords

The C–C motif chemokine ligand 2 (CCL2); The C–C motif chemokine receptor 2 (CCR2); Chronic pain · Central sensitization; Peripheral sensitization

[SpringerLink]