2. Academic Validation
  3. CXCR2 modulates chronic pain comorbid depression in mice by regulating adult neurogenesis in the ventral dentate gyrus

CXCR2 modulates chronic pain comorbid depression in mice by regulating adult neurogenesis in the ventral dentate gyrus

  • Acta Pharmacol Sin. 2025 Feb 19. doi: 10.1038/s41401-025-01496-9.
Xiao-Jie Li # 1 2 3,  Shuo Wu # 1 2,  Zi-Han Liu 4 5,  An-An Liu 4 5,  Hui-Sheng Peng 1 2,  Yu-Jun Wang 4 5 6,  Ye-Xiang Chen 7,  Jing-Gen Liu 8 9 10 11,  Chi Xu 12
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
  • 2 Department of Neurobiology and Acupuncture Research, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310061, China.
  • 3 Department of Rehabilitation Health, Wuhan Hankou Hospital, Wuhan, 430000, China.
  • 4 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 5 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 6 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, China.
  • 7 Department of Neurobiology and Acupuncture Research, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310061, China. yexiangchen@zcmu.edu.cn.
  • 8 School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China. jgliu@simm.ac.cn.
  • 9 Department of Neurobiology and Acupuncture Research, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310061, China. jgliu@simm.ac.cn.
  • 10 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China. jgliu@simm.ac.cn.
  • 11 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. jgliu@simm.ac.cn.
  • 12 Department of Neurobiology and Acupuncture Research, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310061, China. xuchi@zcmu.edu.cn.
  • # Contributed equally.
PMID: 39972170 DOI: 10.1038/s41401-025-01496-9
Abstract

Research shows that chronic pain may induce depression-like behaviors through impairing adult hippocampal neurogenesis (AHN) in the ventral dentate gyrus (DG), whereas restoration of AHN may effectively alleviate depression. The C-X-C motif Chemokine Receptor 2 (CXCR2) is a Chemokine Receptor involved in various neural activities of the hippocampus including AHN. In this study we investigated the role of CXCR2 of neural stem cells (NSCs) in the ventral DG in regulating both AHN and depression-like behaviors of mice with chronic neuropathic pain. Chronic neuropathic pain was induced in mice by the spared nerve injury (SNI) surgery; mechanical allodynia and depression-like behaviors were monitored, then mouse DG was collected for analysis. We observed that chronic neuropathic pain significantly decreased the number of immature neurons in the ventral DG by inhibiting the neuronal differentiation of NSCs; specific overexpression of CXCR2 in NSCs by injecting the adeno-associated virus (AAV) into the DG restored adult neurogenesis accompanied by alleviated depression-like behaviors in SNI mice. In contrast, the knockdown of CXCR2 in hippocampal NSCs of naive mice was sufficient to inhibit adult neurogenesis, inducing depression-like behaviors. Moreover, we found that the Wnt3a/β-catenin pathway was downregulated in the ventral DG of SNI mice, which was restored after CXCR2 overexpression or infusing a CXCR2 Agonist CXCL1 into the ventral DG. We conclude that CXCR2 expressed in hippocampal NSCs is crucial for regulating adult neurogenesis and chronic pain-induced depression-like behavior, thus representing a new target for the treatment of chronic pain comorbid depression.

Keywords

CXCR2; Wnt3a/β-catenin pathway; adult neurogenesis; chronic pain comorbid depression; dentate gyrus.

Figures
Products