Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Acta Pharmacologica Sinica volume 46, pages 1567–1579 (2025)Cite this article

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.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The pain threshold and depression-like behavior in mice with SNI surgery.
Fig. 2: AHN inhibition in the ventral DG of SNI mice with chronic neuropathic pain.
Fig. 3: Inhibition of CXCR2 expression in the ventral DG of SNI mice with chronic neuropathic pain.
Fig. 4: CXCR2 expression regulated AHN in the ventral DG.
Fig. 5: Altered expression of CXCR2 was associated with depression-like behaviors.
Fig. 6: CXCR2 controlled Wnt3a/β-catenin signaling.
Fig. 7: A schematic diagram summarizing the molecular mechanisms.

Similar content being viewed by others

References

  1. Amaro-Díaz L, Montoro CI, Fischer-Jbali LR, Galvez-Sánchez CM. Chronic pain and emotional stroop: a systematic review. J Clin Med. 2022;11:3259.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Flores-García M, Rizzo A, Garçon-Poca MZ, Fernández-Dueñas V, Bonaventura J. Converging circuits between pain and depression: The ventral tegmental area as a therapeutic hub. Front Pharmacol. 2023;14:1278023.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Toda T, Parylak SL, Linker SB, Gage FH. The role of adult hippocampal neurogenesis in brain health and disease. Mol Psychiatry. 2019;24:67–87.

    Article  CAS  PubMed  Google Scholar 

  4. Knezevic E, Nenic K, Milanovic V, Knezevic NN. The role of cortisol in chronic stress, neurodegenerative diseases, and psychological disorders. Cells. 2023;12:2726.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Gohari J, Grosman-Rimon L, Arazi M, Caspi-Avissar N, Granot D, Gleitman S, et al. Clinical factors and pre-surgical depression scores predict pain intensity in cardiac surgery patients. BMC Anesthesiol. 2022;22:204.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Bonilla-Jaime H, Sanchez-Salcedo JA, Estevez-Cabrera MM, Molina-Jimenez T, Cortes-Altamirano JL, Alfaro-Rodriguez A. Depression and pain: Use of antidepressants. Curr Neuropharmacol. 2022;20:384–402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Chiou CS, Huang CC, Liang YC, Tsai YC, Hsu KS. Impairment of long-term depression in the anterior cingulate cortex of mice with bone cancer pain. Pain. 2012;153:2097–108.

    Article  PubMed  Google Scholar 

  8. Xu Y, Zhu X, Chen Y, Chen Y, Zhu Y, Xiao S, et al. Electroacupuncture alleviates mechanical allodynia and anxiety-like behaviors induced by chronic neuropathic pain via regulating rostral anterior cingulate cortex-dorsal raphe nucleus neural circuit. CNS Neurosci Ther. 2023;29:4043–58.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Xia SH, Hu SW, Ge DG, Liu D, Wang D, Zhang S, et al. Chronic pain impairs memory formation via disruption of neurogenesis mediated by mesohippocampal brain-derived neurotrophic factor signaling. Biol Psychiatry. 2020;88:597–610.

    Article  PubMed  Google Scholar 

  10. Li Y, Liu X, Fu Q, Fan W, Shao X, Fang J, et al. Electroacupuncture ameliorates depression-like behaviors comorbid to chronic neuropathic pain via tet1-mediated restoration of adult neurogenesis. Stem Cells. 2023;41:384–99.

    Article  PubMed  Google Scholar 

  11. Toda T, Gage FH. Review: Adult neurogenesis contributes to hippocampal plasticity. Cell Tissue Res. 2018;373:693–709.

    Article  PubMed  Google Scholar 

  12. Levone BR, Cryan JF, O’Leary OF. Specific sub-regions of the longitudinal axis of the hippocampus mediate behavioural responses to chronic psychosocial stress. Neuropharmacology. 2021;201:108843.

    Article  CAS  PubMed  Google Scholar 

  13. Garman A, Ash AM, Kokkinos EK, Nerland D, Winter L, Langreck CB, et al. Novel hippocampal genes involved in enhanced susceptibility to chronic pain-induced behavioral emotionality. Eur J Pharmacol. 2024;964:176273.

    Article  CAS  PubMed  Google Scholar 

  14. Yun S, Reynolds RP, Petrof I, White A, Rivera PD, Segev A, et al. Stimulation of entorhinal cortex-dentate gyrus circuitry is antidepressive. Nat Med. 2018;24:658–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Xu C, Fan W, Zhang Y, Loh HH, Law PY. Kappa opioid receptor controls neural stem cell differentiation via a mir-7a/pax6 dependent pathway. Stem Cells. 2021;39:600–16.

    Article  CAS  PubMed  Google Scholar 

  16. Li HH, Liu Y, Chen HS, Wang J, Li YK, Zhao Y, et al. Pdgf-bb-dependent neurogenesis buffers depressive-like behaviors by inhibition of gabaergic projection from medial septum to dentate gyrus. Adv Sci. 2023;10:e2301110.

    Article  Google Scholar 

  17. Tang X, Walter E, Wohleb E, Fan Y, Wang C. Atg5 (autophagy related 5) in microglia controls hippocampal neurogenesis in alzheimer disease. Autophagy. 2024;20:847–62.

    Article  CAS  PubMed  Google Scholar 

  18. Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature. 2011;477:90–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Edman LC, Mira H, Erices A, Malmersjo S, Andersson E, Uhlen P, et al. Alpha-chemokines regulate proliferation, neurogenesis, and dopaminergic differentiation of ventral midbrain precursors and neurospheres. Stem Cells. 2008;26:1891–900.

    Article  CAS  PubMed  Google Scholar 

  20. Huang F, Lan Y, Qin L, Dong H, Shi H, Wu H, et al. Astragaloside iv promotes adult neurogenesis in hippocampal dentate gyrus of mouse through cxcl1/cxcr2 signaling. Molecules. 2018;23:2178.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Schultheiss C, Abe P, Hoffmann F, Mueller W, Kreuder AE, Schutz D, et al. Cxcr4 prevents dispersion of granule neuron precursors in the adult dentate gyrus. Hippocampus. 2013;23:1345–58.

    Article  CAS  PubMed  Google Scholar 

  22. Shen Y, Jing L, Zhang Y, Bao H, Vohra A, Si Y, et al. Cxcr5 knockdown attenuates hippocampal neurogenesis deficits and cognitive impairment in a mouse model of sepsis-associated encephalopathy. Neuroscience. 2020;433:212–20.

    Article  CAS  PubMed  Google Scholar 

  23. Zonis S, Breunig JJ, Mamelak A, Wawrowsky K, Bresee C, Ginzburg N, et al. Inflammation-induced gro1 triggers senescence in neuronal progenitors: effects of estradiol. J Neuroinflammation. 2018;15:260.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Chai HH, Fu XC, Ma L, Sun HT, Chen GZ, Song MY, et al. The chemokine cxcl1 and its receptor cxcr2 contribute to chronic stress-induced depression in mice. FASEB J. 2019;33:8853–64.

    Article  CAS  PubMed  Google Scholar 

  25. Salter MW, Stevens B. Microglia emerge as central players in brain disease. Nat Med. 2017;23:1018–27.

    Article  CAS  PubMed  Google Scholar 

  26. Bot M, Chan MK, Jansen R, Lamers F, Vogelzangs N, Steiner J, et al. Serum proteomic profiling of major depressive disorder. Transl Psychiatry. 2015;5:e599.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Abbadie C. Chemokines, chemokine receptors and pain. Trends Immunol. 2005;26:529–34.

    Article  CAS  PubMed  Google Scholar 

  28. Heppt J, Wittmann MT, Schaffner I, Billmann C, Zhang J, Vogt-Weisenhorn D, et al. Beta-catenin signaling modulates the tempo of dendritic growth of adult-born hippocampal neurons. EMBO J. 2020;39:e104472.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Tao W, Ruan J, Wu R, Zhao M, Zhao T, Qi M, et al. A natural carotenoid crocin exerts antidepressant action by promoting adult hippocampal neurogenesis through wnt/beta-catenin signaling. J Adv Res. 2023;43:219–31.

    Article  CAS  PubMed  Google Scholar 

  30. Xiao Z, Cao Z, Yang J, Jia Z, Du Y, Sun G, et al. Baicalin promotes hippocampal neurogenesis via the Wnt/beta-catenin pathway in a chronic unpredictable mild stress-induced mouse model of depression. Biochem Pharmacol. 2021;190:114594.

    Article  CAS  PubMed  Google Scholar 

  31. Arredondo SB, Valenzuela-Bezanilla D, Mardones MD, Varela-Nallar L. Role of Wnt signaling in adult hippocampal neurogenesis in health and disease. Front Cell Dev Biol. 2020;8:860.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Han H, Xu M, Wang J, Li MD, Yang Z. Crispr/cas9 based gene editing of frizzled class receptor 6 (fzd6) reveals its role in depressive symptoms through disrupting wnt/beta-catenin signaling pathway. J Adv Res. 2024;58:129–38.

    Article  CAS  PubMed  Google Scholar 

  33. Wu M, Chen Y, Shen Z, Zhu Y, Xiao S, Zhu X, et al. Electroacupuncture alleviates anxiety-like behaviors induced by chronic neuropathic pain via regulating different dopamine receptors of the basolateral amygdala. Mol Neurobiol. 2022;59:5299–311.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Chai W, Tai Y, Shao X, Liang Y, Zheng GQ, Wang P, et al. Electroacupuncture alleviates pain responses and inflammation in a rat model of acute gout arthritis. Evid Based Complement Alternat Med. 2018;2018:2598975.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods. 1994;53:55–63.

    Article  CAS  PubMed  Google Scholar 

  36. Papp M, Willner P, Muscat R. An animal model of anhedonia: Attenuation of sucrose consumption and place preference conditioning by chronic unpredictable mild stress. Psychopharmacology. 1991;104:255–9.

    Article  CAS  PubMed  Google Scholar 

  37. Guo W, Patzlaff NE, Jobe EM, Zhao X. Isolation of multipotent neural stem or progenitor cells from both the dentate gyrus and subventricular zone of a single adult mouse. Nat Protoc. 2012;7:2005–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. O’Leary OF, Cryan JF. A ventral view on antidepressant action: Roles for adult hippocampal neurogenesis along the dorsoventral axis. Trends Pharmacol Sci. 2014;35:675–87.

    Article  PubMed  Google Scholar 

  39. Hill JD, Zuluaga-Ramirez V, Gajghate S, Winfield M, Persidsky Y. Activation of gpr55 increases neural stem cell proliferation and promotes early adult hippocampal neurogenesis. Br J Pharmacol. 2018;175:3407–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ocasio JK, Bates RDP, Rapp CD, Gershon TR. Gsk-3 modulates shh-driven proliferation in postnatal cerebellar neurogenesis and medulloblastoma. Development. 2019;146:dev177550.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Song Y, Shi R, Liu Y, Cui F, Han L, Wang C, et al. M2 microglia extracellular vesicle mir-124 regulates neural stem cell differentiation in ischemic stroke via aak1/notch. Stroke. 2023;54:2629–39.

    Article  CAS  PubMed  Google Scholar 

  42. Hanifa M, Singh M, Randhawa PK, Jaggi AS, Bali A. A focus on rho/rock signaling pathway: an emerging therapeutic target in depression. Eur J Pharmacol. 2023;946:175648.

    Article  CAS  PubMed  Google Scholar 

  43. Chan KL, Poller WC, Swirski FK, Russo SJ. Central regulation of stress-evoked peripheral immune responses. Nat Rev Neurosci. 2023;24:591–604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kofod J, Elfving B, Nielsen EH, Mors O, Kohler-Forsberg O. Depression and inflammation: correlation between changes in inflammatory markers with antidepressant response and long-term prognosis. Eur Neuropsychopharmacol. 2022;54:116–25.

    Article  CAS  PubMed  Google Scholar 

  45. Beurel E, Toups M, Nemeroff CB. The bidirectional relationship of depression and inflammation: double trouble. Neuron. 2020;107:234–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Trojan E, Slusarczyk J, Chamera K, Kotarska K, Glombik K, Kubera M, et al. The modulatory properties of chronic antidepressant drugs treatment on the brain chemokine - chemokine receptor network: a molecular study in an animal model of depression. Front Pharmacol. 2017;8:779.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Sun X, Peng X, Cao Y, Zhou Y, Sun Y. Adnp promotes neural differentiation by modulating wnt/beta-catenin signaling. Nat Commun. 2020;11:2984.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Vachon P, Millecamps M, Low L, Thompsosn SJ, Pailleux F, Beaudry F, et al. Alleviation of chronic neuropathic pain by environmental enrichment in mice well after the establishment of chronic pain. Behav Brain Funct. 2013;9:22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Apkarian AV, Mutso AA, Centeno MV, Kan L, Wu M, Levinstein M, et al. Role of adult hippocampal neurogenesis in persistent pain. Pain. 2016;157:418–28.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Ruetz TJ, Pogson AN, Kashiwagi CM, Gagnon SD, Morton B, Sun ED, et al. Crispr-cas9 screens reveal regulators of ageing in neural stem cells. Nature. 2024;634:1150–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We appreciate the technical support from the Public Platform of Medical Research Center, Academy of Chinese Medical Science, Zhejiang Chinese Medical University. This work was supported by Zhejiang Provincial Medical and Health Program (Grant No. 2025KY985), Zhejiang Provincial Natural Science Foundation of China (Grant No. LY22H270004), Zhejiang Chinese Medical University (Grant No. 2022FSYYZZ11), and National Natural Science Foundation of China (Grant No. 82030112).

Author information

Author notes

  1. These authors contributed equally: Xiao-jie Li, Shuo Wu

Authors and Affiliations

  1. School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China

    Xiao-jie Li, Shuo Wu, Hui-sheng Peng & Jing-gen Liu

  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

    Xiao-jie Li, Shuo Wu, Hui-sheng Peng, Ye-xiang Chen, Jing-gen Liu & Chi Xu

  3. Department of Rehabilitation Health, Wuhan Hankou Hospital, Wuhan, 430000, China

    Xiao-jie Li

  4. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China

    Zi-han Liu, An-an Liu, Yu-jun Wang & Jing-gen Liu

  5. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Zi-han Liu, An-an Liu, Yu-jun Wang & Jing-gen Liu

  6. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, China

    Yu-jun Wang

Authors
  1. Xiao-jie Li
    View author publications

    Search author on:PubMed Google Scholar

  2. Shuo Wu
    View author publications

    Search author on:PubMed Google Scholar

  3. Zi-han Liu
    View author publications

    Search author on:PubMed Google Scholar

  4. An-an Liu
    View author publications

    Search author on:PubMed Google Scholar

  5. Hui-sheng Peng
    View author publications

    Search author on:PubMed Google Scholar

  6. Yu-jun Wang
    View author publications

    Search author on:PubMed Google Scholar

  7. Ye-xiang Chen
    View author publications

    Search author on:PubMed Google Scholar

  8. Jing-gen Liu
    View author publications

    Search author on:PubMed Google Scholar

  9. Chi Xu
    View author publications

    Search author on:PubMed Google Scholar

Contributions

XJL, SW, ZHL, AAL, HSP, and YXC collected and assembled the data; XJL, SW, YJW, YXC, and CX analyzed and interpreted the data; XJL and CX wrote the manuscript; JGL and CX provided conception, design, financial and administrative support, and final approval of the manuscript.

Corresponding authors

Correspondence to Ye-xiang Chen, Jing-gen Liu or Chi Xu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, Xj., Wu, S., Liu, Zh. et al. CXCR2 modulates chronic pain comorbid depression in mice by regulating adult neurogenesis in the ventral dentate gyrus. Acta Pharmacol Sin 46, 1567–1579 (2025). https://doi.org/10.1038/s41401-025-01496-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41401-025-01496-9

Keywords

Search

Advanced search

Quick links