Increased CXCL13 and CXCR5 in Anterior Cingulate Cortex Contributes to Neuropathic Pain-Related Conditioned Place Aversion

  • Xiao-Bo Wu
  • Li-Na He
  • Bao-Chun Jiang
  • Xue Wang
  • Ying Lu
  • Yong-Jing GaoEmail author
Original Article


Pain consists of sensory-discriminative and emotional-affective components. The anterior cingulate cortex (ACC) is a critical brain area in mediating the affective pain. However, the molecular mechanisms involved remain largely unknown. Our recent study indicated that C-X-C motif chemokine 13 (CXCL13) and its sole receptor CXCR5 are involved in sensory sensitization in the spinal cord after spinal nerve ligation (SNL). Whether CXCL13/CXCR5 signaling in the ACC contributes to the pathogenesis of pain-related aversion remains unknown. Here, we showed that SNL increased the CXCL13 level and CXCR5 expression in the ACC after SNL. Knockdown of CXCR5 by microinjection of Cxcr5 shRNA into the ACC did not affect SNL-induced mechanical allodynia but effectively alleviated neuropathic pain-related place avoidance behavior. Furthermore, electrophysiological recording from layer II–III neurons in the ACC showed that SNL increased the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs), decreased the EPSC paired-pulse ratio, and increased the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor/N-methyl-D-aspartate receptor ratio, indicating enhanced glutamatergic synaptic transmission. Finally, superfusion of CXCL13 onto ACC slices increased the frequency and amplitude of spontaneous EPSCs. Pre-injection of Cxcr5 shRNA into the ACC reduced the increase in glutamatergic synaptic transmission induced by SNL. Collectively, these results suggest that CXCL13/CXCR5 signaling in the ACC is involved in neuropathic pain-related aversion via synaptic potentiation.


CXCL13 CXCR5 Anterior cingulate cortex Neuropathic pain Conditioned place aversion Synaptic transmission 



This work was supported by grants from the National Natural Science Foundation of China (31671091 and 81771197), the Natural Science Foundation of Jiangsu Province, China (BK20171255), and the Science and Technology Planning Project of Nantong Municipality, China (MS12017023-9).


  1. 1.
    Miller LR, Cano A. Comorbid chronic pain and depression: who is at risk? J Pain 2009, 10: 619–627.CrossRefGoogle Scholar
  2. 2.
    LaGraize SC, Borzan J, Peng YB, Fuchs PN. Selective regulation of pain affect following activation of the opioid anterior cingulate cortex system. Exp Neurol 2006, 197: 22–30.CrossRefGoogle Scholar
  3. 3.
    Gao YJ, Ren WH, Zhang YQ, Zhao ZQ. Contributions of the anterior cingulate cortex and amygdala to pain- and fear-conditioned place avoidance in rats. Pain 2004, 110: 343–353.CrossRefGoogle Scholar
  4. 4.
    Cao H, Gao YJ, Ren WH, Li TT, Duan KZ, Cui YH, et al. Activation of extracellular signal-regulated kinase in the anterior cingulate cortex contributes to the induction and expression of affective pain. J Neurosci 2009, 29: 3307–3321.CrossRefGoogle Scholar
  5. 5.
    Qu C, King T, Okun A, Lai J, Fields HL, Porreca F. Lesion of the rostral anterior cingulate cortex eliminates the aversiveness of spontaneous neuropathic pain following partial or complete axotomy. Pain 2011, 152: 1641–1648.CrossRefGoogle Scholar
  6. 6.
    Johansen JP, Fields HL, Manning BH. The affective component of pain in rodents: direct evidence for a contribution of the anterior cingulate cortex. Proc Natl Acad Sci USA 2001, 98: 8077–8082.CrossRefGoogle Scholar
  7. 7.
    Cifre I, Sitges C, Fraiman D, Munoz MA, Balenzuela P, Gonzalez-Roldan A, et al. Disrupted functional connectivity of the pain network in fibromyalgia. Psychosom Med 2012, 74: 55–62.CrossRefGoogle Scholar
  8. 8.
    Yuan W, Dan L, Netra R, Shaohui M, Chenwang J, Ming Z. A pharmaco-fMRI study on pain networks induced by electrical stimulation after sumatriptan injection. Exp Brain Res 2013, 226: 15–24.CrossRefGoogle Scholar
  9. 9.
    LaGraize SC, Labuda CJ, Rutledge MA, Jackson RL, Fuchs PN. Differential effect of anterior cingulate cortex lesion on mechanical hypersensitivity and escape/avoidance behavior in an animal model of neuropathic pain. Exp Neurol 2004, 188: 139–148.CrossRefGoogle Scholar
  10. 10.
    Johansen JP, Fields HL. Glutamatergic activation of anterior cingulate cortex produces an aversive teaching signal. Nat Neurosci 2004, 7: 398–403.CrossRefGoogle Scholar
  11. 11.
    Zhou H, Zhang Q, Martinez E, Dale J, Hu S, Zhang E, et al. Ketamine reduces aversion in rodent pain models by suppressing hyperactivity of the anterior cingulate cortex. Nat Commun 2018, 9: 3751.CrossRefGoogle Scholar
  12. 12.
    Ansel KM, Ngo VN, Hyman PL, Luther SA, Forster R, Sedgwick JD, et al. A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature 2000, 406: 309–314.CrossRefGoogle Scholar
  13. 13.
    Krumbholz M, Theil D, Cepok S, Hemmer B, Kivisakk P, Ransohoff RM, et al. Chemokines in multiple sclerosis: CXCL12 and CXCL13 up-regulation is differentially linked to CNS immune cell recruitment. Brain 2006, 129: 200–211.CrossRefGoogle Scholar
  14. 14.
    Rainey-Barger EK, Rumble JM, Lalor SJ, Esen N, Segal BM, Irani DN. The lymphoid chemokine, CXCL13, is dispensable for the initial recruitment of B cells to the acutely inflamed central nervous system. Brain Behav Immun 2011, 25: 922–931.CrossRefGoogle Scholar
  15. 15.
    Kim CH, Rott LS, Clark-Lewis I, Campbell DJ, Wu L, Butcher EC. Subspecialization of CXCR5+ T cells: B helper activity is focused in a germinal center-localized subset of CXCR5+ T cells. J Exp Med 2001, 193: 1373–1381.CrossRefGoogle Scholar
  16. 16.
    Wu XB, Cao DL, Zhang X, Jiang BC, Zhao LX, Qian B, et al. CXCL13/CXCR5 enhances sodium channel Nav1.8 current density via p38 MAP kinase in primary sensory neurons following inflammatory pain. Sci Rep 2016, 6: 34836.CrossRefGoogle Scholar
  17. 17.
    Zhang Q, Cao DL, Zhang ZJ, Jiang BC, Gao YJ. Chemokine CXCL13 mediates orofacial neuropathic pain via CXCR5/ERK pathway in the trigeminal ganglion of mice. J Neuroinflamm 2016, 13: 183.CrossRefGoogle Scholar
  18. 18.
    Jiang BC, Cao DL, Zhang X, Zhang ZJ, He LN, Li CH, et al. CXCL13 drives spinal astrocyte activation and neuropathic pain via CXCR5. J Clin Invest 2016, 126: 745–761.CrossRefGoogle Scholar
  19. 19.
    Li XY, Ko HG, Chen T, Descalzi G, Koga K, Wang H, et al. Alleviating neuropathic pain hypersensitivity by inhibiting PKMzeta in the anterior cingulate cortex. Science 2010, 330: 1400–1404.CrossRefGoogle Scholar
  20. 20.
    Wu LJ, Toyoda H, Zhao MG, Lee YS, Tang J, Ko SW, et al. Upregulation of forebrain NMDA NR2B receptors contributes to behavioral sensitization after inflammation. J Neurosci 2005, 25: 11107–11116.CrossRefGoogle Scholar
  21. 21.
    Koga K, Descalzi G, Chen T, Ko HG, Lu J, Li S, et al. Coexistence of two forms of LTP in ACC provides a synaptic mechanism for the interactions between anxiety and chronic pain. Neuron 2015, 85: 377–389.CrossRefGoogle Scholar
  22. 22.
    Xu H, Wu LJ, Wang H, Zhang X, Vadakkan KI, Kim SS, et al. Presynaptic and postsynaptic amplifications of neuropathic pain in the anterior cingulate cortex. J Neurosci 2008, 28: 7445–7453.CrossRefGoogle Scholar
  23. 23.
    Blom SM, Pfister JP, Santello M, Senn W, Nevian T. Nerve injury-induced neuropathic pain causes disinhibition of the anterior cingulate cortex. J Neurosci 2014, 34: 5754–5764.CrossRefGoogle Scholar
  24. 24.
    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.CrossRefGoogle Scholar
  25. 25.
    Jing PB, Cao DL, Li SS, Zhu M, Bai XQ, Wu XB, et al. Chemokine receptor CXCR3 in the spinal cord contributes to chronic itch in mice. Neurosci Bull 2018, 34: 54–63.CrossRefGoogle Scholar
  26. 26.
    Chen FL, Dong YL, Zhang ZJ, Cao DL, Xu J, Hui J, et al. Activation of astrocytes in the anterior cingulate cortex contributes to the affective component of pain in an inflammatory pain model. Brain Res Bull 2012, 87: 60–66.CrossRefGoogle Scholar
  27. 27.
    Du J, Creson TK, Wu LJ, Ren M, Gray NA, Falke C, et al. The role of hippocampal GluR1 and GluR2 receptors in manic-like behavior. J Neurosci 2008, 28: 68–79.CrossRefGoogle Scholar
  28. 28.
    Zhang ZJ, Cao DL, Zhang X, Ji RR, Gao YJ. Chemokine contribution to neuropathic pain: respective induction of CXCL1 and CXCR2 in spinal cord astrocytes and neurons. Pain 2013, 154: 2185–2197.CrossRefGoogle Scholar
  29. 29.
    Mennicken F, Maki R, de Souza EB, Quirion R. Chemokines and chemokine receptors in the CNS: a possible role in neuroinflammation and patterning. Trends Pharmacol Sci 1999, 20: 73–78.CrossRefGoogle Scholar
  30. 30.
    Ubogu EE, Cossoy MB, Ransohoff RM. The expression and function of chemokines involved in CNS inflammation. Trends Pharmacol Sci 2006, 27: 48–55.CrossRefGoogle Scholar
  31. 31.
    Savarin-Vuaillat C, Ransohoff RM. Chemokines and chemokine receptors in neurological disease: raise, retain, or reduce? Neurotherapeutics 2007, 4: 590–601.CrossRefGoogle Scholar
  32. 32.
    Zhang ZJ, Jiang BC, Gao YJ. Chemokines in neuron-glial cell interaction and pathogenesis of neuropathic pain. Cell Mol Life Sci 2017, 74: 3275–3291.CrossRefGoogle Scholar
  33. 33.
    Bai L, Wang X, Li Z, Kong C, Zhao Y, Qian JL, et al. Upregulation of chemokine CXCL12 in the dorsal root ganglia and spinal cord contributes to the development and maintenance of neuropathic pain following spared nerve injury in rats. Neurosci Bull 2016, 32: 27–40.CrossRefGoogle Scholar
  34. 34.
    Xie RG, Gao YJ, Park CK, Lu N, Luo C, Wang WT, et al. Spinal CCL2 promotes central sensitization, long-term potentiation, and inflammatory pain via CCR2: further insights into molecular, synaptic, and cellular mechanisms. Neurosci Bull 2018, 34: 13–21.CrossRefGoogle Scholar
  35. 35.
    Knerlich-Lukoschus F, Noack M, von der Ropp-Brenner B, Lucius R, Mehdorn HM, Held-Feindt J. Spinal cord injuries induce changes in CB1 cannabinoid receptor and C-C chemokine expression in brain areas underlying circuitry of chronic pain conditions. J Neurotrauma 2011, 28: 619–634.CrossRefGoogle Scholar
  36. 36.
    Leighton SP, Nerurkar L, Krishnadas R, Johnman C, Graham GJ, Cavanagh J. Chemokines in depression in health and in inflammatory illness: a systematic review and meta-analysis. Mol Psychiatry 2017, 23:48–58.CrossRefGoogle Scholar
  37. 37.
    Garre JM, Silva HM, Lafaille JJ, Yang G. CX3CR1+ monocytes modulate learning and learning-dependent dendritic spine remodeling via TNF-alpha. Nat Med 2017, 23: 714–722.CrossRefGoogle Scholar
  38. 38.
    Barthas F, Sellmeijer J, Hugel S, Waltisperger E, Barrot M, Yalcin I. The anterior cingulate cortex is a critical hub for pain-induced depression. Biol Psychiatry 2015, 77: 236–245.CrossRefGoogle Scholar
  39. 39.
    Han M, Xiao X, Yang Y, Huang RY, Cao H, Zhao ZQ, et al. SIP30 is required for neuropathic pain-evoked aversion in rats. J Neurosci 2014, 34: 346–355.CrossRefGoogle Scholar
  40. 40.
    Zhang Q, Manders T, Tong AP, Yang R, Garg A, Martinez E, et al. Chronic pain induces generalized enhancement of aversion. Elife 2017, 6.Google Scholar
  41. 41.
    Sellmeijer J, Mathis V, Hugel S, Li XH, Song Q, Chen QY, et al. Hyperactivity of anterior cingulate cortex areas 24a/24b drives chronic pain-induced anxiodepressive-like consequences. J Neurosci 2018, 38: 3102–3115.CrossRefGoogle Scholar
  42. 42.
    Anggono V, Huganir RL. Regulation of AMPA receptor trafficking and synaptic plasticity. Curr Opin Neurobiol 2012, 22: 461–469.CrossRefGoogle Scholar
  43. 43.
    Kavalali ET. The mechanisms and functions of spontaneous neurotransmitter release. Nat Rev Neurosci 2015, 16: 5–16.CrossRefGoogle Scholar
  44. 44.
    Argilli E, Sibley DR, Malenka RC, England PM, Bonci A. Mechanism and time course of cocaine-induced long-term potentiation in the ventral tegmental area. J Neurosci 2008, 28: 9092–9100.CrossRefGoogle Scholar
  45. 45.
    Zhou Y, Tang H, Liu J, Dong J, Xiong H. Chemokine CCL2 modulation of neuronal excitability and synaptic transmission in rat hippocampal slices. J Neurochem 2011, 116: 406–414.CrossRefGoogle Scholar
  46. 46.
    Vlkolinsky R, Siggins GR, Campbell IL, Krucker T. Acute exposure to CXC chemokine ligand 10, but not its chronic astroglial production, alters synaptic plasticity in mouse hippocampal slices. J Neuroimmunol 2004, 150: 37–47.CrossRefGoogle Scholar
  47. 47.
    Di Castro MA, Trettel F, Milior G, Maggi L, Ragozzino D, Limatola C. The chemokine CXCL16 modulates neurotransmitter release in hippocampal CA1 area. Sci Rep 2016, 6: 34633.CrossRefGoogle Scholar
  48. 48.
    Toyoda H, Zhao MG, Ulzhofer B, Wu LJ, Xu H, Seeburg PH, et al. Roles of the AMPA receptor subunit GluA1 but not GluA2 in synaptic potentiation and activation of ERK in the anterior cingulate cortex. Mol Pain 2009, 5: 46.Google Scholar
  49. 49.
    Toyoda H, Zhao MG, Xu H, Wu LJ, Ren M, Zhuo M. Requirement of extracellular signal-regulated kinase/mitogen-activated protein kinase for long-term potentiation in adult mouse anterior cingulate cortex. Mol Pain 2007, 3: 36.CrossRefGoogle Scholar
  50. 50.
    Holmes SE, Hinz R, Conen S, Gregory CJ, Matthews JC, Anton-Rodriguez JM, et al. Elevated translocator protein in anterior cingulate in major depression and a role for inflammation in suicidal thinking: a positron emission tomography study. Biol Psychiatry 2018, 83: 61–69.CrossRefGoogle Scholar
  51. 51.
    Shukla DK, Wijtenburg SA, Chen H, Chiappelli JJ, Kochunov P, Hong LE, et al. Anterior cingulate glutamate and GABA associations on functional connectivity in schizophrenia. Schizophr Bull 2018.
  52. 52.
    Setiawan E, Wilson AA, Mizrahi R, Rusjan PM, Miler L, Rajkowska G, et al. Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes. JAMA Psychiatry 2015, 72: 268–275.CrossRefGoogle Scholar

Copyright information

© Shanghai Institutes for Biological Sciences, CAS 2019

Authors and Affiliations

  • Xiao-Bo Wu
    • 1
  • Li-Na He
    • 1
  • Bao-Chun Jiang
    • 1
  • Xue Wang
    • 1
  • Ying Lu
    • 2
  • Yong-Jing Gao
    • 1
    • 3
    Email author
  1. 1.Institute of Pain Medicine, Institute of Special Environmental MedicineNantong UniversityNantongChina
  2. 2.Department of Nutrition and Food Hygiene, School of Public HealthNantong UniversityNantongChina
  3. 3.Co-innovation Center of NeuroregenerationNantong UniversityNantongChina

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