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Decreased miR-325-5p Contributes to Visceral Hypersensitivity Through Post-transcriptional Upregulation of CCL2 in Rat Dorsal Root Ganglia

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Abstract

Chronic visceral hypersensitivity is an important type of chronic pain with unknown etiology and pathophysiology. Recent studies have shown that epigenetic regulation plays an important role in the development of chronic pain conditions. However, the role of miRNA-325-5p in chronic visceral pain remains unknown. The present study was designed to determine the roles and mechanism of miRNA-325-5p in a rat model of chronic visceral pain. This model was induced by neonatal colonic inflammation (NCI). In adulthood, NCI led to a significant reduction in the expression of miRNA-325-5p in colon-related dorsal root ganglia (DRGs), starting to decrease at the age of 4 weeks and being maintained to 8 weeks. Intrathecal administration of miRNA-325-5p agomir significantly enhanced the colorectal distention (CRD) threshold in a time-dependent manner. NCI also markedly increased the expression of CCL2 (C-C motif chemokine ligand 2) in colon-related DRGs at the mRNA and protein levels relative to age-matched control rats. The expression of CXCL12, IL33, SFRS7, and LGI1 was not significantly altered in NCI rats. CCL2 was co-expressed in NeuN-positive DRG neurons but not in glutamine synthetase-positive glial cells. Furthermore, CCL2 was mainly expressed in isolectin B4-binding- and calcitonin gene-related peptide-positive DRG neurons but in few NF-200-positive cells. More importantly, CCL2 was expressed in miR-325-5p-positive DRG neurons. Intrathecal injection of miRNA-325-5p agomir remarkably reduced the upregulation of CCL2 in NCI rats. Administration of Bindarit, an inhibitor of CCL2, markedly raised the CRD threshold in NCI rats in a dose- and time-dependent manner. These data suggest that NCI suppresses miRNA-325-5p expression and enhances CCL2 expression, thus contributing to visceral hypersensitivity in adult rats.

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References

  1. Wang Y, Yang Z, Le W. Tiny but mighty: promising roles of micrornas in the diagnosis and treatment of parkinson’s disease. Neurosci Bull 2017, 33: 543–551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ambros V. The functions of animal micrornas. Nature 2004, 431: 350–355.

    Article  CAS  PubMed  Google Scholar 

  3. Bartel DP. Micrornas: Genomics, biogenesis, mechanism, and function. Cell 2004, 116: 281–297.

    Article  CAS  PubMed  Google Scholar 

  4. Zhang J, Banerjee B. Role of microrna in visceral pain. J Neurogastroenterol Motil 2015, 21: 159–171.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Zhou Q, Yang L, Larson S, Basra S, Merwat S, Tan A, et al. Decreased mir-199 augments visceral pain in patients with ibs through translational upregulation of trpv1. Gut 2016, 65: 797–805.

    Article  CAS  PubMed  Google Scholar 

  6. Yang Y, Sun B, Huang J, Xu L, Pan J, Fang C, et al. Up-regulation of mir-325-3p suppresses pineal aralkylamine n-acetyltransferase (aanat) after neonatal hypoxia-ischemia brain injury in rats. Brain Res 2017, 1668: 28–35.

    Article  CAS  PubMed  Google Scholar 

  7. Arshad AR, Sulaiman SA, Saperi AA, Jamal R, Mohamed Ibrahim N, Abdul Murad NA. Micrornas and target genes as biomarkers for the diagnosis of early onset of parkinson disease. Front Mol Neurosci 2017, 10: 352.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zhou Q, Verne GN. Role of microrna in chronic visceral nociception. Pain 2013, 154: 9–10.

    Article  CAS  PubMed  Google Scholar 

  9. Lu Y, Cao DL, Jiang BC, Yang T, Gao YJ. Microrna-146a-5p attenuates neuropathic pain via suppressing traf6 signaling in the spinal cord. Brain Behav Immun 2015, 49: 119–129.

    Article  CAS  PubMed  Google Scholar 

  10. Arisawa T, Tahara T, Fukuyama T, Hayashi R, Matsunaga K, Hayashi N, et al. Genetic polymorphism of pri-microrna 325, targeting slc6a4 3’-utr, is closely associated with the risk of functional dyspepsia in japan. J Gastroenterol 2012, 47: 1091–1098.

    Article  CAS  PubMed  Google Scholar 

  11. Miotla Zarebska J, Chanalaris A, Driscoll C, Burleigh A, Miller RE, Malfait AM, et al. Ccl2 and ccr2 regulate pain-related behaviour and early gene expression in post-traumatic murine osteoarthritis but contribute little to chondropathy. Osteoarthritis Cartilage 2017, 25: 406–412.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zheng Y, Qin L, Zacarias NV, de Vries H, Han GW, Gustavsson M, et al. Structure of cc chemokine receptor 2 with orthosteric and allosteric antagonists. Nature 2016, 540: 458–461.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Van Steenwinckel J, Auvynet C, Sapienza A, Reaux-Le Goazigo A, Combadiere C, Melik Parsadaniantz S. Stromal cell-derived ccl2 drives neuropathic pain states through myeloid cell infiltration in injured nerve. Brain Behav Immun 2015, 45: 198–210.

    Article  CAS  PubMed  Google Scholar 

  14. Xu GY, Shenoy M, Winston JH, Mittal S, Pasricha PJ. P2x receptor-mediated visceral hyperalgesia in a rat model of chronic visceral hypersensitivity. Gut 2008, 57: 1230–1237.

    Article  CAS  PubMed  Google Scholar 

  15. Zhu L, Zhao L, Qu R, Zhu HY, Wang Y, Jiang X, et al. Adrenergic stimulation sensitizes trpv1 through upregulation of cystathionine beta-synthetase in a rat model of visceral hypersensitivity. Sci Rep 2015, 5: 16109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yuan B, Tang WH, Lu LJ, Zhou Y, Zhu HY, Zhou YL, et al. Tlr4 upregulates cbs expression through nf-kappab activation in a rat model of irritable bowel syndrome with chronic visceral hypersensitivity. World J Gastroenterol 2015, 21: 8615–8628.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Du WJ, Hu S, Li X, Zhang PA, Jiang X, Yu SP, et al. Neonatal maternal deprivation followed by adult stress enhances adrenergic signaling to advance visceral hypersensitivity. Neurosci Bull 2019, 35: 4–14.

    Article  CAS  PubMed  Google Scholar 

  18. Kong X, Wei J, Wang D, Zhu X, Zhou Y, Wang S, et al. Upregulation of spinal voltage-dependent anion channel 1 contributes to bone cancer pain hypersensitivity in rats. Neurosci Bull 2017, 33: 711–721.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Dalgarno R, Leduc-Pessah H, Pilapil A, Kwok CH, Trang T. Intrathecal delivery of a palmitoylated peptide targeting y382-384 within the p2x7 receptor alleviates neuropathic pain. Mol Pain 2018, 14: 1744806918795793.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Su S, Shao J, Zhao Q, Ren X, Cai W, Li L, et al. Mir-30b attenuates neuropathic pain by regulating voltage-gated sodium channel nav1.3 in rats. Front Mol Neurosci 2017, 10: 126.

  21. Hu JH, Zheng XY, Yang JP, Wang LN, Ji FH. Involvement of spinal monocyte chemoattractant protein-1 (mcp-1) in cancer-induced bone pain in rats. Neurosci Lett 2012, 517: 60–63.

    Article  CAS  PubMed  Google Scholar 

  22. Zhao L, Xiao Y, Weng RX, Liu X, Zhang PA, Hu CY, et al. Neonatal colonic inflammation increases spinal transmission and cystathionine beta-synthetase expression in spinal dorsal horn of rats with visceral hypersensitivity. Front Pharmacol 2017, 8: 696.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Li H, Huang W, Luo R. The microrna-325 inhibits hepatocellular carcinoma progression by targeting high mobility group box 1. Diagn Pathol 2015, 10: 117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Abidin SZ, Leong JW, Mahmoudi M, Nordin N, Abdullah S, Cheah PS, et al. In silico prediction and validation of gfap as an mir-3099 target in mouse brain. Neurosci Bull 2017, 33: 373–382.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Distrutti E, Cipriani S, Mencarelli A, Renga B, Fiorucci S. Probiotics vsl#3 protect against development of visceral pain in murine model of irritable bowel syndrome. PLoS One 2013, 8: e63893.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Illias AM, Gist AC, Zhang H, Kosturakis AK, Dougherty PM. Chemokine ccl2 and its receptor ccr2 in the dorsal root ganglion contribute to oxaliplatin-induced mechanical hypersensitivity. Pain 2018, 159:1308-1316.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Tanaka T, Minami M, Nakagawa T, Satoh M. Enhanced production of monocyte chemoattractant protein-1 in the dorsal root ganglia in a rat model of neuropathic pain: Possible involvement in the development of neuropathic pain. Neurosci Res 2004, 48: 463–469.

    Article  CAS  PubMed  Google Scholar 

  28. 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.

    Article  CAS  PubMed  Google Scholar 

  29. Liu S, Gao H, Gao C, Liu W, Xing D. Bindarit attenuates pain and cancer-related inflammation by influencing myeloid cells in a model of bone cancer. Arch Immunol Ther Exp (Warsz) 2018, 66: 221–229.

    Article  CAS  Google Scholar 

  30. Wu Z, Chang J, Ren W, Hu Z, Li B, Liu H. Bindarit reduces the incidence of acute aortic dissection complicated lung injury via modulating nf-kappab pathway. Exp Ther Med 2017, 14: 2613–2618.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 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.

    Article  CAS  PubMed  Google Scholar 

  32. McCoy ES, Taylor-Blake B, Zylka MJ. Cgrpalpha-expressing sensory neurons respond to stimuli that evoke sensations of pain and itch. PLoS One 2012, 7: e36355.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Han Q, Liu D, Convertino M, Wang Z, Jiang C, Kim YH, et al. Mirna-711 binds and activates trpa1 extracellularly to evoke acute and chronic pruritus. Neuron 2018, 99: 449–463 e446.

    Google Scholar 

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (81471137, 31730040, and 81771187) and from the Priority Academic Program Development of Jiangsu Higher Education Institutions of China.

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Author notes

  1. Rui Wu and Ping-An Zhang have contributed equally to this work.

Authors and Affiliations

  1. Center for Translational Medicine, Affiliated Zhangjiagang Hospital of Soochow University, Zhangjiagang, 215600, China

    Rui Wu, Ping-An Zhang, Meijie Xu & Guang-Yin Xu

  2. Department of Physiology and Neurobiology, Institute of Neuroscience, Soochow University, Suzhou, 215123, China

    Rui Wu, Ping-An Zhang, Xuelian Liu, Yuan Zhou, Xinghong Jiang & Guang-Yin Xu

  3. The Second Affiliated of Hospital Soochow University, Suzhou, 215004, China

    Jun Yan

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  1. Rui Wu
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Correspondence to Guang-Yin Xu.

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Wu, R., Zhang, PA., Liu, X. et al. Decreased miR-325-5p Contributes to Visceral Hypersensitivity Through Post-transcriptional Upregulation of CCL2 in Rat Dorsal Root Ganglia. Neurosci. Bull. 35, 791–801 (2019). https://doi.org/10.1007/s12264-019-00372-x

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