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Spinal P2X4 Receptors Involved in Visceral Hypersensitivity of Neonatal Maternal Separation Rats

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Abstract

Recent studies have demonstrated the vital role of P2X4 receptors (a family of ATP-gated non-selective cation channels) in the transmission of neuropathic and inflammatory pain. In this study, we investigated the role of spinal P2X4 receptors in chronic functional visceral hypersensitivity of neonatal maternal separation (NMS) rats. A rat model of irritable bowel syndrome was established by neonatal maternal separation. Visceral sensitivity was assessed by recording the response of the external oblique abdominal muscle to colorectal distension. P2X4 receptor antagonist and agonist were administrated intrathecally. The expression of P2X4 receptor was examined by Western Blot and immunofluorescence. The effect of P2X4 receptor antagonist on expression of brain-derived neurotrophic factor (BDNF) was assessed by Western Blot. We found neonatal maternal separation enhanced visceral hypersensitivity and increased the expression of P2X4 receptor in spinal thoracolumbar and lumbosacral segments of rats. Pharmacological results showed that visceral sensitivity was attenuated after intrathecal injection of P2X4 receptor antagonist, 5-BDBD, at doses of 10 nM or 100 nM, while visceral sensitivity was enhanced after intrathecal injection of P2X4 receptor agonist C5-TDS at doses of 10 μM or 15 μM. In addition, the spinal expression of BDNF significantly increased in NMS rats and intrathecal injection of 5-BDBD significantly decreased the expression of BDNF especially in NMS rats. C5-TDS failed to increase EMG amplitude in the presence of ANA-12 in control rats. Our results suggested the spinal P2X4 receptors played an important role in visceral hypersensitivity of NMS rats through BDNF.

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Data availability

The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Taft TH, Keszthelyi D, Van Oudenhove L (2021) A Review of Irritable Bowel Syndrome. Jama-J Am Med Assoc 326:189–189 (<Go to ISI>://WOS:000672962200024)

    Article  Google Scholar 

  2. Tsuda M, Tozaki-Saitoh H, Inoue K (2010) Pain and purinergic signaling. Brain research reviews 63: 222–32. http://www.ncbi.nlm.nih.gov/pubmed/19931560, https://www.sciencedirect.com/science/article/abs/pii/S0165017309001222?via%3Dihub

  3. Tsuda M, Tozaki-Saitoh H, Inoue K (2012) Purinergic system, microglia and neuropathic pain. Current opinion in pharmacology 12: 74–9. http://www.ncbi.nlm.nih.gov/pubmed/22036170

  4. Tsuda M, Shigemoto-Mogami Y, Koizumi S, Mizokoshi A, Kohsaka S, et al. (2003) P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 424: 778–83. http://www.ncbi.nlm.nih.gov/pubmed/12917686

  5. Inoue K, Tsuda M (2012) P2X4 receptors of microglia in neuropathic pain. CNS & neurological disorders drug targets 11: 699–704. http://www.ncbi.nlm.nih.gov/pubmed/22963435

  6. Chen L, Liu YW, Yue K, Ru Q, Xiong Q, et al. (2016) Differential expression of ATP-gated P2X receptors in DRG between chronic neuropathic pain and visceralgia rat models. Purinergic signalling 12: 79–87. http://www.ncbi.nlm.nih.gov/pubmed/26531254

  7. Obata K, Noguchi K (2006) BDNF in sensory neurons and chronic pain. Neuroscience research 55: 1–10. http://www.ncbi.nlm.nih.gov/pubmed/16516994

  8. Lever IJ, Bradbury EJ, Cunningham JR, Adelson DW, Jones MG, et al. (2001) Brain-derived neurotrophic factor is released in the dorsal horn by distinctive patterns of afferent fiber stimulation. The Journal of neuroscience : the official journal of the Society for Neuroscience 21: 4469–77. http://www.ncbi.nlm.nih.gov/pubmed/11404434

  9. Pezet S, Malcangio M, McMahon SB (2002) BDNF: a neuromodulator in nociceptive pathways? Brain research Brain research reviews 40: 240–9. http://www.ncbi.nlm.nih.gov/pubmed/12589922

  10. Garraway SM, Petruska JC, Mendell LM (2003) BDNF sensitizes the response of lamina II neurons to high threshold primary afferent inputs. The European journal of neuroscience 18: 2467–76. http://www.ncbi.nlm.nih.gov/pubmed/14622147

  11. Zimmermann M (1983) Ethical guidelines for investigations of experimental pain in conscious animals. Pain 16: 109–110. http://www.ncbi.nlm.nih.gov/pubmed/6877845

  12. Kannampalli P, Sengupta JN (2015) Role of principal ionotropic and metabotropic receptors in visceral pain. Journal of neurogastroenterology and motility 21: 147–58. http://www.ncbi.nlm.nih.gov/pubmed/25843070

  13. Tang Y, Chen A, Chen Y, Guo L, Dai H, et al. (2016) Zeta Inhibitory Peptide as a Novel Therapy to Control Chronic Visceral Hypersensitivity in a Rat Model. PloS one 11: e0163324. http://www.ncbi.nlm.nih.gov/pubmed/27776136

  14. Sawynok J (2007) Adenosine and ATP receptors. Handbook of experimental pharmacology: 309–28. http://www.ncbi.nlm.nih.gov/pubmed/17087128

  15. Burnstock G (2006) Pathophysiology and therapeutic potential of purinergic signaling. Pharmacological reviews 58: 58–86. http://www.ncbi.nlm.nih.gov/pubmed/16507883

  16. Hu J, Qin X, Song ZY, Yang PP, Feng Y, et al. (2017) Alpha-lipoic Acid suppresses P2X receptor activities and visceral hypersensitivity to colorectal distention in diabetic rats. Scientific reports 7: 3928. http://www.ncbi.nlm.nih.gov/pubmed/28659591

  17. Xu GY, Li G, Liu N, Huang LY (2011) Mechanisms underlying purinergic P2X3 receptor-mediated mechanical allodynia induced in diabetic rats. Molecular pain 7: 60. http://www.ncbi.nlm.nih.gov/pubmed/21851615

  18. Wu B, Ma Y, Yi Z, Liu S, Rao S, et al. (2017) Resveratrol-decreased hyperalgesia mediated by the P2X7 receptor in gp120-treated rats. Molecular pain 13: 1744806917707667. http://www.ncbi.nlm.nih.gov/pubmed/28554250

  19. Zhang PA, Zhu HY, Xu QY, Du WJ, Hu S, et al. (2018) Sensitization of P2X3 receptors in insular cortex contributes to visceral pain of adult rats with neonatal maternal deprivation. Molecular pain 14: 1744806918764731. http://www.ncbi.nlm.nih.gov/pubmed/29560791

  20. Inoue K (2017) Purinergic signaling in microglia in the pathogenesis of neuropathic pain. Proceedings of the Japan Academy Series B, Physical and biological sciences 93: 174–182. http://www.ncbi.nlm.nih.gov/pubmed/28413195

  21. Ji RR, Berta T, Nedergaard M (2013) Glia and pain: is chronic pain a gliopathy? Pain 154 Suppl 1: S10-S28. http://www.ncbi.nlm.nih.gov/pubmed/23792284

  22. Tsuda M, Masuda T, Tozaki-Saitoh H, Inoue K (2013) P2X4 receptors and neuropathic pain. Frontiers in cellular neuroscience 7: 191. http://www.ncbi.nlm.nih.gov/pubmed/24191146

  23. Ming Q, Wang J, Li D, Rong C, Rao Z (2006) The changes of p2x4 receptor expression in nucleus of tractus solitarius and the dorsal horn of thoracic cord after visceral pain induced by acetic acid (in Chinese). J Neuroanatomy 05:551–554

    Google Scholar 

  24. Trang T, Salter MW (2012) P2X4 purinoceptor signaling in chronic pain. Purinergic signalling 8: 621–8. http://www.ncbi.nlm.nih.gov/pubmed/22528681

  25. Kuan YH, Shyu BC (2016) Nociceptive transmission and modulation via P2X receptors in central pain syndrome. Molecular brain 9: 58. http://www.ncbi.nlm.nih.gov/pubmed/27230068

  26. Liu C, Zhang Y, Liu Q, Jiang L, Li M, et al. (2018) P2X4-receptor participates in EAAT3 regulation via BDNF-TrkB signaling in a model of trigeminal allodynia. Molecular pain 14: 1744806918795930. http://www.ncbi.nlm.nih.gov/pubmed/30146940

  27. Bekinschtein P, Cammarota M, Katche C, Slipczuk L, Rossato JI, et al. (2008) BDNF is essential to promote persistence of long-term memory storage. Proceedings of the National Academy of Sciences of the United States of America 105: 2711–6. http://www.ncbi.nlm.nih.gov/pubmed/18263738

  28. Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, et al. (2005) BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438: 1017–21. http://www.ncbi.nlm.nih.gov/pubmed/16355225

  29. Sorge RE, Mapplebeck JC, Rosen S, Beggs S, Taves S, et al. (2015) Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nature neuroscience 18: 1081–3. http://www.ncbi.nlm.nih.gov/pubmed/26120961

  30. Yuan B, Tang WH, Lu LJ, Zhou Y, Zhu HY, et al. (2015) TLR4 upregulates CBS expression through NF-kappaB activation in a rat model of irritable bowel syndrome with chronic visceral hypersensitivity. World journal of gastroenterology 21: 8615–28. http://www.ncbi.nlm.nih.gov/pubmed/26229403

  31. Lin C, Al-Chaer ED (2003) Long-term sensitization of primary afferents in adult rats exposed to neonatal colon pain. Brain research 971: 73–82. http://www.ncbi.nlm.nih.gov/pubmed/12691839

  32. Toyomitsu E, Tsuda M, Yamashita T, Tozaki-Saitoh H, Tanaka Y, et al. (2012) CCL2 promotes P2X4 receptor trafficking to the cell surface of microglia. Purinergic signalling 8: 301–10. http://www.ncbi.nlm.nih.gov/pubmed/22222817

  33. Yamashita T, Yamamoto S, Zhang J, Kometani M, Tomiyama D, et al. (2016) Duloxetine Inhibits Microglial P2X4 Receptor Function and Alleviates Neuropathic Pain after Peripheral Nerve Injury. PloS one 11: e0165189. http://www.ncbi.nlm.nih.gov/pubmed/27768754

  34. Chen A, Chen Y, Tang Y, Bao C, Cui Z, et al. (2017) Hippocampal AMPARs involve the central sensitization of rats with irritable bowel syndrome. Brain and behavior 7: e00650. http://www.ncbi.nlm.nih.gov/pubmed/28293483

  35. Xiao Y, Chen X, Zhang PA, Xu Q, Zheng H, et al. (2016) TRPV1-mediated presynaptic transmission in basolateral amygdala contributes to visceral hypersensitivity in adult rats with neonatal maternal deprivation. Scientific reports 6: 29026. http://www.ncbi.nlm.nih.gov/pubmed/27364923

  36. Lalisse S, Hua J, Lenoir M, Linck N, Rassendren F, et al. (2018) Sensory neuronal P2RX4 receptors controls BDNF signaling in inflammatory pain. Scientific reports 8: 964. http://www.ncbi.nlm.nih.gov/pubmed/29343707

  37. de Rivero Vaccari JP, Bastien D, Yurcisin G, Pineau I, Dietrich WD, et al. (2012) P2X4 receptors influence inflammasome activation after spinal cord injury. The Journal of neuroscience : the official journal of the Society for Neuroscience 32: 3058–66. http://www.ncbi.nlm.nih.gov/pubmed/22378878

  38. Trang T, Beggs S, Salter MW (2012) ATP receptors gate microglia signaling in neuropathic pain. Experimental neurology 234: 354–61. http://www.ncbi.nlm.nih.gov/pubmed/22116040

  39. Masuda T, Iwamoto S, Yoshinaga R, Tozaki-Saitoh H, Nishiyama A, et al. (2014) Transcription factor IRF5 drives P2X4R+-reactive microglia gating neuropathic pain. Nature communications 5: 3771. http://www.ncbi.nlm.nih.gov/pubmed/24818655

  40. Masuda T, Tsuda M, Yoshinaga R, Tozaki-Saitoh H, Ozato K, et al. (2012) IRF8 is a critical transcription factor for transforming microglia into a reactive phenotype. Cell reports 1: 334–340. http://www.ncbi.nlm.nih.gov/pubmed/22832225

  41. Bathina S, Das UN (2015) Brain-derived neurotrophic factor and its clinical implications. Archives of medical science : AMS 11: 1164–78. http://www.ncbi.nlm.nih.gov/pubmed/26788077

  42. Saito A, Cai L, Matsuhisa K, Ohtake Y, Kaneko M, et al. (2018) Neuronal activity-dependent local activation of dendritic unfolded protein response promotes expression of brain-derived neurotrophic factor in cell soma. Journal of neurochemistry 144: 35–49. http://www.ncbi.nlm.nih.gov/pubmed/28921568

  43. Azogu I, Plamondon H (2017) Inhibition of TrkB at the nucleus accumbens, using ANA-12, regulates basal and stress-induced orexin A expression within the mesolimbic system and affects anxiety, sociability and motivation. Neuropharmacology 125:129–145 (<Go to ISI>://WOS:000411775700011)

    Article  CAS  PubMed  Google Scholar 

  44. Barnes AK, Koul-Tiwari R, Garner JM, Geist PA, Datta S (2017) Activation of brain-derived neurotrophic factor-tropomyosin receptor kinase B signaling in the pedunculopontine tegmental nucleus: a novel mechanism for the homeostatic regulation of rapid eye movement sleep. J Neurochem 141:111–123 (<Go to ISI>://WOS:000397502400010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by grants from Fujian Science and Technology Innovation Joint Fund (2016Y9036, 2018Y9069), Natural Science Foundation of Fujian Province (2020J01608), Financial Special Fund of Fujian Province (2019B028), and Educational Research Projects for Young and Middle-aged Teachers of Fujian Provincial Education Department (JAT190172).

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Authors and Affiliations

  1. Pain Research Institute, Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350108, People’s Republic of China

    Ying Tang, Bin Liu, Pei Sun, Zhong Chen, Yang Huang, Chen Ai-qin, Yu Chen & Chun Lin

  2. School of Pharmacy Sciences, Fujian Medical University, Fuzhou, 350108, People’s Republic of China

    Li Chen

  3. Department of Pediatrics, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350108, People’s Republic of China

    Chun Lin

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  1. Ying Tang
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Contributions

CL and AC designed the study. BL, PS, ZC, YC, LC, and YT collected and analyzed the data. YH advised on histological staining and analysis. YT and LC drafted and wrote the manuscript. CL and AC revised the manuscript critically for intellectual content. All authors gave intellectual input to the study and approved the final version of the manuscript.

Corresponding author

Correspondence to Chun Lin.

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Ethical approval

All animal experiments were approved by the Animal Care and Use Committee, and the study protocol was approved by the Fujian Medical University. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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The authors declare that they have no competing interests.

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Tang, Y., Chen, L., Liu, B. et al. Spinal P2X4 Receptors Involved in Visceral Hypersensitivity of Neonatal Maternal Separation Rats. Purinergic Signalling 19, 113–122 (2023). https://doi.org/10.1007/s11302-022-09868-0

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