Skip to main content

Advertisement

SpringerLink
Log in

Role of TRPV4-P2X7 Pathway in Neuropathic Pain in Rats with Chronic Compression of the Dorsal Root Ganglion

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Transient receptor potential vanilloid 4 (TRPV4) is a Ca2+-permeable non-selective cation channel that is involved in the development of neuropathic pain. P2X7 receptor (P2X7) belongs to a class of ATP-gated nonselective cation channels that plays an important role in neuropathic pain. Nevertheless, little is known about the interaction between them for neuropathic pain. In this paper, we investigated role of TRPV4-P2X7 pathway in neuropathic pain. We evaluated the effect of TRPV4-P2X7 pathway on neuropathic pain in a chronic compression of the dorsal root ganglion (DRG) (hereafter termed CCD) model. We analyzed the effect of P2X7 on mechanical and thermal hyperalgesia mediated by TRPV4 in CCD. Furthermore, we assessed the effect of TRPV4 on the expression of P2X7 and the release of IL-1β and IL-6 in DRG after CCD. We found that intraperitoneal injection of TRPV4 agonist GSK-1016790A led to a significant increase of mechanical and thermal hyperalgesia in CCD, which was partially suppressed by P2X7 blockade with antagonist Brilliant Blue G (BBG). Then, we further noticed that GSK-1016790A injection increased the P2X7 expression of CCD, which was decreased by TRPV4 blockade with antagonist RN-1734 and HC-067047. Furthermore, we also discovered that the expressions of IL-1β and IL-6 were upregulated by GSK-1016790A injection but reduced by RN-1734 and HC-067047. Our results provide evidence that P2X7 contributes to development of neuropathic pain mediated by TRPV4 in the CCD model, which may be the basis for treatment of neuropathic pain relief.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Jensen TS, Baron R, Haanpaa M, Kalso E, Loeser JD, Rice AS, Treede RD (2011) A new definition of neuropathic pain. Pain 152:2204–2205

    Article  PubMed  Google Scholar 

  2. Moore C, Gupta R, Jordt SE, Chen Y, Liedtke WB (2018) Regulation of pain and Itch by TRP channels. Neurosci Bull 34:120–142

    Article  CAS  PubMed  Google Scholar 

  3. Everaerts W, Nilius B, Owsianik G (2010) The vanilloid transient receptor potential channel TRPV4: from structure to disease. Prog Biophys Mol Biol 103:2–17

    Article  CAS  PubMed  Google Scholar 

  4. Costa R, Bicca MA, Manjavachi MN, Segat GC, Dias FC, Fernandes ES, Calixto JB (2018) Kinin receptors sensitize TRPV4 channel and induce mechanical hyperalgesia: relevance to paclitaxel-induced peripheral neuropathy in mice. Mol Neurobiol 55:2150–2161

    Article  CAS  PubMed  Google Scholar 

  5. Materazzi S, Fusi C, Benemei S, Pedretti P, Patacchini R, Nilius B, Prenen J, Creminon C, Geppetti P, Nassini R (2012) TRPA1 and TRPV4 mediate paclitaxel-induced peripheral neuropathy in mice via a glutathione-sensitive mechanism. Pflugers Arch 463:561–569

    Article  CAS  PubMed  Google Scholar 

  6. Maqboul A, Elsadek B (2018) Expression profiles of TRPV1, TRPV4, TLR4 and ERK1/2 in the dorsal root ganglionic neurons of a cancer-induced neuropathy rat model. PeerJ 6:e4622

    Article  PubMed  PubMed Central  Google Scholar 

  7. Ding XL, Wang YH, Ning LP, Zhang Y, Ge HY, Jiang H, Wang R, Yue SW (2010) Involvement of TRPV4-NO-cGMP-PKG pathways in the development of thermal hyperalgesia following chronic compression of the dorsal root ganglion in rats. Behav Brain Res 208:194–201

    Article  CAS  PubMed  Google Scholar 

  8. Ning L, Wang C, Fan X, Ding X, Wang Y, Zhang Y, Wang J, Yue S (2014) Role of colchicine-induced microtubule depolymerization in hyperalgesia via TRPV4 in rats with chronic compression of the dorsal root ganglion. Neurol Res 36:70–78

    Article  CAS  PubMed  Google Scholar 

  9. Rahman M, Sun R, Mukherjee S, Nilius B, Janssen LJ (2018) TRPV4 stimulation releases ATP via pannexin channels in human pulmonary fibroblasts. Am J Respir Cell Mol Biol 59:87–95

    Article  CAS  PubMed  Google Scholar 

  10. Ohsaki A, Tanuma SI, Tsukimoto M (2018) TRPV4 channel-regulated ATP release contributes to gamma-irradiation-induced production of IL-6 and IL-8 in epidermal keratinocytes. Biol Pharm Bull 41:1620–1626

    Article  CAS  PubMed  Google Scholar 

  11. Bonvini SJ, Birrell MA, Grace MS, Maher SA, Adcock JJ, Wortley MA, Dubuis E, Ching YM, Ford AP, Shala F, Miralpeix M, Tarrason G, Smith JA, Belvisi MG (2016) Transient receptor potential cation channel, subfamily V, member 4 and airway sensory afferent activation: role of adenosine triphosphate. J Allergy Clin Immunol 138(249–261):e212

    Google Scholar 

  12. Burnstock G, Kennedy C (1985) Is there a basis for distinguishing two types of P2-purinoceptor? Gen Pharmacol 16:433–440

    Article  CAS  PubMed  Google Scholar 

  13. Kolachala VL, Bajaj R, Chalasani M, Sitaraman SV (2008) Purinergic receptors in gastrointestinal inflammation. Am J Physiol Gastrointest Liver Physiol 294:G401-410

    Article  CAS  PubMed  Google Scholar 

  14. Kennedy C, Burnstock G (1985) ATP produces vasodilation via P1 purinoceptors and vasoconstriction via P2 purinoceptors in the isolated rabbit central ear artery. Blood Vessels 22:145–155

    CAS  PubMed  Google Scholar 

  15. Abbracchio MP, Burnstock G (1994) Purinoceptors: are there families of P2X and P2Y purinoceptors? Pharmacol Ther 64:445–475

    Article  CAS  PubMed  Google Scholar 

  16. Burnstock G (2016) Purinergic mechanisms and pain. Adv Pharmacol 75:91–137

    Article  CAS  PubMed  Google Scholar 

  17. Burnstock G (2013) Purinergic mechanisms and pain–an update. Eur J Pharmacol 716:24–40

    Article  CAS  PubMed  Google Scholar 

  18. Zou L, Gong Y, Liu S, Liang S (2019) Natural compounds acting at P2 receptors alleviate peripheral neuropathy. Brain Res Bull 151:125–131

    Article  CAS  PubMed  Google Scholar 

  19. Liu PY, Lee IH, Tan PH, Wang YP, Tsai CF, Lin HC, Lee FY, Lu CL (2015) P2X7 receptor mediates spinal microglia activation of visceral hyperalgesia in a rat model of chronic pancreatitis. Cell Mol Gastroenterol Hepatol 1(710–720):e715

    Google Scholar 

  20. Xie J, Liu S, Wu B, Li G, Rao S, Zou L, Yi Z, Zhang C, Jia T, Zhao S, Schmalzing G, Hausmann R, Nie H, Li G, Liang S (2017) The protective effect of resveratrol in the transmission of neuropathic pain mediated by the P2X7 receptor in the dorsal root ganglia. Neurochem Int 103:24–35

    Article  CAS  PubMed  Google Scholar 

  21. Chu YX, Zhang Y, Zhang YQ, Zhao ZQ (2010) Involvement of microglial P2X7 receptors and downstream signaling pathways in long-term potentiation of spinal nociceptive responses. Brain Behav Immun 24:1176–1189

    Article  CAS  PubMed  Google Scholar 

  22. Thoppil RJ, Adapala RK, Cappelli HC, Kondeti V, Dudley AC, Gary Meszaros J, Paruchuri S, Thodeti CK (2015) TRPV4 channel activation selectively inhibits tumor endothelial cell proliferation. Sci Rep 5:14257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Mueller-Tribbensee SM, Karna M, Khalil M, Neurath MF, Reeh PW, Engel MA (2015) Differential contribution of TRPA1, TRPV4 and TRPM8 to colonic nociception in mice. PLoS ONE 10:e0128242

    Article  PubMed  PubMed Central  Google Scholar 

  24. Everaerts W, Zhen X, Ghosh D, Vriens J, Gevaert T, Gilbert JP, Hayward NJ, McNamara CR, Xue F, Moran MM, Strassmaier T, Uykal E, Owsianik G, Vennekens R, De Ridder D, Nilius B, Fanger CM, Voets T (2010) Inhibition of the cation channel TRPV4 improves bladder function in mice and rats with cyclophosphamide-induced cystitis. Proc Natl Acad Sci USA 107:19084–19089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Rodriguez-Alvarez N, Jimenez-Mateos EM, Engel T, Quinlan S, Reschke CR, Conroy RM, Bhattacharya A, Boylan GB, Henshall DC (2017) Effects of P2X7 receptor antagonists on hypoxia-induced neonatal seizures in mice. Neuropharmacology 116:351–363

    Article  CAS  PubMed  Google Scholar 

  26. Sakamoto K, Endo K, Suzuki T, Fujimura K, Kurauchi Y, Mori A, Nakahara T, Ishii K (2015) P2X7 receptor antagonists protect against N-methyl-d-aspartic acid-induced neuronal injury in the rat retina. Eur J Pharmacol 756:52–58

    Article  CAS  PubMed  Google Scholar 

  27. Zhang Y, Wang YH, Ge HY, Arendt-Nielsen L, Wang R, Yue SW (2008) A transient receptor potential vanilloid 4 contributes to mechanical allodynia following chronic compression of dorsal root ganglion in rats. Neurosci Lett 432:222–227

    Article  CAS  PubMed  Google Scholar 

  28. Qu YJ, Jia L, Zhang X, Wei H, Yue SW (2016) MAPK pathways are involved in neuropathic pain in rats with chronic compression of the dorsal root ganglion. Evid-Based Complement Altern Med 2016:6153215

    Article  Google Scholar 

  29. Kobayashi K, Yamanaka H, Noguchi K (2013) Expression of ATP receptors in the rat dorsal root ganglion and spinal cord. Anat Sci Int 88:10–16

    Article  CAS  PubMed  Google Scholar 

  30. Chen Y, Li G, Huang LY (2012) P2X7 receptors in satellite glial cells mediate high functional expression of P2X3 receptors in immature dorsal root ganglion neurons. Mol Pain 8:9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hu SJ, Xing JL (1998) An experimental model for chronic compression of dorsal root ganglion produced by intervertebral foramen stenosis in the rat. Pain 77:15–23

    Article  PubMed  Google Scholar 

  32. Song XJ, Xu DS, Vizcarra C, Rupert RL (2003) Onset and recovery of hyperalgesia and hyperexcitability of sensory neurons following intervertebral foramen volume reduction and restoration. J Manipulative Physiol Ther 26:426–436

    Article  PubMed  Google Scholar 

  33. Ma C, Greenquist KW, Lamotte RH (2006) Inflammatory mediators enhance the excitability of chronically compressed dorsal root ganglion neurons. J Neurophysiol 95:2098–2107

    Article  CAS  PubMed  Google Scholar 

  34. Zhou J, Feng D, Zhang X, Xia C, Zhang Z, Kang J, Tan Z, Wu B (2019) Involvement of P2X7 receptors in satellite glial cells of dorsal root ganglia in the BmK I -induced pain model of rats. Gen Physiol Biophys 38:407–416

    Article  PubMed  Google Scholar 

  35. Chessell IP, Hatcher JP, Bountra C, Michel AD, Hughes JP, Green P, Egerton J, Murfin M, Richardson J, Peck WL, Grahames CB, Casula MA, Yiangou Y, Birch R, Anand P, Buell GN (2005) Disruption of the P2X7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain. Pain 114:386–396

    Article  CAS  PubMed  Google Scholar 

  36. Ji RR, Chamessian A, Zhang YQ (2016) Pain regulation by non-neuronal cells and inflammation. Science 354:572–577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Halassa MM, Fellin T, Haydon PG (2009) Tripartite synapses: roles for astrocytic purines in the control of synaptic physiology and behavior. Neuropharmacology 57:343–346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Koizumi S, Fujishita K, Inoue K (2005) Regulation of cell-to-cell communication mediated by astrocytic ATP in the CNS. Purinergic Signalling 1:211–217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Jasmin L, Vit JP, Bhargava A, Ohara PT (2010) Can satellite glial cells be therapeutic targets for pain control? Neuron Glia Biol 6:63–71

    Article  PubMed  PubMed Central  Google Scholar 

  40. North RA (2002) Molecular physiology of P2X receptors. Physiol Rev 82:1013–1067

    Article  CAS  PubMed  Google Scholar 

  41. Lecca D, Ceruti S, Fumagalli M, Abbracchio MP (2012) Purinergic trophic signalling in glial cells: functional effects and modulation of cell proliferation, differentiation, and death. Purinergic Signalling 8:539–557

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zhang X, Chen Y, Wang C, Huang LY (2007) Neuronal somatic ATP release triggers neuron-satellite glial cell communication in dorsal root ganglia. Proc Natl Acad Sci USA 104:9864–9869

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Mihara H, Boudaka A, Sugiyama T, Moriyama Y, Tominaga M (2011) Transient receptor potential vanilloid 4 (TRPV4)-dependent calcium influx and ATP release in mouse oesophageal keratinocytes. J Physiol 589:3471–3482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Turner RD, Birring SS (2019) Chronic cough: ATP, afferent pathways and hypersensitivity. Eur Respir Jl 54:1900889

    Article  CAS  Google Scholar 

  45. Clark AK, Staniland AA, Marchand F, Kaan TK, McMahon SB, Malcangio M (2010) P2X7-dependent release of interleukin-1beta and nociception in the spinal cord following lipopolysaccharide. J Neurosci 30:573–582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Li J, Li X, Jiang X, Yang M, Yang R, Burnstock G, Xiang Z, Yuan H (2017) Microvesicles shed from microglia activated by the P2X7-p38 pathway are involved in neuropathic pain induced by spinal nerve ligation in rats. Purinergic Signalling 13:13–26

    Article  PubMed  Google Scholar 

  47. Zhang J, Chu M (2019) Targeting of IL-6-relevant long noncoding RNA profiles in inflammatory and tumorous disease. Inflammation 42:1139–1146

    Article  CAS  PubMed  Google Scholar 

  48. Dubovy P, Brazda V, Klusakova I, Hradilova-Svizenska I (2013) Bilateral elevation of interleukin-6 protein and mRNA in both lumbar and cervical dorsal root ganglia following unilateral chronic compression injury of the sciatic nerve. J Neuroinflammation 10:55

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Shieh CH, Heinrich A, Serchov T, van Calker D, Biber K (2014) P2X7-dependent, but differentially regulated release of IL-6, CCL2, and TNF-alpha in cultured mouse microglia. Glia 62:592–607

    Article  PubMed  Google Scholar 

  50. Di Virgilio F, Dal Ben D, Sarti AC, Giuliani AL, Falzoni S (2017) The P2X7 receptor in infection and inflammation. Immunity 47:15–31

    Article  PubMed  Google Scholar 

  51. Rabah Y, Rubino B, Moukarzel E, Agulhon C (2020) Characterization of transgenic mouse lines for selectively targeting satellite glial cells and macrophages in dorsal root ganglia. PLoS ONE 15:e0229475

    Article  PubMed  PubMed Central  Google Scholar 

  52. Hu X, Liu Y, Wu J, Liu Y, Liu W, Chen J, Yang F (2020) Inhibition of P2X7R in the amygdala ameliorates symptoms of neuropathic pain after spared nerve injury in rats. Brain Behav Immun 88:507–514

    Article  CAS  PubMed  Google Scholar 

  53. Shi J, Jiang K, Li Z (2018) MiR-145 ameliorates neuropathic pain via inhibiting inflammatory responses and mTOR signaling pathway by targeting Akt3 in a rat model. Neurosci Res 134:10–17

    Article  CAS  PubMed  Google Scholar 

  54. Sluyter R (2017) The P2X7 Receptor. Adv Exp Med Biol 1051:17–53

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant No. 81401868, Liping Ning; Grant No. 81502148, Chuanwei Wang), the Shandong Province Medical and Health Science and Technology Development Project (Grant No. 2017WS468, Liang Zhou), and the Teaching reform and research project of undergraduate education in Clinical Medicine College of Shandong University (Grant No. LCJY-72, Shaocan Tang).

Author information

Authors and Affiliations

  1. Department of Rehabilitation Medicine, Shandong Provincial Hospital, 324 Jing Wu Wei Qi Road, Jinan, 250012, China

    Xiaohua Fan, Xinli Ding, Shaocan Tang & Liping Ning

  2. Department of Neurosurgery, Qilu Hospital Affiliated To Shandong University, 44 West Wenhua Road, Jinan, 250012, China

    Chuanwei Wang

  3. Department of Rehabilitation Medicine, Shandong First Medical University, Taian, 250012, China

    Xiaohua Fan, Junting Han, Xinli Ding, Shaocan Tang & Liping Ning

Authors
  1. Xiaohua Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chuanwei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Junting Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xinli Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shaocan Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Liping Ning
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Liping Ning.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Ethical Approval

Experiments were approved by the Institutional Animal Care and Use Committee of Shandong Provincial Hospital.

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (TIF 4963 kb)

Confocal laser scanning micrographs of SGCs showing immunostaining for P2X7 (green; A) and GFAP (red; B) in CCD rats. C. Merged image showed a partial colocalization between P2X7 and GFAP. Scale bars=25um, n = 3 rats in each group.

Supplementary file2 (TIF 3475 kb)

Role of TRPV4 antagonist in hyperalgesia of CCD rats. A: Effect of RN-1734 and HC-067047 on CCD-induced mechanical hyperalgesia. B: Effect of RN-1734 and HC-067047 on CCD-induced thermal hyperalgesia. **P < 0.01 compared with sham group. ##P < 0.01 compared with CCD+NS group. n = 6 rats in each group. CCD: chronic compression of the dorsal root ganglion; PWMT: paw withdrawal mechanical threshold; PWTL: paw withdrawal thermal latency.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fan, X., Wang, C., Han, J. et al. Role of TRPV4-P2X7 Pathway in Neuropathic Pain in Rats with Chronic Compression of the Dorsal Root Ganglion. Neurochem Res 46, 2143–2153 (2021). https://doi.org/10.1007/s11064-021-03352-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-021-03352-8

Keywords

Search

Navigation