Effects of resveratrol in the signaling of neuropathic pain involving P2X3 in the dorsal root ganglion of rats

  • Jinhui GuoEmail author
  • Chaowei Wang
  • Xiaolu Niu
  • Fang Zhou
  • Huiling Li
  • Weifang Gao
Original article


Neuropathic pain is a major public health problem because it has a considerable impact on life quality of patients. Neuropathic pain caused by a lesion or disease of the somatosensory nervous system, which causes unpleasant and abnormal sensation (dysesthesia), an increased response to painful stimuli (hyperalgesia), and pain in response to a stimulus that does not normally provoke pain (allodynia). P2X receptors from dorsal root ganglion (DRG) play a crucial role in facilitating pain transmission at peripheral and spinal sites. Resveratrol (Res) has neuroprotective effects and improves the pathological and behavioral outcomes of various types of nerve injury. The present study examined the effects of Res on neuropathic pain. Neuropathic pain animal model was created by partial sciatic nerve ligation (pSNL) surgery. We found that consecutive intraperitoneal administration of Res for 21 days reduced the mechanical and thermal nociceptive responses induced by pSNL in a dose-dependent manner. Moreover, Res administration reversed P2X3 expression and phosphorylation of ERK in DRG neurons after peripheral nerve injury. Our results suggested that Res may ameliorate neuropathic pain by suppressing P2X3 up-regulation and ERK phosphorylation in DRG of neuropathic pain rats. Therefore, we concluded that Res has a significant analgesic effect on alleviating neuropathic pain, and thus may serve as a therapeutic approach for neuropathic pain.


Resveratrol Chinese medicine P2X3 DRG Neuropathic pain 


Author contributions

JG was responsible for the concept and design of the study; JG, CW, XN, FZ, HL and WG were involved with experimental and analytical aspects of the manuscript; JG performed data interpretation, presentation and writing of the manuscript.


This work was supported by Grant from Start-up Foundation of Xinxiang Medical University (no. 20170156).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Burke D, Fullen BM, Stokes D, Lennon O (2017) Neuropathic pain prevalence following spinal cord injury: a systematic review and meta-analysis. Eur J Pain 21(1):29–44. CrossRefGoogle Scholar
  2. 2.
    Hao Y, Luo X, Ba X, Wang J, Zhou S, Yang S, Fang C, Jiang C, Sun W (2018) Huachansu suppresses TRPV1 up-regulation and spinal astrocyte activation to prevent oxaliplatin-induced peripheral neuropathic pain in rats. Gene 680:43–50. CrossRefGoogle Scholar
  3. 3.
    Finnerup NB, Haroutounian S, Kamerman P, Baron R, Bennett DL, Bouhassira D, Cruccu G, Freeman R, Hansson P, Nurmikko T, Raja SN, Rice AS, Serra J, Smith BH, Treede RD, Jensen TS (2016) Neuropathic pain: an updated grading system for research and clinical practice. Pain 157(8):1599–1606. CrossRefGoogle Scholar
  4. 4.
    Burnstock G (2009) Purinergic receptors and pain. Curr Pharm Des 15(15):1717–1735CrossRefGoogle Scholar
  5. 5.
    North RA (2002) Molecular physiology of P2X receptors. Physiol Rev 82(4):1013–1067. CrossRefGoogle Scholar
  6. 6.
    Xiang Z, Xiong Y, Yan N, Li X, Mao Y, Ni X, He C, LaMotte RH, Burnstock G, Sun J (2008) Functional up-regulation of P2X3 receptors in the chronically compressed dorsal root ganglion. Pain 140(1):23–34. CrossRefGoogle Scholar
  7. 7.
    Maruo K, Yamamoto H, Yamamoto S, Nagata T, Fujikawa H, Kanno T, Yaguchi T, Maruo S, Yoshiya S, Nishizaki T (2006) Modulation of P2X receptors via adrenergic pathways in rat dorsal root ganglion neurons after sciatic nerve injury. Pain 120(1–2):106–112. CrossRefGoogle Scholar
  8. 8.
    Mo G, Bernier LP, Zhao Q, Chabot-Dore AJ, Ase AR, Logothetis D, Cao CQ, Seguela P (2009) Subtype-specific regulation of P2X3 and P2X2/3 receptors by phosphoinositides in peripheral nociceptors. Mol Pain 5:47. CrossRefGoogle Scholar
  9. 9.
    Cantin LD, Bayrakdarian M, Buon C, Grazzini E, Hu YJ, Labrecque J, Leung C, Luo X, Martino G, Pare M, Payza K, Popovic N, Projean D, Santhakumar V, Walpole C, Yu XH, Tomaszewski MJ (2012) Discovery of P2X3 selective antagonists for the treatment of chronic pain. Bioorg Med Chem Lett 22(7):2565–2571. CrossRefGoogle Scholar
  10. 10.
    Xu GY, Li G, Liu N, Huang LY (2011) Mechanisms underlying purinergic P2X3 receptor-mediated mechanical allodynia induced in diabetic rats. Mol Pain 7:60. Google Scholar
  11. 11.
    Schiavuzzo JG, Teixeira JM, Melo B, da Silva dos Santos DF, Jorge CO, Oliveira-Fusaro MC, Parada CA (2015) Muscle hyperalgesia induced by peripheral P2X3 receptors is modulated by inflammatory mediators. Neuroscience 285:24–33. CrossRefGoogle Scholar
  12. 12.
    Baur JA, Sinclair DA (2006) Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 5(6):493–506. CrossRefGoogle Scholar
  13. 13.
    Girbovan C, Morin L, Plamondon H (2012) Repeated resveratrol administration confers lasting protection against neuronal damage but induces dose-related alterations of behavioral impairments after global ischemia. Behav Pharmacol 23(1):1–13. CrossRefGoogle Scholar
  14. 14.
    Singleton RH, Yan HQ, Fellows-Mayle W, Dixon CE (2010) Resveratrol attenuates behavioral impairments and reduces cortical and hippocampal loss in a rat controlled cortical impact model of traumatic brain injury. J Neurotrauma 27(6):1091–1099. CrossRefGoogle Scholar
  15. 15.
    Ates O, Cayli S, Altinoz E, Gurses I, Yucel N, Kocak A, Yologlu S, Turkoz Y (2006) Effects of resveratrol and methylprednisolone on biochemical, neurobehavioral and histopathological recovery after experimental spinal cord injury. Acta Pharmacol Sin 27(10):1317–1325. CrossRefGoogle Scholar
  16. 16.
    Xu M, Cheng Z, Ding Z, Wang Y, Guo Q, Huang C (2018) Resveratrol enhances IL-4 receptor-mediated anti-inflammatory effects in spinal cord and attenuates neuropathic pain following sciatic nerve injury. Mol Pain 14:1744806918767549. Google Scholar
  17. 17.
    Singh AK, Vinayak M (2016) Anti-nociceptive effect of resveratrol during inflammatory hyperalgesia via differential regulation of pro-inflammatory mediators. Phytother Res PTR 30(7):1164–1171. CrossRefGoogle Scholar
  18. 18.
    Yang YJ, Hu L, Xia YP, Jiang CY, Miao C, Yang CQ, Yuan M, Wang L (2016) Resveratrol suppresses glial activation and alleviates trigeminal neuralgia via activation of AMPK. J Neuroinflamm 13(1):84. CrossRefGoogle Scholar
  19. 19.
    Yang S, Yu Z, Sun W, Jiang C, Ba X, Zhou Q, Xiong D, Xiao L, Deng Q, Hao Y (2018) The antiviral alkaloid berberine ameliorates neuropathic pain in rats with peripheral nerve injury. Acta Neurol Belg. Google Scholar
  20. 20.
    Sun W, Zhou Q, Ba X, Feng X, Hu X, Cheng X, Liu T, Guo J, Xiao L, Jiang J, Xiong D, Hao Y, Chen Z, Jiang C (2018) Oxytocin relieves neuropathic pain through GABA release and presynaptic TRPV1 inhibition in spinal cord. Front Mol Neurosci 11:248. CrossRefGoogle Scholar
  21. 21.
    Greenwood D, Jagger DJ, Huang LC, Hoya N, Thorne PR, Wildman SS, King BF, Pak K, Ryan AF, Housley GD (2007) P2X receptor signaling inhibits BDNF-mediated spiral ganglion neuron development in the neonatal rat cochlea. Development 134(7):1407–1417. CrossRefGoogle Scholar
  22. 22.
    Ji RR, Chamessian A, Zhang YQ (2016) Pain regulation by non-neuronal cells and inflammation. Science 354(6312):572–577. CrossRefGoogle Scholar
  23. 23.
    Descalzi G, Mitsi V, Purushothaman I, Gaspari S, Avrampou K, Loh YE, Shen L, Zachariou V (2017) Neuropathic pain promotes adaptive changes in gene expression in brain networks involved in stress and depression. Sci Signal. Google Scholar
  24. 24.
    Kuner R (2010) Central mechanisms of pathological pain. Nat Med 16(11):1258–1266. CrossRefGoogle Scholar
  25. 25.
    Gewandter JS, Dworkin RH, Turk DC, Farrar JT, Fillingim RB, Gilron I, Markman JD, Oaklander AL, Polydefkis MJ, Raja SN, Robinson JP, Woolf CJ, Ziegler D, Ashburn MA, Burke LB, Cowan P, George SZ, Goli V, Graff OX, Iyengar S, Jay GW, Katz J, Kehlet H, Kitt RA, Kopecky EA, Malamut R, McDermott MP, Palmer P, Rappaport BA, Rauschkolb C, Steigerwald I, Tobias J, Walco GA (2015) Research design considerations for chronic pain prevention clinical trials: IMMPACT recommendations. Pain 156(7):1184–1197. CrossRefGoogle Scholar
  26. 26.
    Dworkin RH, O’Connor AB, Audette J, Baron R, Gourlay GK, Haanpaa ML, Kent JL, Krane EJ, Lebel AA, Levy RM, Mackey SC, Mayer J, Miaskowski C, Raja SN, Rice AS, Schmader KE, Stacey B, Stanos S, Treede RD, Turk DC, Walco GA, Wells CD (2010) Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc 85(3 Suppl):S3–S14. CrossRefGoogle Scholar
  27. 27.
    Zhou YF, Ying XM, He XF, Shou SY, Wei JJ, Tai ZX, Shao XM, Liang Y, Fang F, Fang JQ, Jiang YL (2018) Suppressing PKC-dependent membrane P2X3 receptor upregulation in dorsal root ganglia mediated electroacupuncture analgesia in rat painful diabetic neuropathy. Purinergic Signal 14(4):359–369. CrossRefGoogle Scholar
  28. 28.
    Ginnetti AT, Paone DV, Stauffer SR, Potteiger CM, Shaw AW, Deng J, Mulhearn JJ, Nguyen DN, Segerdell C, Anquandah J, Calamari A, Cheng G, Leitl MD, Liang A, Moore E, Panigel J, Urban M, Wang J, Fillgrove K, Tang C, Cook S, Kane S, Salvatore CA, Graham SL, Burgey CS (2018) Identification of second-generation P2X3 antagonists for treatment of pain. Bioorg Med Chem Lett 28(8):1392–1396. CrossRefGoogle Scholar
  29. 29.
    Edelmayer RM, Brederson JD, Jarvis MF, Bitner RS (2014) Biochemical and pharmacological assessment of MAP-kinase signaling along pain pathways in experimental rodent models: a potential tool for the discovery of novel antinociceptive therapeutics. Biochem Pharmacol 87(3):390–398. CrossRefGoogle Scholar
  30. 30.
    Ding S, Zhu L, Tian Y, Zhu T, Huang X, Zhang X (2017) P2X3 receptor involvement in endometriosis pain via ERK signaling pathway. PLoS One 12(9):e0184647. CrossRefGoogle Scholar
  31. 31.
    Han Y, Jiang C, Tang J, Wang C, Wu P, Zhang G, Liu W, Jamangulova N, Wu X, Song X (2014) Resveratrol reduces morphine tolerance by inhibiting microglial activation via AMPK signalling. Eur J Pain 18(10):1458–1470. CrossRefGoogle Scholar

Copyright information

© Belgian Neurological Society 2019

Authors and Affiliations

  • Jinhui Guo
    • 1
    Email author
  • Chaowei Wang
    • 2
  • Xiaolu Niu
    • 2
  • Fang Zhou
    • 1
  • Huiling Li
    • 1
  • Weifang Gao
    • 1
  1. 1.Department of Pharmaceuticsthe First Affiliated Hospital of Xinxiang Medical UniversityWeihuiPeople’s Republic of China
  2. 2.Department of Neurologythe First Affiliated Hospital of Xinxiang Medical UniversityWeihuiPeople’s Republic of China

Personalised recommendations