Metabolic Brain Disease

, Volume 30, Issue 6, pp 1349–1358 | Cite as

Chronic inflammatory pain upregulates expression of P2Y2 receptor in small-diameter sensory neurons

  • Huiqin Zhu
  • Yi Yu
  • Lingyan Zheng
  • Lu Wang
  • Chenli Li
  • Jiangyuan Yu
  • Jing Wei
  • Chuang Wang
  • Junfang Zhang
  • Shujun Xu
  • Xiaofei Wei
  • Wei Cui
  • Qinwen Wang
  • Xiaowei Chen
Research Article

Abstract

Roles of ionotropic purinergic (P2X) receptors in chronic pain have been intensively investigated. However, the contribution of metabotropic purinergic (P2Y) receptors to pathological pain is controversial. In the present study, using single cell RT-PCR (reverse transcription-polymerase chain reaction) and single cell nested-PCR techniques, we examined the expression of P2X2, P2X3, P2Y1 and P2Y2 mRNA transcripts in retrogradely labeled cutaneous sensory neurons from mouse lumber dorsal root ganglia (DRGs) following peripheral inflammation. The percentage of cutaneous sensory neurons expressing P2Y2 mRNA transcripts increased after complete Freund’s adjuvant (CFA) treatment. Particularly, the P2Y2 mRNA transcripts were more frequently detected in small-diameter cutaneous neurons from CFA-treated mice than those from control mice. Coexpression of P2Y2 and P2X (P2X2 or P2X3) mRNAs was more frequently observed in cutaneous sensory neurons from CFA-treated mice relative to controls. Pain behavioral tests showed that the blockade of P2Y receptors by suramin attenuated mechanical allodynia evoked either by CFA or uridine triphosphate (UTP), an endogenous P2Y2 and P2Y4 agonist. These results suggest that chronic inflammatory pain enhances expression of P2Y2 receptor in peripheral sensory neurons that innervate the injured tissue and the activation of P2Y receptors contributes to mechanical allodynia following inflammation.

Keywords

Inflammatory pain Purinergic receptor P2Y Single cell PCR 

Notes

Acknowledgments

This work was supported by the National Natural Science Foundation of China (81100822), Zhejiang Provincial Natural Science Foundation of China (LY15H090011), Leading and top Talents Project of Ningbo City (ZX2012000399) and Sponsored by K.C.Wong Magna Fund in Ningbo University.

Conflict of interest

All authors declare that they have no conflicts of interest.

References

  1. Ando RD, Mehesz B, Gyires K, Illes P, Sperlagh B (2010) A comparative analysis of the activity of ligands acting at P2X and P2Y receptor subtypes in models of neuropathic, acute and inflammatory pain. Br J Pharmacol 159:1106–1117PubMedCentralCrossRefPubMedGoogle Scholar
  2. Bradbury EJ, Burnstock G, McMahon SB (1998) The expression of P2X3 purinoreceptors in sensory neurons: effects of axotomy and glial-derived neurotrophic factor. Mol Cell Neurosci 12:256–268CrossRefPubMedGoogle Scholar
  3. Burnstock G (2009) Purinergic mechanosensory transduction and visceral pain. Mol Pain 5:69PubMedCentralCrossRefPubMedGoogle Scholar
  4. Burnstock G (2014a) Physiopathological roles of p2x receptors in the central nervous system. Curr Med ChemGoogle Scholar
  5. Burnstock G (2014b) Purinergic signalling in the gastrointestinal tract and related organs in health and disease. Purinergic Signal 10:3–50PubMedCentralCrossRefPubMedGoogle Scholar
  6. Burnstock G, Krugel U, Abbracchio MP, Illes P (2011) Purinergic signalling: from normal behaviour to pathological brain function. Prog Neurobiol 95:229–274CrossRefPubMedGoogle Scholar
  7. Chen X, Gebhart GF (2010) Differential purinergic signaling in bladder sensory neurons of naive and bladder-inflamed mice. Pain 148:462–472PubMedCentralCrossRefPubMedGoogle Scholar
  8. Chen X, Molliver DC, Gebhart GF (2010) The P2Y2 receptor sensitizes mouse bladder sensory neurons and facilitates purinergic currents. J Neurosci Off J Soc Neurosci 30:2365–2372CrossRefGoogle Scholar
  9. Ford AP (2012) P2X3 antagonists: novel therapeutics for afferent sensitization and chronic pain. Pain Manag 2:267–277CrossRefPubMedGoogle Scholar
  10. Franceschini A, Adinolfi E (2014) P2X receptors: new players in cancer pain. World J Biol Che 5:429–436CrossRefGoogle Scholar
  11. Gerevich Z, Borvendeg SJ, Schroder W, Franke H, Wirkner K, Norenberg W, Furst S, Gillen C, Illes P (2004) Inhibition of N-type voltage-activated calcium channels in rat dorsal root ganglion neurons by P2Y receptors is a possible mechanism of ADP-induced analgesia. J Neurosci Off J Soc Neurosci 24:797–807CrossRefGoogle Scholar
  12. Gerevich Z, Illes P (2004) P2Y receptors and pain transmission. Purinergic Signal 1:3–10PubMedCentralCrossRefPubMedGoogle Scholar
  13. Gold MS, Gebhart GF (2010) Nociceptor sensitization in pain pathogenesis. Nat Med 16:1248–1257CrossRefPubMedGoogle Scholar
  14. Jankowski MP, Rau KK, Soneji DJ, Ekmann KM, Anderson CE, Molliver DC, Koerber HR (2012) Purinergic receptor P2Y1 regulates polymodal C-fiber thermal thresholds and sensory neuron phenotypic switching during peripheral inflammation. Pain 153:410–419PubMedCentralCrossRefPubMedGoogle Scholar
  15. Jarvis MF, Khakh BS (2009) ATP-gated P2X cation-channels. Neuropharmacology 56:208–215CrossRefPubMedGoogle Scholar
  16. Kaan TK, Yip PK, Patel S, Davies M, Marchand F, Cockayne DA, Nunn PA, Dickenson AH, Ford AP, Zhong Y, Malcangio M, McMahon SB (2010) Systemic blockade of P2X3 and P2X2/3 receptors attenuates bone cancer pain behaviour in rats. Brain J Neurol 133:2549–2564CrossRefGoogle Scholar
  17. Kobayashi K, Fukuoka T, Yamanaka H, Dai Y, Obata K, Tokunaga A, Noguchi K (2006) Neurons and glial cells differentially express P2Y receptor mRNAs in the rat dorsal root ganglion and spinal cord. J Comp Neurol 498:443–454CrossRefPubMedGoogle Scholar
  18. Kobayashi K, Yamanaka H, Noguchi K (2013) Expression of ATP receptors in the rat dorsal root ganglion and spinal cord. Anat Sci Int 88:10–16CrossRefPubMedGoogle Scholar
  19. Kwon SG, Roh DH, Yoon SY, Moon JY, Choi SR, Choi HS, Kang SY, Han HJ, Beitz AJ, Lee JH (2014) Blockade of peripheral P2Y1 receptors prevents the induction of thermal hyperalgesia via modulation of TRPV1 expression in carrageenan-induced inflammatory pain rats: involvement of p38 MAPK phosphorylation in DRGs. Neuropharmacology 79:368–379CrossRefPubMedGoogle Scholar
  20. Li N, Lu ZY, Yu LH, Burnstock G, Deng XM, Ma B (2014) Inhibition of G protein-coupled P2Y2 receptor induced analgesia in a rat model of trigeminal neuropathic pain. Mol Pain 10:21PubMedCentralCrossRefPubMedGoogle Scholar
  21. Magni G, Ceruti S (2013) P2Y purinergic receptors: new targets for analgesic and antimigraine drugs. Biochem Pharmacol 85:466–477CrossRefPubMedGoogle Scholar
  22. Magni G, Merli D, Verderio C, Abbracchio MP, Ceruti S (2015) P2Y2receptor antagonists as anti-allodynic agents in acute and sub-chronic trigeminal sensitization: role of satellite glial cells. Glia 63:1256–1269CrossRefPubMedGoogle Scholar
  23. Malin SA, Davis BM, Koerber HR, Reynolds IJ, Albers KM, Molliver DC (2008) Thermal nociception and TRPV1 function are attenuated in mice lacking the nucleotide receptor P2Y2. Pain 138:484–496PubMedCentralCrossRefPubMedGoogle Scholar
  24. Malin SA, Molliver DC (2010) Gi- and Gq-coupled ADP (P2Y) receptors act in opposition to modulate nociceptive signaling and inflammatory pain behavior. Mol Pain 6:21PubMedCentralCrossRefPubMedGoogle Scholar
  25. Mo G, Peleshok JC, Cao CQ, Ribeiro-da-Silva A, Seguela P (2013) Control of P2X3 channel function by metabotropic P2Y2 utp receptors in primary sensory neurons. Mol Pharmacol 83:640–647CrossRefPubMedGoogle Scholar
  26. Molliver DC, Cook SP, Carlsten JA, Wright DE, McCleskey EW (2002) ATP and UTP excite sensory neurons and induce CREB phosphorylation through the metabotropic receptor, P2Y2. Eur J Neurosci 16:1850–1860CrossRefPubMedGoogle Scholar
  27. Moriyama T, Iida T, Kobayashi K, Higashi T, Fukuoka T, Tsumura H, Leon C, Suzuki N, Inoue K, Gachet C, Noguchi K, Tominaga M (2003) Possible involvement of P2Y2 metabotropic receptors in ATP-induced transient receptor potential vanilloid receptor 1-mediated thermal hypersensitivity. J Neurosci Off J Soc Neurosci 23:6058–6062Google Scholar
  28. Okada M, Nakagawa T, Minami M, Satoh M (2002) Analgesic effects of intrathecal administration of P2Y nucleotide receptor agonists UTP and UDP in normal and neuropathic pain model rats. J Pharmacol Exp Ther 303:66–73CrossRefPubMedGoogle Scholar
  29. Rozanski GM, Li Q, Kim H, Stanley EF (2013a) Purinergic transmission and transglial signaling between neuron somata in the dorsal root ganglion. Eur J Neurosci 37:359–365CrossRefPubMedGoogle Scholar
  30. Rozanski GM, Li Q, Stanley EF (2013b) Transglial transmission at the dorsal root ganglion sandwich synapse: glial cell to postsynaptic neuron communication. Eur J Neurosci 37:1221–1228CrossRefPubMedGoogle Scholar
  31. Ruan HZ, Burnstock G (2003) Localisation of P2Y1 and P2Y4 receptors in dorsal root, nodose and trigeminal ganglia of the rat. Histochem Cell Biol 120:415–426CrossRefPubMedGoogle Scholar
  32. Vulchanova L, Riedl MS, Shuster SJ, Stone LS, Hargreaves KM, Buell G, Surprenant A, North RA, Elde R (1998) P2X3 is expressed by DRG neurons that terminate in inner lamina II. Eur J Neurosci 10:3470–3478CrossRefPubMedGoogle Scholar
  33. Wang L, Feng D, Yan H, Wang Z, Pei L (2014) Comparative analysis of P2X1, P2X2, P2X3, and P2X4 receptor subunits in rat nodose ganglion neurons. PLoS One 9:e96699PubMedCentralCrossRefPubMedGoogle Scholar
  34. Xiao HS, Huang QH, Zhang FX, Bao L, Lu YJ, Guo C, Yang L, Huang WJ, Fu G, Xu SH, Cheng XP, Yan Q, Zhu ZD, Zhang X, Chen Z, Han ZG, Zhang X (2002) Identification of gene expression profile of dorsal root ganglion in the rat peripheral axotomy model of neuropathic pain. Proc Natl Acad Sci U S A 99:8360–8365PubMedCentralCrossRefPubMedGoogle Scholar
  35. Yousuf A, Klinger F, Schicker K, Boehm S (2011) Nucleotides control the excitability of sensory neurons via two P2Y receptors and a bifurcated signaling cascade. Pain 152:1899–1908PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Huiqin Zhu
    • 1
  • Yi Yu
    • 1
  • Lingyan Zheng
    • 1
  • Lu Wang
    • 1
  • Chenli Li
    • 1
  • Jiangyuan Yu
    • 1
  • Jing Wei
    • 1
  • Chuang Wang
    • 1
  • Junfang Zhang
    • 1
  • Shujun Xu
    • 1
  • Xiaofei Wei
    • 1
  • Wei Cui
    • 1
  • Qinwen Wang
    • 1
  • Xiaowei Chen
    • 1
  1. 1.Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of PathophysiologySchool of Medicine, Ningbo UniversityNingboChina

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