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BioMed Research International
Volume 2014, Article ID 495789, 13 pages
http://dx.doi.org/10.1155/2014/495789
Review Article

The Purinergic System and Glial Cells: Emerging Costars in Nociception

1Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via Balzaretti, 9-20133 Milan, Italy
2Department of Drug Discovery and Development (D3), Italian Institute of Technology (IIT), Via Morego, 30-16163 Genoa, Italy

Received 28 May 2014; Accepted 8 July 2014; Published 3 September 2014

Academic Editor: Livio Luongo

Copyright © 2014 Giulia Magni and Stefania Ceruti. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. C. J. Woolf and M. W. Salter, “Neuronal plasticity: increasing the gain in pain,” Science, vol. 288, no. 5472, pp. 1765–1768, 2000. View at Publisher · View at Google Scholar · View at Scopus
  2. F. Xu, Y. Li, S. Li et al., “Complete Freund's adjuvant-induced acute inflammatory pain could be attenuated by triptolide via inhibiting spinal glia activation in rats,” Journal of Surgical Research, vol. 188, pp. 174–182, 2014. View at Google Scholar
  3. R. Ji, T. Berta, and M. Nedergaard, “Glia and pain: is chronic pain a gliopathy?” Pain, vol. 154, supplement 1, pp. S10–S28, 2013. View at Publisher · View at Google Scholar · View at Scopus
  4. M. Tsuda, K. Inoue, and M. W. Salter, “Neuropathic pain and spinal microglia: a big problem from molecules in “small” glia,” Trends in Neurosciences, vol. 28, no. 2, pp. 101–107, 2005. View at Publisher · View at Google Scholar · View at Scopus
  5. M. R. Suter, Y. Wen, I. Decosterd, and R. Ji, “Do glial cells control pain?” Neuron Glia Biology, vol. 3, no. 3, pp. 255–268, 2007. View at Publisher · View at Google Scholar · View at Scopus
  6. I. Kazuhide and T. Makoto, “Microglia and neuropathic pain,” Glia, vol. 57, no. 14, pp. 1469–1479, 2009. View at Publisher · View at Google Scholar · View at Scopus
  7. K. Inoue, “ATP receptors of microglia involved in pain,” Novartis Foundation Symposium, vol. 276, pp. 263–272, 2006. View at Publisher · View at Google Scholar · View at Scopus
  8. V. Tiwari, Y. Guan, and S. N. Raja, “Modulating the delicate glial-neuronal interactions in neuropathic pain: promises and potential caveats,” Neuroscience & Biobehavioral Reviews, vol. 45, pp. 19–27, 2014. View at Publisher · View at Google Scholar
  9. A. Buffo, C. Rolando, and S. Ceruti, “Astrocytes in the damaged brain: molecular and cellular insights into their reactive response and healing potential,” Biochemical Pharmacology, vol. 79, no. 2, pp. 77–89, 2010. View at Publisher · View at Google Scholar · View at Scopus
  10. M. Hanani, “Satellite glial cells in sympathetic and parasympathetic ganglia: in search of function,” Brain Research Reviews, vol. 64, no. 2, pp. 304–327, 2010. View at Publisher · View at Google Scholar · View at Scopus
  11. M. Takeda, T. Tanimoto, J. Kadoi et al., “Enhanced excitability of nociceptive trigeminal ganglion neurons by satellite glial cytokine following peripheral inflammation,” Pain, vol. 129, no. 1-2, pp. 155–166, 2007. View at Publisher · View at Google Scholar · View at Scopus
  12. X. Zhang, Y. Chen, C. Wang, and L.-Y. M. Huang, “Neuronal somatic ATP release triggers neuron-satellite glial cell communication in dorsal root ganglia,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 23, pp. 9864–9869, 2007. View at Publisher · View at Google Scholar · View at Scopus
  13. M. Ledda, E. Blum, S. de Palo, and M. Hanani, “Augmentation in gap junction-mediated cell coupling in dorsal root ganglia following sciatic nerve neuritis in the mouse,” Neuroscience, vol. 164, no. 4, pp. 1538–1545, 2009. View at Publisher · View at Google Scholar · View at Scopus
  14. G. Villa, S. Ceruti, M. Zanardelli et al., “Temporomandibular joint inflammation activates glial and immune cells in both the trigeminal ganglia and in the spinal trigeminal nucleus,” Molecular Pain, vol. 6, article 89, 2010. View at Publisher · View at Google Scholar · View at Scopus
  15. M. Donegan, M. Kernisant, C. Cua et al., “Satellite glial cell proliferation in the trigeminal ganglia after chronic constriction injury of the infraorbital nerve,” Glia, vol. 61, pp. 2000–2008, 2013. View at Google Scholar
  16. M. P. Abbracchio, G. Burnstock, A. Verkhratsky, and H. Zimmermann, “Purinergic signalling in the nervous system: an overview,” Trends in Neurosciences, vol. 32, no. 1, pp. 19–29, 2009. View at Publisher · View at Google Scholar · View at Scopus
  17. G. Burnstock, U. Krügel, M. P. Abbracchio, and P. Illes, “Purinergic signalling: from normal behaviour to pathological brain function,” Progress in Neurobiology, vol. 95, no. 2, pp. 229–274, 2011. View at Publisher · View at Google Scholar · View at Scopus
  18. R. A. North and M. F. Jarvis, “P2X receptors as drug targets,” Molecular Pharmacology, vol. 83, no. 4, pp. 759–769, 2013. View at Publisher · View at Google Scholar · View at Scopus
  19. V. Khmyz, O. Maximyuk, V. Teslenko, A. Verkhratsky, and O. Krishtal, “P2X3 receptor gating near normal body temperature,” Pflugers Archiv European Journal of Physiology, vol. 456, no. 2, pp. 339–347, 2008. View at Publisher · View at Google Scholar · View at Scopus
  20. S. P. H. Alexander, H. E. Benson, E. Faccenda et al., “The concise guide to PHARMACOLOGY 2013/14: ligand-gated ion channels,” British Journal of Pharmacology, vol. 170, no. 8, pp. 1582–1606, 2013. View at Publisher · View at Google Scholar
  21. T. Bleehen and C. A. Keele, “Observations on the algogenic actions of adenosine compounds on the human blister base preparation,” Pain, vol. 3, no. 4, pp. 367–377, 1977. View at Publisher · View at Google Scholar · View at Scopus
  22. P. M. Dunn, Y. Zhong, and G. Burnstock, “P2X receptors in peripheral neurons,” Progress in Neurobiology, vol. 65, no. 2, pp. 107–134, 2001. View at Publisher · View at Google Scholar · View at Scopus
  23. Y. S. Kim, S. K. Paik, Y. S. Cho et al., “Expression of P2X3 receptor in the trigeminal sensory nuclei of the rat,” Journal of Comparative Neurology, vol. 506, no. 4, pp. 627–639, 2008. View at Publisher · View at Google Scholar · View at Scopus
  24. G. Burnstock, “Purines and sensory nerves,” Handbook of Experimental Pharmacology, vol. 194, pp. 333–392, 2009. View at Publisher · View at Google Scholar · View at Scopus
  25. J. H. Cho, K. Y. Jung, Y. Jung et al., “Design and synthesis of potent and selective P2X3 receptor antagonists derived from PPADS as potential pain modulators,” European Journal of Medicinal Chemistry, vol. 70, pp. 811–830, 2013. View at Publisher · View at Google Scholar
  26. C. C. Chen, A. N. Akopian, L. Sivilotti, D. Colquhoun, G. Burnstock, and J. N. Wood, “A P2X purinoceptor expressed by a subset of sensory neurons,” Nature, vol. 377, no. 6548, pp. 428–431, 1995. View at Publisher · View at Google Scholar · View at Scopus
  27. R. A. North, “P2X3 receptors and peripheral pain mechanisms,” The Journal of Physiology, vol. 554, no. 2, pp. 301–308, 2004. View at Publisher · View at Google Scholar · View at Scopus
  28. S. Ceruti, M. Fumagalli, G. Villa, C. Verderio, and M. P. Abbracchio, “Purinoceptor-mediated calcium signaling in primary neuron-glia trigeminal cultures,” Cell Calcium, vol. 43, no. 6, pp. 576–590, 2008. View at Publisher · View at Google Scholar · View at Scopus
  29. S. K. Hullugundi, M. D. Ferrari, A. M. J. M. van den Maagdenberg, and A. Nistri, “The mechanism of functional up-regulation of P2X3 receptors of trigeminal sensory neurons in a genetic mouse model of familial hemiplegic migraine type 1 (FHM-1),” PLoS ONE, vol. 8, no. 4, Article ID e60677, 2013. View at Publisher · View at Google Scholar · View at Scopus
  30. I. J. Llewellyn-Smith and G. Burnstock, “Ultrastructural localization of P2X3 receptors in rat sensory neurons,” NeuroReport, vol. 9, no. 11, pp. 2545–2550, 1998. View at Publisher · View at Google Scholar · View at Scopus
  31. M. Tsuda, S. Koizumi, A. Kita, Y. Shigemoto, S. Ueno, and K. Inoue, “Mechanical allodynia caused by intraplantar injection of P2X receptor agonist in rats: involvement of heteromeric P2X2/3 receptor signaling in capsaicin-insensitive primary afferent neurons,” Journal of Neuroscience, vol. 20, no. 15, article RC90, 2000. View at Google Scholar · View at Scopus
  32. Y. Chen, G. W. Li, C. Wang, Y. Gu, and L. M. Huang, “Mechanisms underlying enhanced P2X receptor-mediated responses in the neuropathic pain state,” Pain, vol. 119, no. 1–3, pp. 38–48, 2005. View at Publisher · View at Google Scholar · View at Scopus
  33. K. Kage, W. Niforatos, C. Z. Zhu, K. J. Lynch, P. Honore, and M. F. Jarvis, “Alteration of dorsal root ganglion P2X3 receptor expression and function following spinal nerve ligation in the rat,” Experimental Brain Research, vol. 147, no. 4, pp. 511–519, 2002. View at Publisher · View at Google Scholar · View at Scopus
  34. R. D. Cheng, W. Z. Tu, W. S. Wang et al., “Effect of electroacupuncture on the pathomorphology of the sciatic nerve and the sensitization of P2X3 receptors in the dorsal root ganglion in rats with chronic constrictive injury,” Chinese Journal of Integrative Medicine, vol. 19, no. 5, pp. 374–379, 2013. View at Publisher · View at Google Scholar · View at Scopus
  35. J. Barclay, S. Patel, G. Dorn et al., “Functional downregulation of P2X3 receptor subunit in rat sensory neurons reveals a significant role in chronic neuropathic and inflammatory pain,” The Journal of Neuroscience, vol. 22, no. 18, pp. 8139–8147, 2002. View at Google Scholar · View at Scopus
  36. P. Honore, J. Mikusa, B. Bianchi et al., “TNP-ATP, a potent P2X3 receptor antagonist, blocks acetic acid-induced abdominal constriction in mice: comparison with reference analgesics,” Pain, vol. 96, no. 1-2, pp. 99–105, 2002. View at Publisher · View at Google Scholar · View at Scopus
  37. A. P. Ford, “In pursuit of P2X3 antagonists: novel therapeutics for chronic pain and afferent sensitization,” Purinergic Signalling, vol. 8, no. 1, pp. 3–26, 2012. View at Publisher · View at Google Scholar · View at Scopus
  38. A. M. W. Taylor and A. Ribeiro-da-Silva, “GDNF levels in the lower lip skin in a rat model of trigeminal neuropathic pain: implications for nonpeptidergic fiber reinnervation and parasympathetic sprouting,” Pain, vol. 152, no. 7, pp. 1502–1510, 2011. View at Publisher · View at Google Scholar · View at Scopus
  39. T. Hautaniemi, N. Petrenko, A. Skorinkin, and R. Giniatullin, “The inhibitory action of the antimigraine nonsteroidal anti-inflammatory drug naproxen on P2X3 receptor-mediated responses in rat trigeminal neurons,” Neuroscience, vol. 209, pp. 32–38, 2012. View at Publisher · View at Google Scholar · View at Scopus
  40. S. Liang, C. Xu, G. Li, and Y. Gao, “P2X receptors and modulation of pain transmission: focus on effects of drugs and compounds used in traditional Chinese medicine,” Neurochemistry International, vol. 57, no. 7, pp. 705–712, 2010. View at Publisher · View at Google Scholar · View at Scopus
  41. J. A. M. Coull, S. Beggs, D. Boudreau et al., “BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain,” Nature, vol. 438, no. 7070, pp. 1017–1021, 2005. View at Publisher · View at Google Scholar · View at Scopus
  42. M. F. Jarvis, “The neural-glial purinergic receptor ensemble in chronic pain states,” Trends in Neurosciences, vol. 33, no. 1, pp. 48–57, 2010. View at Publisher · View at Google Scholar · View at Scopus
  43. M. Maeda, M. Tsuda, H. Tozaki-Saitoh, K. Inoue, and H. Kiyama, “Nerve injury-activated microglia engulf myelinated axons in a P2Y12 signaling-dependent manner in the dorsal horn,” Gila, vol. 58, no. 15, pp. 1838–1846, 2010. View at Publisher · View at Google Scholar · View at Scopus
  44. T. Trang, S. Beggs, and M. W. Salter, “ATP receptors gate microglia signaling in neuropathic pain,” Experimental Neurology, vol. 234, no. 2, pp. 354–361, 2012. View at Publisher · View at Google Scholar · View at Scopus
  45. T. Trang, S. Beggs, and M. W. Salter, “Brain-derived neurotrophic factor from microglia: a molecular substrate for neuropathic pain,” Neuron Glia Biology, vol. 7, no. 1, pp. 99–108, 2012. View at Publisher · View at Google Scholar · View at Scopus
  46. M. R. Bianco, G. Cirillo, V. Petrosino et al., “Neuropathic pain and reactive gliosis are reversed by dialdehydic compound in neuropathic pain rat models,” Neuroscience Letters, vol. 530, no. 1, pp. 85–90, 2012. View at Publisher · View at Google Scholar · View at Scopus
  47. M. Tsuda, Y. Shigemoto-Mogami, S. Koizumi et al., “P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury,” Nature, vol. 424, no. 6950, pp. 778–783, 2003. View at Publisher · View at Google Scholar · View at Scopus
  48. L. Ulmann, J. P. Hatcher, J. P. Hughes et al., “Up-regulation of P2X4 receptors in spinal microglia after peripheral nerve injury mediates BDNF release and neuropathic pain,” Journal of Neuroscience, vol. 28, no. 44, pp. 11263–11268, 2008. View at Publisher · View at Google Scholar · View at Scopus
  49. M. Tsuda, E. Toyomitsu, T. Komatsu et al., “Fibronectin/integrin system is involved in P2X(4) receptor upregulation in the spinal cord and neuropathic pain after nerve injury,” Glia, vol. 56, no. 5, pp. 579–585, 2008. View at Google Scholar
  50. K. Biber, M. Tsuda, H. Tozaki-Saitoh et al., “Neuronal CCL21 up-regulates microglia P2X4 expression and initiates neuropathic pain development,” EMBO Journal, vol. 30, no. 9, pp. 1864–1873, 2011. View at Publisher · View at Google Scholar · View at Scopus
  51. M. Tsuda, T. Masuda, J. Kitano, H. Shimoyama, H. Tozaki-Saitoh, and K. Inoue, “IFN-γ receptor signaling mediates spinal microglia activation driving neuropathic pain,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 19, pp. 8032–8037, 2009. View at Publisher · View at Google Scholar · View at Scopus
  52. H. Yuan, X. Zhu, S. Zhou et al., “Role of mast cell activation in inducing microglial cells to release neurotrophin,” Journal of Neuroscience Research, vol. 88, no. 6, pp. 1348–1354, 2010. View at Publisher · View at Google Scholar · View at Scopus
  53. K. Nasu-Tada, S. Koizumi, M. Tsuda, E. Kunifusa, and K. Inoue, “Possible involvement of increase in spinal fibronectin following peripheral nerve injury in upregulation of microglial P2X4, a key molecule for mechanical allodynia,” Glia, vol. 53, no. 7, pp. 769–775, 2006. View at Publisher · View at Google Scholar · View at Scopus
  54. M. Tsuda, H. Tozaki-Saitoh, T. Masuda et al., “Lyn tyrosine kinase is required for P2X4 receptor upregulation and neuropathic pain after peripheral nerve injury,” GLIA, vol. 56, no. 1, pp. 50–58, 2008. View at Publisher · View at Google Scholar · View at Scopus
  55. T. Trang, S. Beggs, X. Wan, and M. W. Salter, “P2X4-receptor-mediated synthesis and release of brain-derived neurotrophic factor in microglia is dependent on calcium and p38-mitogen-activated protein kinase activation,” Journal of Neuroscience, vol. 29, no. 11, pp. 3518–3528, 2009. View at Publisher · View at Google Scholar · View at Scopus
  56. S. Beggs, T. Trang, and M. W. Salter, “P2X4R + microglia drive neuropathic pain,” Nature Neuroscience, vol. 15, no. 8, pp. 1068–1073, 2012. View at Publisher · View at Google Scholar · View at Scopus
  57. R. A. North, “Molecular physiology of P2X receptors,” Physiological Reviews, vol. 82, no. 4, pp. 1013–1067, 2002. View at Google Scholar · View at Scopus
  58. M. Monif, G. Burnstock, and D. A. Williams, “Microglia: proliferation and activation driven by the P2X7 receptor,” International Journal of Biochemistry and Cell Biology, vol. 42, no. 11, pp. 1753–1756, 2010. View at Publisher · View at Google Scholar · View at Scopus
  59. A. K. Clark, A. A. Staniland, F. Marchand, T. K. Y. Kaan, S. B. McMahon, and M. Malcangio, “P2X7-dependent release of interleukin-1β and nociception in the spinal cord following lipopolysaccharide,” Journal of Neuroscience, vol. 30, no. 2, pp. 573–582, 2010. View at Publisher · View at Google Scholar · View at Scopus
  60. A. K. Clark, R. Wodarski, F. Guida, O. Sasso, and M. Malcangio, “Cathepsin S release from primary cultured microglia is regulated by the P2X7 receptor,” Glia, vol. 58, no. 14, pp. 1710–1726, 2010. View at Publisher · View at Google Scholar · View at Scopus
  61. I. P. Chessell, J. P. Hatcher, C. Bountra et al., “Disruption of the P2X7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain,” Pain, vol. 114, no. 3, pp. 386–396, 2005. View at Publisher · View at Google Scholar · View at Scopus
  62. S. McGaraughty, K. L. Chu, M. T. Namovic et al., “P2X7-related modulation of pathological nociception in rats,” Neuroscience, vol. 146, no. 4, pp. 1817–1828, 2007. View at Publisher · View at Google Scholar · View at Scopus
  63. A. Perez-Medrano, D. L. Donnelly-Roberts, P. Honore et al., “Discovery and biological evaluation of novel cyanoguanidine P2X7 antagonists with analgesic activity in a rat model of neuropathic pain,” Journal of Medicinal Chemistry, vol. 52, no. 10, pp. 3366–3376, 2009. View at Publisher · View at Google Scholar · View at Scopus
  64. W. He, J. Cui, L. Du et al., “Spinal P2X 7 receptor mediates microglia activation-induced neuropathic pain in the sciatic nerve injury rat model,” Behavioural Brain Research, vol. 226, no. 1, pp. 163–170, 2012. View at Publisher · View at Google Scholar · View at Scopus
  65. R. E. Sorge, T. Trang, R. Dorfman et al., “Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity,” Nature Medicine, vol. 18, no. 4, pp. 595–599, 2012. View at Publisher · View at Google Scholar · View at Scopus
  66. G. Ito, Y. Suekawa, M. Watanabe et al., “P2X7 receptor in the trigeminal sensory nuclear complex contributes to tactile allodynia/hyperalgesia following trigeminal nerve injury,” European Journal of Pain, vol. 17, no. 2, pp. 185–199, 2013. View at Publisher · View at Google Scholar · View at Scopus
  67. C. Guo, M. Masin, O. S. Qureshi, and R. D. Murrell-Lagnado, “Evidence for functional P2X4/P2X7 heteromeric receptors,” Molecular Pharmacology, vol. 72, no. 6, pp. 1447–1456, 2007. View at Publisher · View at Google Scholar · View at Scopus
  68. G. Dell'Antonio, A. Quattrini, E. Dal Cin, A. Fulgenzi, and M. E. Ferrero, “Antinociceptive effect of a new P2Z/P2X7 antagonist, oxidized ATP, in arthritic rats,” Neuroscience Letters, vol. 327, no. 2, pp. 87–90, 2002. View at Publisher · View at Google Scholar · View at Scopus
  69. A. Wahlert, L. Funkelstein, B. Fitzsimmons, T. Yaksh, and V. Hook, “Spinal astrocytes produce and secrete dynorphin neuropeptides,” Neuropeptides, vol. 47, no. 2, pp. 109–115, 2013. View at Publisher · View at Google Scholar · View at Scopus
  70. Y. Chen, X. Zhang, C. Wang, G. Li, Y. Gu, and L. M. Huang, “Activation of P2X7 receptors in glial satellite cells reduces pain through downregulation of P2X3 receptors in nociceptive neurons,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 43, pp. 16773–16778, 2008. View at Publisher · View at Google Scholar · View at Scopus
  71. R. Kushnir, P. S. Cherkas, and M. Hanani, “Peripheral inflammation upregulates P2X receptor expression in satellite glial cells of mouse trigeminal ganglia: a calcium imaging study,” Neuropharmacology, vol. 61, no. 4, pp. 739–746, 2011. View at Publisher · View at Google Scholar · View at Scopus
  72. T. C. Stock, B. J. Bloom, N. Wei et al., “Efficacy and safety of CE-224,535, an antagonist of P2X7 receptor, in treatment of patients with rheumatoid arthritis inadequately controlled by methotrexate,” Journal of Rheumatology, vol. 39, no. 4, pp. 720–727, 2012. View at Publisher · View at Google Scholar · View at Scopus
  73. E. C. Keystone, M. M. Wang, M. Layton, S. Hollis, and I. B. McInnes, “Clinical evaluation of the efficacy of the P2X7 purinergic receptor antagonist AZD9056 on the signs and symptoms of rheumatoid arthritis in patients with active disease despite treatment with methotrexate or sulphasalazine,” Annals of the Rheumatic Diseases, vol. 71, no. 10, pp. 1630–1635, 2012. View at Publisher · View at Google Scholar · View at Scopus
  74. Z. Ali, B. Laurijssens, T. Ostenfeld et al., “Pharmacokinetic and pharmacodynamic profiling of a P2X7 receptor allosteric modulator GSK1482160 in healthy human subjects,” British Journal of Clinical Pharmacology, vol. 75, no. 1, pp. 197–207, 2013. View at Publisher · View at Google Scholar · View at Scopus
  75. G. Magni and S. Ceruti, “P2Y purinergic receptors: new targets for analgesic and antimigraine drugs,” Biochemical Pharmacology, vol. 85, no. 4, pp. 466–477, 2013. View at Publisher · View at Google Scholar · View at Scopus
  76. K. D. Lustig, A. K. Shiau, A. J. Brake, and D. Julius, “Expression cloning of an ATP receptor from mouse neuroblastoma cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 90, no. 11, pp. 5113–5117, 1993. View at Google Scholar · View at Scopus
  77. T. E. Webb, J. Simon, B. J. Krishek et al., “Cloning and functional expression of a brain G-protein-coupled ATP receptor,” FEBS Letters, vol. 324, no. 2, pp. 219–225, 1993. View at Publisher · View at Google Scholar · View at Scopus
  78. M. P. Abbracchio, G. Burnstock, J. Boeynaems et al., “International Union of Pharmacology LVIII: update on the P2Y G protein-coupled nucleotide receptors: from molecular mechanisms and pathophysiology to therapy,” Pharmacological Reviews, vol. 58, no. 3, pp. 281–341, 2006. View at Publisher · View at Google Scholar · View at Scopus
  79. R. L. Carter, I. P. Fricks, M. O. Barrett et al., “Quantification of Gi-mediated inhibition of adenylyl cyclase activity reveals that UDP is a potent agonist of the human P2Y14 receptor,” Molecular Pharmacology, vol. 76, no. 6, pp. 1341–1348, 2009. View at Publisher · View at Google Scholar · View at Scopus
  80. Z. Gerevich, C. Müller, and P. Illes, “Metabotropic P2Y1 receptors inhibit P2X3 receptor-channels in rat dorsal root ganglion neurons,” European Journal of Pharmacology, vol. 521, no. 1-3, pp. 34–38, 2005. View at Publisher · View at Google Scholar · View at Scopus
  81. S. A. Malin and D. C. Molliver, “Gi- and Gq-coupled ADP (P2Y) receptors act in opposition to modulate nociceptive signaling and inflammatory pain behavior,” Molecular Pain, vol. 6, article 21, 2010. View at Publisher · View at Google Scholar · View at Scopus
  82. M. Tominaga, M. Wada, and M. Masu, “Potentiation of capsaicin receptor activity by metabotropic ATP receptors as a possible mechanism for ATP-evoked pain and hyperalgesia,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 12, pp. 6951–6956, 2001. View at Publisher · View at Google Scholar · View at Scopus
  83. T. Moriyama, T. Iida, K. Kobayashi et al., “Possible involvement of P2Y2 metabotropic receptors in ATP-induced transient receptor potential vanilloid receptor 1-mediated thermal hypersensitivity,” Journal of Neuroscience, vol. 23, no. 14, pp. 6058–6062, 2003. View at Google Scholar · View at Scopus
  84. S. Koizumi, Y. Shigemoto-Mogami, K. Nasu-Tada et al., “UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis,” Nature, vol. 446, no. 7139, pp. 1091–1095, 2007. View at Publisher · View at Google Scholar · View at Scopus
  85. K. Kobayashi, H. Yamanaka, T. Fukuoka, Y. Dai, K. Obata, and K. Noguchi, “P2Y12 receptor upregulation in activated microglia is a gateway of p38 signaling and neuropathic pain,” Journal of Neuroscience, vol. 28, no. 11, pp. 2892–2902, 2008. View at Publisher · View at Google Scholar · View at Scopus
  86. H. Tozaki-Saitoh, M. Tsuda, H. Miyata, K. Ueda, S. Kohsaka, and K. Inoue, “P2Y12 receptors in spinal microglia are required for neuropathic pain after peripheral nerve injury,” Journal of Neuroscience, vol. 28, no. 19, pp. 4949–4956, 2008. View at Publisher · View at Google Scholar · View at Scopus
  87. K. Kobayashi, H. Yamanaka, F. Yanamoto, M. Okubo, and K. Noguchi, “Multiple P2Y subtypes in spinal microglia are involved in neuropathic pain after peripheral nerve injury,” Glia, vol. 60, no. 10, pp. 1529–1539, 2012. View at Publisher · View at Google Scholar · View at Scopus
  88. L. P. Bernier, A. R. Ase, É. Boué-Grabot, and P. Séguéla, “Inhibition of P2X4 function by P2Y6 UDP receptors in microglia,” Glia, vol. 61, no. 12, pp. 2038–2049, 2013. View at Publisher · View at Google Scholar
  89. F. Di Virgilio, S. Ceruti, P. Bramanti, and M. P. Abbracchio, “Purinergic signalling in inflammation of the central nervous system,” Trends in Neurosciences, vol. 32, no. 2, pp. 79–87, 2009. View at Publisher · View at Google Scholar · View at Scopus
  90. M. Xia and Y. Zhu, “Signaling pathways of ATP-induced PGE2 release in spinal cord astrocytes are EGFR transactivation-dependent,” GLIA, vol. 59, no. 4, pp. 664–674, 2011. View at Publisher · View at Google Scholar · View at Scopus
  91. M. Boccazzi, C. Rolando, M. P. Abbracchio et al., “Purines regulate adult brain subventricular zone cell functions: contribution of reactive astrocytes,” Glia, vol. 62, pp. 428–439, 2014. View at Publisher · View at Google Scholar
  92. K. Kobayashi, H. Yamanaka, and K. Noguchi, “Expression of ATP receptors in the rat dorsal root ganglion and spinal cord,” Anatomical Science International, vol. 88, no. 1, pp. 10–16, 2013. View at Publisher · View at Google Scholar · View at Scopus
  93. G. Villa, M. Fumagalli, C. Verderio, M. P. Abbracchio, and S. Ceruti, “Expression and contribution of satellite glial cells purinoceptors to pain transmission in sensory ganglia: an update,” Neuron Glia Biology, vol. 6, no. 1, pp. 31–42, 2010. View at Publisher · View at Google Scholar · View at Scopus
  94. K. Kobayashi, T. Fukuoka, H. Iyamanaka et al., “Neurons and glial cells differentially express P2Y receptor mRNAs in the rat dorsal root ganglion and spinal cord,” Journal of Comparative Neurology, vol. 498, no. 4, pp. 443–454, 2006. View at Publisher · View at Google Scholar · View at Scopus
  95. S. Ceruti, G. Villa, M. Fumagalli et al., “Calcitonin gene-related peptide-mediated enhancement of purinergic neuron/glia communication by the algogenic factor bradykinin in mouse trigeminal ganglia from wild-type and R192Q Cav2.1 knock-in mice: Implications for basic mechanisms of migraine pain,” Journal of Neuroscience, vol. 31, no. 10, pp. 3638–3649, 2011. View at Publisher · View at Google Scholar · View at Scopus
  96. N. Li, Z. Y. Lu, L. H. Yu et al., “Inhibition of G protein-coupled P2Y2 receptor induced analgesia in a rat model of trigeminal neuropathic pain,” Molecular Pain, vol. 10, article 21, 2014. View at Google Scholar
  97. A. Katagiri, M. Shinoda, K. Honda, A. Toyofuku, B. J. Sessle, and K. Iwata, “Satellite glial cell P2Y12 receptor in the trigeminal ganglion is involved in lingual neuropathic pain mechanisms in rats,” Molecular Pain, vol. 8, article 23, 2012. View at Publisher · View at Google Scholar · View at Scopus
  98. J. F. Chen, H. K. Eltzschig, and B. B. Fredholm, “Adenosine receptors as drug targets-what are the challenges?” Nature Reviews Drug Discovery, vol. 12, no. 4, pp. 265–286, 2013. View at Publisher · View at Google Scholar · View at Scopus
  99. J. Sawynok, A. R. Reid, and J. Liu, “Spinal and peripheral adenosine A1 receptors contribute to antinociception by tramadol in the formalin test in mice,” European Journal of Pharmacology, vol. 714, no. 1–3, pp. 373–378, 2013. View at Publisher · View at Google Scholar · View at Scopus
  100. J. Liu, A. R. Reid, and J. Sawynok, “Antinociception by systemically-administered acetaminophen (paracetamol) involves spinal serotonin 5-HT7 and adenosine A1 receptors, as well as peripheral adenosine A1 receptors,” Neuroscience Letters, vol. 536, no. 1, pp. 64–68, 2013. View at Publisher · View at Google Scholar · View at Scopus
  101. J. Liu, A. R. Reid, and J. Sawynok, “Spinal serotonin 5-HT7 and adenosine A1 receptors, as well as peripheral adenosine A1 receptors, are involved in antinociception by systemically administered amitriptyline,” European Journal of Pharmacology, vol. 698, no. 1–3, pp. 213–219, 2013. View at Publisher · View at Google Scholar · View at Scopus
  102. X. Gao, Q. Lu, G. Chou et al., “Norisoboldine attenuates inflammatory pain via the adenosine A1 receptor,” European Journal of Pain, vol. 18, no. 7, pp. 939–948, 2014. View at Publisher · View at Google Scholar
  103. L. Luongo, R. Petrelli, L. Gatta et al., “5'-Chloro-5'-deoxy-(±)-ENBA, a potent and selective adenosine A1 receptor agonist, alleviates neuropathic pain in mice through functional glial and microglial changes without affecting motor or cardiovascular functions,” Molecules, vol. 17, no. 12, pp. 13712–13726, 2012. View at Publisher · View at Google Scholar · View at Scopus
  104. L. Luongo, F. Guida, R. Imperatore et al., “The A1 adenosine receptor as a new player in microglia physiology,” Glia, vol. 62, no. 1, pp. 122–132, 2014. View at Publisher · View at Google Scholar
  105. S. Ferré, I. Diamond, S. R. Goldberg et al., “Adenosine A2A receptors in ventral striatum, hypothalamus and nociceptive circuitry: implications for drug addiction, sleep and pain,” Progress in Neurobiology, vol. 83, no. 5, pp. 332–347, 2007. View at Publisher · View at Google Scholar · View at Scopus
  106. L. Li, J. X. Hao, B. B. Fredholm, G. Schulte, Z. Wiesenfeld-Hallin, and X. J. Xu, “Peripheral adenosine A2A receptors are involved in carrageenan-induced mechanical hyperalgesia in mice,” Neuroscience, vol. 170, no. 3, pp. 923–928, 2010. View at Publisher · View at Google Scholar · View at Scopus
  107. J. M. Pocock and H. Kettenmann, “Neurotransmitter receptors on microglia,” Trends in Neurosciences, vol. 30, no. 10, pp. 527–535, 2007. View at Publisher · View at Google Scholar · View at Scopus
  108. L. C. Loram, F. R. Taylor, K. A. Strand et al., “Intrathecal injection of adenosine 2A receptor agonists reversed neuropathic allodynia through protein kinase (PK)A/PKC signaling,” Brain, Behavior, and Immunity, vol. 33, pp. 112–122, 2013. View at Publisher · View at Google Scholar · View at Scopus
  109. Z. Chen, K. Janes, C. Chen et al., “Controlling murine and rat chronic pain through A3 adenosine receptor activation,” The FASEB Journal, vol. 26, no. 5, pp. 1855–1865, 2012. View at Publisher · View at Google Scholar · View at Scopus
  110. K. Ohsawa, T. Sanagi, Y. Nakamura, E. Suzuki, K. Inoue, and S. Kohsaka, “Adenosine A3 receptor is involved in ADP-induced microglial process extension and migration,” Journal of Neurochemistry, vol. 121, no. 2, pp. 217–227, 2012. View at Publisher · View at Google Scholar · View at Scopus
  111. E. Daré, G. Schulte, O. Karovic, C. Hammarberg, and B. B. Fredholm, “Modulation of glial cell functions by adenosine receptors,” Physiology and Behavior, vol. 92, no. 1-2, pp. 15–20, 2007. View at Publisher · View at Google Scholar · View at Scopus
  112. L. Antonioli, B. Csóka, M. Fornai et al., “Adenosine and inflammation: what's new on the horizon?” Drug Discovery Today, vol. 19, no. 8, pp. 1051–1068, 2014. View at Publisher · View at Google Scholar
  113. A. P. Ford, “P2X3 antagonists: novel therapeutics for afferent sensitization and chronic pain,” Pain Management, vol. 2, pp. 267–277, 2012. View at Google Scholar
  114. M. Furber, L. Alcaraz, J. E. Bent et al., “Discovery of potent and selective adamantane-based small-molecule P2X7 receptor antagonists/interleukin-1β inhibitors,” Journal of Medicinal Chemistry, vol. 50, no. 24, pp. 5882–5885, 2007. View at Publisher · View at Google Scholar · View at Scopus
  115. V. Hernandez-Olmos, A. Abdelrahman, A. El-Tayeb, D. Freudendahl, S. Weinhausen, and C. E. Müller, “N-substituted phenoxazine and acridone derivatives: structure-activity relationships of potent P2X4 receptor antagonists,” Journal of Medicinal Chemistry, vol. 55, no. 22, pp. 9576–9588, 2012. View at Publisher · View at Google Scholar · View at Scopus
  116. K. Zhang, J. Zhang, Z. G. Gao et al., “Structure of the human P2Y12 receptor in complex with an antithrombotic drug,” Nature, vol. 509, pp. 115–118, 2014. View at Google Scholar
  117. F. Vincenzi, M. Targa, R. Romagnoli et al., “TRR469, a potent A1 adenosine receptor allosteric modulator, exhibits anti-nociceptive properties in acute and neuropathic pain models in mice,” Neuropharmacology, vol. 81, pp. 6–14, 2014. View at Google Scholar
  118. S. Koizumi, K. Ohsawa, K. Inoue, and S. Kohsaka, “Purinergic receptors in microglia: functional modal shifts of microglia mediated by P2 and P1 receptors,” Glia, vol. 61, no. 1, pp. 47–54, 2013. View at Publisher · View at Google Scholar · View at Scopus