Skip to main content Accesibility Help

Expression and contribution of satellite glial cells purinoceptors to pain transmission in sensory ganglia: an update

  • Giovanni Villa (a1), Marta Fumagalli (a1), Claudia Verderio (a2), Maria P. Abbracchio (a1) and Stefania Ceruti (a1)...

The role of adenosine-5′-triphosphate (ATP) and of the ligand-gated P2X3 receptor in neuronal dorsal root ganglia (DRG) pain transmission is relatively well established. Much less is known about the purinergic system in trigeminal ganglia (TG), which are involved in certain types of untreatable neuropathic and inflammatory pain, as well as in migraine. Emerging data suggest that purinergic metabotropic P2Y receptors on both neurons and satellite glial cells (SGCs) may also participate in both physiological and pathological pain development. Here, we provide an updated literature review on the role of purinergic signaling in sensory ganglia, with special emphasis on P2Y receptors on SGCs. We also provide new original data showing a time-dependent downregulation of P2Y2 and P2Y4 receptor expression and function in purified SGCs cultures from TG, in comparison with primary mixed neuron–SGCs cultures. These data highlight the importance of the neuron–glia cross-talk in determining the SGCs phenotype. Finally, we show that, in mixed TG cultures, both adenine and guanosine induce intracellular calcium transients in neurons but not in SGCs, suggesting that also these purinergic-related molecules can participate in pain signaling. These findings may have relevant implications for the development of new therapeutic strategies for chronic pain treatment.

Corresponding author
Correspondence should be addressed to: Maria P. Abbracchio, Department of Pharmacological Sciences, Università degli Studi di Milano, via Balzaretti, 9-20133 Milan, Italy phone: +39-0250318304 email:
Hide All
Abbracchio, M.P., Burnstock, G., Boeynaems, J.M., Barnard, E.A., Boyer, J.L., Kennedy, C. et al. (2006) International Union of Pharmacology LVIII: update on the P2Y G protein-coupled nucleotide receptors: from molecular mechanisms and pathophysiology to therapy. Pharmacological Reviews 58, 281341.
Abbracchio, M.P. and Verderio, C. (2006) Pathophysiological roles of P2 receptors in glial cells. Novartis Foundation Symposium 276, 91103; discussion 103–112, 275–181.
Bender, E., Buist, A., Jurzak, M., Langlois, X., Baggerman, G., Verhasselt, P. et al. (2002) Characterization of an orphan G protein-coupled receptor localized in the dorsal root ganglia reveals adenine as a signaling molecule. Proceedings of the National Academy of Sciences of the U.S.A. 99, 85738578.
Benfenati, V., Caprini, M., Nobile, M., Rapisarda, C. and Ferroni, S. (2006) Guanosine promotes the up-regulation of inward rectifier potassium current mediated by Kir4.1 in cultured rat cortical astrocytes. Journal of Neurochemistry 98, 430445.
Bianchi, B.R., Lynch, K.J., Touma, E., Niforatos, W., Burgard, E.C., Alexander, K.M. et al. (1999) Pharmacological characterization of recombinant human and rat P2X receptor subtypes. European Journal of Pharmacology 376, 127138.
Bianco, F., Colombo, A., Saglietti, L., Lecca, D., Abbracchio, M.P., Matteoli, M. et al. (2009) Different properties of P2X7 receptor in hippocampal and cortical astrocytes. Purinergic Signaling 5, 233240.
Bianco, F., Fumagalli, M., Pravettoni, E., D'Ambrosi, N., Volonte, C., Matteoli, M. et al. (2005a) Pathophysiological roles of extracellular nucleotides in glial cells: differential expression of purinergic receptors in resting and activated microglia. Brain Research and Brain Research Reviews 48, 144156.
Bianco, F., Pravettoni, E., Colombo, A., Schenk, U., Möller, T., Matteoli, M. et al. (2005b) Astrocyte-derived ATP induces vesicle shedding and IL-1 beta release from microglia. Journal of Immunology 174, 72687277.
Bleehen, T. and Keele, C.A. (1977) Observations on the algogenic actions of adenosine compounds on the human blister base preparation. Pain 3, 367377.
Burnstock, G. (1996) A unifying purinergic hypothesis for the initiation of pain. The Lancet 347, 16041605.
Burnstock, G. (2001) Purine-mediated signalling in pain and visceral perception. Trends in Pharmacological Sciences 22, 182188.
Burnstock, G. (2006) Purinergic P2 receptors as targets for novel analgesics. Pharmacology and Therapeutics 110, 433454.
Burnstock, G. (2008) Purinergic signalling and disorders of the central nervous system. Nature Reviews Drug Discovery 7, 575590.
Burnstock, G. (2009a) Purinergic receptors and pain. Current Pharmacological Design 15, 17171735.
Burnstock, G. (2009b) Purines and sensory nerves. Handbook of Experimental Pharmacology 194, 333392.
Capuano, A., De Corato, A., Lisi, L., Tringali, G., Navarra, P. and Dello Russo, C. (2009) Proinflammatory-activated trigeminal satellite cells promote neuronal sensitization: relevance for migraine pathology. Molecular Pain 5, 43.
Carruthers, A.M., Sellers, L.A., Jenkins, D.W., Jarvie, E.M., Feniuk, W. and Humphrey, P.P. (2001) Adenosine A1 receptor-mediated inhibition of protein kinase A-induced calcitonin gene-related peptide release from rat trigeminal neurons. Molecular Pharmacology 59, 15331541.
Ceruti, S., Fumagalli, M., Villa, G., Verderio, C. and Abbracchio, M.P. (2008) Purinoceptor-mediated calcium signaling in primary neuron–glia trigeminal cultures. Cell Calcium 43, 576590.
Chen, C.C., Akopian, A.N., Sivilotti, L., Colquhoun, D., Burnstock, G. and Wood, J.N. (1995) A P2X purinoceptor expressed by a subset of sensory neurons. Nature 377, 428431.
Chen, Y., Zhang, X., Wang, C., Li, G., Gu, Y. and Huang, L.Y. (2008) 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 U.S.A. 105, 1677316778.
Chessell, I.P., Hatcher, J.P., Bountra, C., Michel, A.D., Hughes, J.P., Green, P. et al. (2005) Disruption of the P2X7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain. Pain 114, 386396.
Chizh, B.A. and Illes, P. (2001) P2X receptors and nociception. Pharmacology Review 53, 553568.
Dolphin, A.C., Forda, S.R. and Scott, R.H. (1986) Calcium-dependent currents in cultured rat dorsal root ganglion neurones are inhibited by an adenosine analogue. Journal of Physiology 373, 4761.
Dong, X., Han, S., Zylka, M.J., Simon, M.I. and Anderson, D.J. (2001) A diverse family of GPCRs expressed in specific subsets of nociceptive sensory neurons. Cell 106, 619632.
Donnelly-Roberts, D., McGaraughty, S., Shieh, C.C., Honore, P. and Jarvis, M.F. (2008) Painful purinergic receptors. Journal of Pharmacology and Experimental Therapeutics 324, 409415.
Dunn, P.M., Zhong, Y. and Burnstock, G. (2001) P2X receptors in peripheral neurons. Progress in Neurobiology 65, 107134.
England, S., Heblich, F., James, I.F., Robbins, J. and Docherty, R.J. (2001) Bradykinin evokes a Ca2 +-activated chloride current in non-neuronal cells isolated from neonatal rat dorsal root ganglia. Journal of Physiology 530, 395403.
Ferrari, D., Pizzirani, C., Adinolfi, E., Lemoli, R.M., Curti, A., Idzko, M. et al. (2006) The P2X7 receptor: a key player in IL-1 processing and release. Journal of Immunology 176, 38773883.
Fields, R.D. and Stevens, B. (2000) ATP: an extracellular signaling molecule between neurons and glia. Trends in Neuroscience 23, 625633.
Fredholm, B.B., IJzerman, A.P., Jacobson, K.A., Klotz, K.N. and Linden, J. (2001) International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacological Reviews 53, 527552.
Gerevich, Z. and Illes, P. (2004) P2Y receptors and pain transmission. Purinergic Signalling 1, 310.
Gerevich, Z., Muller, C. and Illes, P. (2005) Metabotropic P2Y1 receptors inhibit P2X3 receptor-channels in rat dorsal root ganglion neurons. European Journal of Pharmacology 521, 3438.
Giaume, C. and Venance, L. (1998) Intercellular calcium signaling and gap junctional communication in astrocytes. Glia 24, 5064.
Gorzalka, S., Vittori, S., Volpini, R., Cristalli, G., von Kugelgen, I. and Muller, C.E. (2005) Evidence for the functional expression and pharmacological characterization of adenine receptors in native cells and tissues. Molecular Pharmacology 67, 955964.
Hanani, M. (2005) Satellite glial cells in sensory ganglia: from form to function. Brain Research Brain Research Reviews 48, 457476.
Hanani, M., Huang, T.Y., Cherkas, P.S., Ledda, M. and Pannese, E. (2002) Glial cell plasticity in sensory ganglia induced by nerve damage. Neuroscience 114, 279283.
Haydon, P.G. (2001) GLIA: listening and talking to the synapse. Nature Reviews Neuroscience 2, 185193.
Honore, P., Donnelly-Roberts, D., Namovic, M.T., Hsieh, G., Zhu, C.Z., Mikusa, J.P. et al. (2006) A-740003 [N-(1-{[(cyanoimino)(5-quinolinylamino) methyl]amino}-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide], a novel and selective P2X7 receptor antagonist, dose-dependently reduces neuropathic pain in the rat. Journal of Pharmacology and Experimental Therapeutics 319, 13761385.
Huang, T.Y., Belzer, V. and Hanani, M. (2009) Gap junctions in dorsal root ganglia: possible contribution to visceral pain. European Journal of Pain 14, 49.e149.e11.
Huang, H., Wu, X., Nicol, G.D., Meller, S. and Vasko, M.R. (2003) ATP augments peptide release from rat sensory neurons in culture through activation of P2Y receptors. Journal of Pharmacology and Experimental Therapeutics 306, 11371144.
Illes, P. and Ribeiro, J.A. (2004) Neuronal P2 receptors of the central nervous system. Current Topics in Medicinal Chemistry 4, 831838.
Inoue, K. (2008) Purinergic systems in microglia. Cellular and Molecular Life Sciences 65, 30743080.
Jacobson, K.A., Jarvis, M.F. and Williams, M. (2002) Purine and pyrimidine (P2) receptors as drug targets. Journal of Medicinal Chemistry 45, 40574093.
Jarvis, M.F. (2003) Contributions of P2X3 homomeric and heteromeric channels to acute and chronic pain. Expert Opinion on Therapeutic Targets 7, 513522.
Jarvis, M.F. (2010) The neural–glial purinergic receptor ensemble in chronic pain states. Trends in Neurosciences 33, 4857.
Kim, Y.S., Paik, S.K., Cho, Y.S., Shin, H.S., Bae, J.Y., Moritani, M. et al. (2008) Expression of P2X3 receptor in the trigeminal sensory nuclei of the rat. Journal of Comparative Neurology 506, 627639.
Kobayashi, K., Fukuoka, T., Yamanaka, H., Dai, Y., Obata, K., Tokunaga, A. et al. (2005) Differential expression patterns of mRNAs for P2X receptor subunits in neurochemically characterized dorsal root ganglion neurons in the rat. Journal of Comparative Neurology 481, 377390.
Kobayashi, K., Fukuoka, T., Yamanaka, H., Dai, Y., Obata, K., Tokunaga, A. et al. (2006) Neurons and glial cells differentially express P2Y receptor mRNAs in the rat dorsal root ganglion and spinal cord. Journal of Comparative Neurology 498, 443454.
Krishtal, O.A., Marchenko, S.M. and Pidoplichko, V.I. (1983) Receptor for ATP in the membrane of mammalian sensory neurones. Neuroscience Letters 35, 4145.
Ledda, M., Blum, E., De Palo, S. and Hanani, M. (2009) Augmentation in gap junction-mediated cell coupling in dorsal root ganglia following sciatic nerve neuritis in the mouse. Neuroscience 164, 15381545.
Li, J., Vause, C.V. and Durham, P.L. (2008) Calcitonin gene-related peptide stimulation of nitric oxide synthesis and release from trigeminal ganglion glial cells. Brain Research 1196, 2232.
Liu, X.J. and Salter, M.W. (2005) Purines and pain mechanisms: recent developments. Current Opinion in Investigational Drugs 6, 6575.
Malin, S.A., Davis, B.M., Koerber, H.R., Reynolds, I.J., Albers, K.M. and Molliver, D.C. (2008) Thermal nociception and TRPV1 function are attenuated in mice lacking the nucleotide receptor P2Y2. Pain 138, 484496.
Matsuka, Y., Ono, T., Iwase, H., Mitrirattanakul, S., Omoto, K.S., Cho, T. et al. (2008) Altered ATP release and metabolism in dorsal root ganglia of neuropathic rats. Molecular Pain 4, 66.
McGaraughty, S., Chu, K.L., Namovic, M.T., Donnelly-Roberts, D.L., Harris, R.R., Zhang, X.F. et al. (2007) P2X7-related modulation of pathological nociception in rats. Neuroscience 146, 18171828.
Moriyama, T., Iida, T., Kobayashi, K., Higashi, T., Fukuoka, T., Tsumura, H. et al. (2003) Possible involvement of P2Y2 metabotropic receptors in ATP-induced transient receptor potential vanilloid receptor 1-mediated thermal hypersensitivity. Journal of Neuroscience 23, 60586062.
Nakayama, S., Yamashita, T., Konishi, M., Kazama, H. and Kokubun, S. (2004) P2Y-mediated Ca2+ response is spatiotemporally graded and synchronized in sensory neurons: a two-photon photolysis study. The Faseb Journal 18, 15621564.
Neusch, C., Weishaupt, J.H. and Bahr, M. (2003) Kir channels in the CNS: emerging new roles and implications for neurological diseases. Cell and Tissue Research 311, 131138.
North, R.A. (2002) Molecular physiology of P2X receptors. Physiology Reviews 82, 10131067.
Ohara, P.T., Vit, J.P., Bhargava, A. and Jasmin, L. (2008) Evidence for a role of connexin 43 in trigeminal pain using RNA interference in vivo. Journal of Neurophysiology 100, 30643073.
Ohara, P.T., Vit, J.P., Bhargava, A., Romero, M., Sundberg, C., Charles, A.C. et al. (2009) Gliopathic pain: when satellite glial cells go bad. Neuroscientist 15, 450463.
Petruska, J.C., Cooper, B.Y., Gu, J.G., Rau, K.K. and Johnson, R.D. (2000) Distribution of P2X1, P2X2, and P2X3 receptor subunits in rat primary afferents: relation to population markers and specific cell types. Journal of Chemical Neuroanatomy 20, 141162.
Rathbone, M.P., Middlemiss, P., Andrew, C., Caciagli, F., Ciccarelli, R., Di Iorio, P. et al. (1998) The trophic effects of purines and purinergic signaling in pathologic reactions of astrocytes. Alzheimer Disease and Associated Disorders 12 Suppl 2, S36S45.
Ruan, H.Z. and Burnstock, G. (2003) Localisation of P2Y1 and P2Y4 receptors in dorsal root, nodose and trigeminal ganglia of the rat. Histochemistry and Cell Biology 120, 415426.
Sanada, M., Yasuda, H., Omatsu-Kanbe, M., Sango, K., Isono, T., Matsuura, H. et al. (2002) Increase in intracellular Ca2+ and calcitonin gene-related peptide release through metabotropic P2Y receptors in rat dorsal root ganglion neurons. Neuroscience 111, 413422.
Sanz, J.M., Chiozzi, P., Ferrari, D., Colaianna, M., Idzko, M., Falzoni, S. et al. (2009) Activation of microglia by amyloid-beta requires P2X7 receptor expression. Journal of Immunology 182, 43784385.
Sawynok, J. (1998) Adenosine receptor activation and nociception. European Journal of Pharmacology 347, 111.
Sawynok, J. (2007) Adenosine and ATP receptors. Handbook of Experimental Pharmacology 177, 309328.
Scemes, E. and Giaume, C. (2006) Astrocyte calcium waves: what they are and what they do. Glia 54, 716725.
Schmidt, A.P., Paniz, L., Schallenberger, C., Bohmer, A.E., Wofchuk, S.T., Elisabetsky, E. et al. (2010) Guanosine prevents thermal hyperalgesia in a rat model of peripheral mononeuropathy. Journal of Pain 11, 131141.
Simonetti, M., Fabbro, A., D'Arco, M., Zweyer, M., Nistri, A., Giniatullin, R. et al. (2006) Comparison of P2X and TRPV1 receptors in ganglia or primary culture of trigeminal neurons and their modulation by NGF or serotonin. Molecular Pain 2, 11.
Suadicani, S.O., Cherkas, P.S., Zuckerman, J., Smith, D.N., Spray, D.C. and Hanani, M. (2009) Bidirectional calcium signaling between satellite glial cells and neurons in cultured mouse trigeminal ganglia. Neuron Glia Biology 6, 19.
Svichar, N., Shmigol, A., Verkhratsky, A. and Kostyuk, P. (1997) ATP induces Ca2+ release from IP3-sensitive Ca2+ stores exclusively in large DRG neurones. Neuroreport 8, 15551559.
Takeda, M., Tanimoto, T., Kadoi, J., Nasu, M., Takahashi, M., Kitagawa, J. et al. (2007) Enhanced excitability of nociceptive trigeminal ganglion neurons by satellite glial cytokine following peripheral inflammation. Pain 129, 155166.
Takeda, M., Takahashi, M. and Matsumoto, S. (2009) Contribution of the activation of satellite glia in sensory ganglia to pathological pain. Neuroscience Biobehavioural Reviews 33, 784792.
Thalakoti, S., Patil, V.V., Damodaram, S., Vause, C.V., Langford, L.E., Freeman, S.E. et al. (2007) Neuron–glia signaling in trigeminal ganglion: implications for migraine pathology. Headache 47, 10081023; discussion 1024–1005.
Traversa, U., Bombi, G., Camaioni, E., Macchiarulo, A., Costantino, G., Palmieri, C. et al. (2003) Rat brain guanosine binding site. Biological studies and pseudo-receptor construction. Bioorganic Medicinal Chemistry 11, 54175425.
Traversa, U., Bombi, G., Di Iorio, P., Ciccarelli, R., Werstiuk, E.S. and Rathbone, M.P. (2002) Specific [3H]-guanosine binding sites in rat brain membranes. British Journal of Pharmacology 135, 969976.
Tsuda, M., Kuboyama, K., Inoue, T., Nagata, K., Tozaki-Saitoh, H. and Inoue, K. (2009a) Behavioral phenotypes of mice lacking purinergic P2X4 receptors in acute and chronic pain assays. Molecular Pain 5, 28.
Tsuda, M., Tozaki-Saitoh, H. and Inoue, K. (2010) Pain and purinergic signaling. Brain Research Reviews 63, 222232.
Tung, E.K., Choi, R.C., Siow, N.L., Jiang, J.X., Ling, K.K., Simon, J. et al. (2004) P2Y2 receptor activation regulates the expression of acetylcholinesterase and acetylcholine receptor genes at vertebrate neuromuscular junctions. Molecular Pharmacology 66, 794806.
van den Maagdenberg, A.M., Pietrobon, D., Pizzorusso, T., Kaja, S., Broos, L.A., Cesetti, T. et al. (2004) A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression. Neuron 41, 701710.
Vega-Avelaira, D., Géranton, S.M. and Fitzgerald, M. (2009) Differential regulation of immune responses and macrophage/neuron interactions in the dorsal root ganglion in young and adult rats following nerve injury. Molecular Pain 5, 70.
Verkhratsky, A., Krishtal, O.A. and Burnstock, G. (2009) Purinoceptors on neuroglia. Molecular Neurobiology 39, 190208.
Vit, J.P., Jasmin, L., Bhargava, A. and Ohara, P.T. (2006) Satellite glial cells in the trigeminal ganglion as a determinant of orofacial neuropathic pain. Neuron Glia Biology 2, 247257.
Vit, J.P., Ohara, P.T., Bhargava, A., Kelley, K. and Jasmin, L. (2008) Silencing the Kir4.1 potassium channel subunit in satellite glial cells of the rat trigeminal ganglion results in pain-like behavior in the absence of nerve injury. Journal of Neuroscience 28, 41614171.
Vulchanova, L., Riedl, M.S., Shuster, S.J., Buell, G., Surprenant, A., North, R.A. et al. (1997) Immunohistochemical study of the P2X2 and P2X3 receptor subunits in rat and monkey sensory neurons and their central terminals. Neuropharmacology 36, 12291242.
Weick, M., Cherkas, P.S., Hartig, W., Pannicke, T., Uckermann, O., Bringmann, A. et al. (2003) P2 receptors in satellite glial cells in trigeminal ganglia of mice. Neuroscience 120, 969977.
Willis, W.D. (2001) Role of neurotransmitters in sensitization of pain responses. Annual New York Academy of Sciences 933, 142156.
Xiao, H.S., Huang, Q.H., Zhang, F.X., Bao, L., Lu, Y.J., Guo, C. et al. (2002) Identification of gene expression profile of dorsal root ganglion in the rat peripheral axotomy model of neuropathic pain. Proceedings of the National Academy of Sciences of the U.S.A. 99, 83608365.
Zhang, X., Chen, Y., Wang, C. and Huang, L.Y. (2007) Neuronal somatic ATP release triggers neuron-satellite glial cell communication in dorsal root ganglia. Proceedings of the National Academy of Sciences of the U.S.A. 104, 98649869.
Zhang, X.F., Han, P., Faltynek, C.R., Jarvis, M.F. and Shieh, C.C. (2005) Functional expression of P2X7 receptors in non-neuronal cells of rat dorsal root ganglia. Brain Research 1052, 6370.
Zimmermann, K., Reeh, P.W. and Averbeck, B. (2002) ATP can enhance the proton-induced CGRP release through P2Y receptors and secondary PGE2 release in isolated rat dura mater. Pain 97, 259265.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Neuron Glia Biology
  • ISSN: 1740-925X
  • EISSN: 1741-0533
  • URL: /core/journals/neuron-glia-biology
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed