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The Adenosine-Receptor Axis in Chronic Pain

  • Daniela Salvemini
  • Timothy M. Doyle
  • Tally M. Largent-Milnes
  • Todd W. Vanderah
Chapter
Part of the The Receptors book series (REC, volume 34)

Abstract

Chronic pain is a widespread problem that plagues an estimated 10 to 30% of the world’s population. The current therapeutic repertoire is inadequate in managing patient pain with narcotic use resulting in a drug overdose epidemic, affirming the need for the development of new therapeutics. Adenosine and its four cognate receptors (A1AR, A2AAR, A2BAR, and A3AR) play essential roles in physiological and pathophysiological states, including chronic pain. For decades, preclinical and clinical studies have revealed that adenosine and A1AR- and to a lesser extent A2AAR-selective agonists have analgesic properties, yet their therapeutic utility has been limited by adverse cardiovascular side effects. There is no evidence that A2BAR plays a role in pain. Recent preclinical studies have demonstrated that selective A3AR agonists result in antinociception in models of acute and chronic pain while lacking unwanted side effects. These exciting preclinical observations of A3AR agonists have been bolstered by clinical trials of A3AR agonists in other disease states including rheumatoid arthritis and psoriasis that suggests a clinical benefit without cardiotoxicity. Our goal herein is to briefly discuss adenosine and its receptors in the context of pathological pain and examine what is known at present regarding A3AR-mediated antinociception. We will highlight recent findings pertaining to A3AR in pain and describe possible pathways by which A3AR may mediate its effects and the current state of selective A3AR agonists used in pain studies. The adenosine-to-A3AR pathway represents an important endogenous system that can be targeted to provide safe, effective pain relief in patients suffering with chronic pain.

Keywords

Adenosine receptors A3AR A3AR agonists A3AR-mediated antinociception Acute pain Chronic pain 

References

  1. Abbracchio MP, Rainaldi G, Giammarioli AM et al (1997) The A3 adenosine receptor mediates cell spreading, reorganization of actin cytoskeleton, and distribution of Bcl-XL:studies in human astroglioma cells. Biochem Biophys Res Commun 241:297–304PubMedPubMedCentralCrossRefGoogle Scholar
  2. Amadesi S, Cottrell GS, Divino L et al (2006) Protease-activated receptor 2 sensitizes TRPV1 by protein kinase Cepsilon- and A-dependent mechanisms in rats and mice. J Physiol 575:555–571PubMedPubMedCentralCrossRefGoogle Scholar
  3. Asemu G, Dent MR, Singal T et al (2005) Differential changes in phospholipase D and phosphatidate phosphohydrolase activities in ischemia-reperfusion of rat heart. Arch Biochem Biophys 436:136–144PubMedCrossRefGoogle Scholar
  4. Ballarin M, Fredholm BB, Ambrosio S et al (1991) Extracellular levels of adenosine and its metabolites in the striatum of awake rats:inhibition of uptake and metabolism. Acta Physiol Scand 142:97–103CrossRefPubMedGoogle Scholar
  5. Bar Yehuda S, Fishman P, Stemmer S et al (2010) CF102 exerts a differential effect in various pathological liver conditions:protection from inflammation damage and anti-tumor activity. Purinergic Signal 6:88Google Scholar
  6. Biggs JE, Lu VB, Stebbing MJ et al (2010) Is BDNF sufficient for information transfer between microglia and dorsal horn neurons during the onset of central sensitization? Mol Pain 6:44PubMedPubMedCentralCrossRefGoogle Scholar
  7. Blackburn MR, Kellems RE (1996) Regulation and function of adenosine deaminase in mice. Prog Nucleic Acid Res Mol Biol 55:195–226PubMedCrossRefGoogle Scholar
  8. Boison D (2008a) Adenosine as a neuromodulator in neurological diseases. Curr Opin Pharmacol 8:2–7PubMedCrossRefGoogle Scholar
  9. Boison D (2008b) The adenosine kinase hypothesis of epileptogenesis. Prog Neurobiol 84:249–262PubMedCrossRefPubMedCentralGoogle Scholar
  10. Boison D (2013) Adenosine kinase:exploitation for therapeutic gain. Pharmacol Rev 65:906–943PubMedPubMedCentralCrossRefGoogle Scholar
  11. Boison D (2016) Adenosinergic signaling in epilepsy. Neuropharmacology 104:131–139PubMedCrossRefPubMedCentralGoogle Scholar
  12. Boison D, Chen JF, Fredholm BB (2010) Adenosine signaling and function in glial cells. Cell Death Differ 17:1071–1082PubMedCrossRefPubMedCentralGoogle Scholar
  13. Bonan CD (2012) Ectonucleotidases and nucleotide/nucleoside transporters as pharmacological targets for neurological disorders. CNS Neurol Disord Drug Targets 11:739–750PubMedCrossRefGoogle Scholar
  14. Borea PA, Varani K, Vincenzi F et al (2015) The A3 adenosine receptor:history and perspectives. Pharmacol Rev 67:74–102PubMedCrossRefPubMedCentralGoogle Scholar
  15. Bradesi S, Eutamene H, Theodorou V et al (2001) Effect of ovarian hormones on intestinal mast cell reactivity to substance P. Life Sci 68:1047–1056PubMedCrossRefGoogle Scholar
  16. Brundege JM, Dunwiddie TV (1998) Metabolic regulation of endogenous adenosine release from single neurons. Neuroreport 9:3007–3011PubMedCrossRefGoogle Scholar
  17. By Y, Condo J, Durand-Gorde JM et al (2011) Intracerebroventricular injection of an agonist-like monoclonal antibody to adenosine A(2A) receptor has antinociceptive effects in mice. J Neuroimmunol 230:178–182PubMedCrossRefGoogle Scholar
  18. Cao H, Zhang YQ (2008) Spinal glial activation contributes to pathological pain states. Neurosci Biobehav Rev 32:972–983PubMedCrossRefGoogle Scholar
  19. Chen Z, Muscoli C, Doyle T et al (2010) NMDA-receptor activation and nitroxidative regulation of the glutamatergic pathway during nociceptive processing. Pain 149:100–106PubMedPubMedCentralCrossRefGoogle Scholar
  20. Chen Z, Janes K, Chen C et al (2012) Controlling murine and rat chronic pain through A3 adenosine receptor activation. FASEB J 26:1855–1865PubMedPubMedCentralCrossRefGoogle Scholar
  21. Chen JF, Eltzschig HK, Fredholm BB (2013) Adenosine receptors as drug targets--what are the challenges? Nat Rev 12:265–286Google Scholar
  22. Choi JS, Berdis AJ (2012) Nucleoside transporters: biological insights and therapeutic applications. Future Med Chem 4:1461–1478PubMedCrossRefGoogle Scholar
  23. Choi IY, Lee JC, Ju C et al (2011) A3 adenosine receptor agonist reduces brain ischemic injury and inhibits inflammatory cell migration in rats. Am J Pathol 179:2042–2052PubMedPubMedCentralCrossRefGoogle Scholar
  24. Coull JA, Boudreau D, Bachand K et al (2003) Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain. Nature 424:938–942PubMedCrossRefGoogle Scholar
  25. Cross HR, Murphy E, Black RG et al (2002) Overexpression of A(3) adenosine receptors decreases heart rate, preserves energetics, and protects ischemic hearts. Am J Phys Heart Circ Phys 283:H1562–H1568Google Scholar
  26. Cui JG, Sollevi A, Linderoth B et al (1997) Adenosine receptor activation suppresses tactile hypersensitivity and potentiates spinal cord stimulation in mononeuropathic rats. Neurosci Lett 223:173–176PubMedCrossRefGoogle Scholar
  27. Cunha RA (2001) Adenosine as a neuromodulator and as a homeostatic regulator in the nervous system:different roles, different sources and different receptors. Neurochem Int 38:107–125PubMedCrossRefPubMedCentralGoogle Scholar
  28. Cunha RA (2005) Neuroprotection by adenosine in the brain:from A(1) receptor activation to A (2A) receptor blockade. Purinergic Signal 1:111–134PubMedPubMedCentralCrossRefGoogle Scholar
  29. Cunha RA (2008) Different cellular sources and different roles of adenosine:A1 receptor-mediated inhibition through astrocytic-driven volume transmission and synapse-restricted A2A receptor-mediated facilitation of plasticity. Neurochem Int 52:65–72PubMedCrossRefGoogle Scholar
  30. Daniele S, Zappelli E, Natali L et al (2014) Modulation of A1 and A2B adenosine receptor activity:a new strategy to sensitise glioblastoma stem cells to chemotherapy. Cell Death Dis 5:e1539PubMedPubMedCentralCrossRefGoogle Scholar
  31. Deussen A, Stappert M, Schafer S et al (1999) Quantification of extracellular and intracellular adenosine production: understanding the transmembranous concentration gradient. Circulation 99:2041–2047PubMedCrossRefGoogle Scholar
  32. Dias RB, Rombo DM, Ribeiro JA et al (2013) Adenosine: setting the stage for plasticity. Trends Neurosci 36:248–257PubMedCrossRefGoogle Scholar
  33. Dickenson AH, Suzuki R, Reeve AJ (2000) Adenosine as a potential analgesic target in inflammatory and neuropathic pains. CNS Drugs 13:77–85CrossRefGoogle Scholar
  34. Doyle T, Chen Z, Muscoli C et al (2012) Targeting the overproduction of peroxynitrite for the prevention and reversal of paclitaxel-induced neuropathic pain. J Neurosci 32:6149–6160PubMedPubMedCentralCrossRefGoogle Scholar
  35. Dunwiddie TV, Masino SA (2001) The role and regulation of adenosine in the central nervous system. Annu Rev Neurosci 24:31–55PubMedCrossRefGoogle Scholar
  36. Eaton MJ, Plunkett JA, Karmally S et al (1998) Changes in GAD- and GABA- immunoreactivity in the spinal dorsal horn after peripheral nerve injury and promotion of recovery by lumbar transplant of immortalized serotonergic precursors. J Chem Neuroanat 16:57–72PubMedCrossRefGoogle Scholar
  37. Elliott K, Minami N, Kolesnikov YA et al (1994) The NMDA receptor antagonists, LY274614 and MK-801, and the nitric oxide synthase inhibitor, NG-nitro-L-arginine, attenuate analgesic tolerance to the mu-opioid morphine but not to kappa opioids. Pain 56:69–75PubMedCrossRefGoogle Scholar
  38. Engler RL (1991) Adenosine. The signal of life? Circulation 84:951–954PubMedCrossRefGoogle Scholar
  39. Fedorova IM, Jacobson MA, Basile A et al (2003) Behavioral characterization of mice lacking the A3 adenosine receptor:sensitivity to hypoxic neurodegeneration. Cell Mol Neurobiol 23:431–447PubMedPubMedCentralCrossRefGoogle Scholar
  40. Feoktistov I, Biaggioni I (2011) Role of adenosine A(2B) receptors in inflammation. Adv Pharmacol 61:115–144PubMedPubMedCentralCrossRefGoogle Scholar
  41. Ferrini F, De Koninck Y (2013) Microglia control neuronal network excitability via BDNF signalling. Neural Plast 2013:429815PubMedPubMedCentralCrossRefGoogle Scholar
  42. Feuerbach D, Lingenhoehl K, Olpe HR et al (2009) The selective nicotinic acetylcholine receptor alpha7 agonist JN403 is active in animal models of cognition, sensory gating, epilepsy and pain. Neuropharmacology 56:254–263PubMedCrossRefGoogle Scholar
  43. Fishman P, Bar-Yehuda S, Madi L et al (2002) A3 adenosine receptor as a target for cancer therapy. Anti-Cancer Drugs 13:437–443PubMedCrossRefPubMedCentralGoogle Scholar
  44. Fishman P, Bar-Yehuda S, Madi L et al (2006) The PI3K-NF-kappaB signal transduction pathway is involved in mediating the anti-inflammatory effect of IB-MECA in adjuvant-induced arthritis. Arthritis Res Ther 8:R33PubMedPubMedCentralCrossRefGoogle Scholar
  45. Fishman P, Bar-Yehuda S, Synowitz M et al (2009) Adenosine receptors and cancer. Handb Exp Pharmacol 193:399–441Google Scholar
  46. Fishman P, Bar-Yehuda S, Liang BT et al (2012) Pharmacological and therapeutic effects of A3 adenosine receptor agonists. Drug Discov Today 17:359–366PubMedCrossRefGoogle Scholar
  47. Ford A, Castonguay A, Cottet M et al (2015) Engagement of the GABA to KCC2 signaling pathway contributes to the analgesic effects of A3AR agonists in neuropathic pain. J Neurosci 35:6057–6067PubMedPubMedCentralCrossRefGoogle Scholar
  48. Fredholm BB, AP IJ, Jacobson KA et al (2001) International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 53:527–552PubMedPubMedCentralGoogle Scholar
  49. Fredholm BB, AP IJ, Jacobson KA et al (2011) International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors--an update. Pharmacol Rev 63:1–34PubMedPubMedCentralCrossRefGoogle Scholar
  50. Gallo-Rodriguez C, Ji XD, Melman N et al (1994) Structure-activity relationships of N6-benzyladenosine-5′-uronamides as A3-selective adenosine agonists. J Med Chem 37:636–646PubMedPubMedCentralCrossRefGoogle Scholar
  51. Gan TJ, Habib AS (2007) Adenosine as a non-opioid analgesic in the perioperative setting. Anesth Analg 105:487–494PubMedCrossRefGoogle Scholar
  52. Gao ZG, Jacobson KA (2007) Emerging adenosine receptor agonists. Expert Opin Emerg Drugs 12:479–492PubMedCrossRefPubMedCentralGoogle Scholar
  53. Gao ZG, Jacobson KA (2011) Emerging adenosine receptor agonists:an update. Expert Opin Emerg Drugs 16:597–602PubMedPubMedCentralCrossRefGoogle Scholar
  54. Gao ZG, Teng B, Wu H et al (2009) Synthesis and pharmacological characterization of [(125)I]MRS1898, a high-affinity, selective radioligand for the rat A(3) adenosine receptor. Purinergic Signal 5:31–37PubMedCrossRefGoogle Scholar
  55. Gessi S, Merighi S, Varani K et al (2011) Adenosine receptors in health and disease. Adv Pharmacol 61:41–75PubMedCrossRefGoogle Scholar
  56. Giannaccini G, Betti L, Palego L et al (2008) Species comparison of adenosine receptor subtypes in brain and testis. Neurochem Res 33:852–860PubMedCrossRefGoogle Scholar
  57. Goldberg DS, McGee SJ (2011) Pain as a global public health priority. BMC Public Health 11:770PubMedPubMedCentralCrossRefGoogle Scholar
  58. Gomes CV, Kaster MP, Tomé AR et al (2011) Adenosine receptors and brain diseases: neuroprotection and neurodegeneration. Biochim Biophys Acta Biomembr 1808:1380–1399CrossRefGoogle Scholar
  59. Gong QJ, Li YY, Xin WJ et al (2010) Differential effects of adenosine A1 receptor on pain-related behavior in normal and nerve-injured rats. Brain Res 1361:23–30PubMedCrossRefGoogle Scholar
  60. Grandoch M, Hoffmann J, Rock K et al (2013) Novel effects of adenosine receptors on pericellular hyaluronan matrix: implications for human smooth muscle cell phenotype and interactions with monocytes during atherosclerosis. Basic Res Cardiol 108:340PubMedCrossRefGoogle Scholar
  61. Habib AS, Minkowitz H, Osborn T et al (2008) Phase 2, double-blind, placebo-controlled, dose-response trial of intravenous adenosine for perioperative analgesia. Anesthesiology 109:1085–1091PubMedCrossRefGoogle Scholar
  62. Haeusler D, Grassinger L, Fuchshuber F et al (2015) Hide and seek:a comparative autoradiographic in vitro investigation of the adenosine A3 receptor. Eur J Nucl Med Mol Imaging 42:928–939PubMedPubMedCentralCrossRefGoogle Scholar
  63. Harrison GJ, Cerniway RJ, Peart J et al (2002) Effects of A(3) adenosine receptor activation and gene knock-out in ischemic-reperfused mouse heart. Cardiovasc Res 53:147–155PubMedCrossRefGoogle Scholar
  64. Hashizume H, DeLeo JA, Colburn RW et al (2000) Spinal glial activation and cytokine expression after lumbar root injury in the rat. Spine (Phila Pa 1976) 25:1206–1217CrossRefGoogle Scholar
  65. Hasko G, Szabo C, Nemeth ZH et al (1996) Adenosine receptor agonists differentially regulate IL-10, TNF-alpha, and nitric oxide production in RAW 2647 macrophages and in endotoxemic mice. J Immunol 157:4634–4640PubMedGoogle Scholar
  66. Hasko G, Nemeth ZH, Vizi ES et al (1998) An agonist of adenosine A3 receptors decreases interleukin-12 and interferon-gamma production and prevents lethality in endotoxemic mice. Eur J Pharmacol 358:261–268PubMedCrossRefGoogle Scholar
  67. Hayashida M, Fukuda K, Fukunaga A (2005) Clinical application of adenosine and ATP for pain control. J Anesth 19:225–235PubMedCrossRefGoogle Scholar
  68. Headrick JP, Peart J (2005) A3 adenosine receptor-mediated protection of the ischemic heart. Vasc Pharmacol 42:271–279CrossRefGoogle Scholar
  69. Headrick JP, Peart JN, Reichelt ME et al (2011) Adenosine and its receptors in the heart:regulation, retaliation and adaptation. Biochim Biophys Acta 1808:1413–1428PubMedCrossRefGoogle Scholar
  70. Hinze AV, Mayer P, Harst A et al (2012) Adenosine A(3) receptor-induced proliferation of primary human coronary smooth muscle cells involving the induction of early growth response genes. J Mol Cell Cardiol 53:639–645PubMedCrossRefGoogle Scholar
  71. Institute of Medicine (US) Committee on Advancing Pain Research, Care, and Education (2011) Relieving pain in America: a blueprint for transforming prevention, care, education, and research. National Academies Press, Washington, DCGoogle Scholar
  72. Jacobson KA (1998) Adenosine A3 receptors:novel ligands and paradoxical effects. Trends Pharmacol Sci 19:184–191PubMedPubMedCentralCrossRefGoogle Scholar
  73. Jacobson KA, Gao ZG (2006) Adenosine receptors as therapeutic targets. Nat Rev Drug Discov 5:247–264PubMedPubMedCentralCrossRefGoogle Scholar
  74. Jacobson KA, Nikodijevic O, Shi D et al (1993) A role for central A3-adenosine receptors. Mediation of behavioral depressant effects. FEBS Lett 336:57–60PubMedPubMedCentralCrossRefGoogle Scholar
  75. Jajoo S, Mukherjea D, Watabe K et al (2009) Adenosine A(3) receptor suppresses prostate cancer metastasis by inhibiting NADPH oxidase activity. Neoplasia 11:1132–1145PubMedPubMedCentralCrossRefGoogle Scholar
  76. Janes K, Doyle T, Bryant L et al (2013) Bioenergetic deficits in peripheral nerve sensory axons during chemotherapy-induced neuropathic pain resulting from peroxynitrite-mediated post-translational nitration of mitochondrial superoxide dismutase. Pain 154:2432–2440PubMedPubMedCentralCrossRefGoogle Scholar
  77. Janes K, Esposito E, Doyle T et al (2014a) A3 adenosine receptor agonist prevents the development of paclitaxel-induced neuropathic pain by modulating spinal glial-restricted redox-dependent signaling pathways. Pain 155:2560–2567PubMedPubMedCentralCrossRefGoogle Scholar
  78. Janes K, Little JW, Li C et al (2014b) The development and maintenance of paclitaxel-induced neuropathic pain require activation of the sphingosine 1-phosphate receptor subtype 1. J Biol Chem 289:21082–21097PubMedPubMedCentralCrossRefGoogle Scholar
  79. Janes K, Wahlman C, Little JW et al (2015) Spinal neuroimmmune activation is independent of T-cell infiltration and attenuated by A3 adenosine receptor agonists in a model of oxaliplatin-induced peripheral neuropathy. Brain Behav Immun 44:91–99PubMedCrossRefGoogle Scholar
  80. Johnston JB, Silva C, Gonzalez G et al (2001) Diminished adenosine A1 receptor expression on macrophages in brain and blood of patients with multiple sclerosis. Ann Neurol 49:650–658PubMedCrossRefGoogle Scholar
  81. Katz NK, Ryals JM, Wright DE (2015) Central or peripheral delivery of an adenosine A1 receptor agonist improves mechanical allodynia in a mouse model of painful diabetic neuropathy. Neuroscience 285:312–323PubMedCrossRefGoogle Scholar
  82. Keil GJ 2nd, DeLander GE (1992) Spinally-mediated antinociception is induced in mice by an adenosine kinase-, but not by an adenosine deaminase-, inhibitor. Life Sci 51:PL171–PL176PubMedCrossRefGoogle Scholar
  83. Kiesman WF, Elzein E, Zablocki J (2009) A1 adenosine receptor antagonists, agonists, and allosteric enhancers. Handb Exp Pharmacol 193:25–58CrossRefGoogle Scholar
  84. Klaasse EC, Ijzerman AP, de Grip WJ et al (2008) Internalization and desensitization of adenosine receptors. Purinergic Signal 4:21–37PubMedCrossRefGoogle Scholar
  85. Kowaluk EA, Kohlhaas KL, Bannon A et al (1999) Characterization of the effects of adenosine kinase inhibitors on acute thermal nociception in mice. Pharmacol Biochem Behav 63:83–91PubMedCrossRefGoogle Scholar
  86. Kowaluk EA, Mikusa J, Wismer CT et al (2000) ABT-702 (4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin- 3-yl)pyrido[2,3-d]pyrimidine), a novel orally effective adenosine kinase inhibitor with analgesic and anti-inflammatory properties. II. In vivo characterization in the rat. J Pharmacol Exp Ther 295:1165–1174PubMedGoogle Scholar
  87. Latini S, Pedata F (2001) Adenosine in the central nervous system:release mechanisms and extracellular concentrations. J Neurochem 79:463–484PubMedCrossRefPubMedCentralGoogle Scholar
  88. Ledent C, Vaugeois JM, Schiffmann SN et al (1997) Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2a receptor. Nature 388:674–678PubMedCrossRefGoogle Scholar
  89. Lee HC, Fellenz-Maloney MP, Liscovitch M et al (1993) Phospholipase D-catalyzed hydrolysis of phosphatidylcholine provides the choline precursor for acetylcholine synthesis in a human neuronal cell line. Proc Natl Acad Sci U S A 90:10086–10090PubMedPubMedCentralCrossRefGoogle Scholar
  90. Lee JE, Bokoch G, Liang BT (2001) A novel cardioprotective role of RhoA: new signaling mechanism for adenosine. FASEB J 15:1886–1894PubMedCrossRefGoogle Scholar
  91. Li Y, Zhang H, Kosturakis AK et al (2014) Toll-like receptor 4 signaling contributes to paclitaxel-induced peripheral neuropathy. J Pain 15:712–725PubMedPubMedCentralCrossRefGoogle Scholar
  92. Little JW, Ford A, Symons-Liguori AM et al (2015) Endogenous adenosine A3 receptor activation selectively alleviates persistent pain states. Brain 138:28–35PubMedCrossRefGoogle Scholar
  93. Lopes LV, Rebola N, Pinheiro PC et al (2003) Adenosine A3 receptors are located in neurons of the rat hippocampus. Neuroreport 14:1645–1648PubMedCrossRefGoogle Scholar
  94. Loram LC, Harrison JA, Sloane EM et al (2009) Enduring reversal of neuropathic pain by a single intrathecal injection of adenosine 2A receptor agonists:a novel therapy for neuropathic pain. J Neurosci 29:14015–14025PubMedPubMedCentralCrossRefGoogle Scholar
  95. Luongo L, Guida F, Imperatore R et al (2014) The A1 adenosine receptor as a new player in microglia physiology. Glia 62:122–132PubMedCrossRefGoogle Scholar
  96. Madi L, Bar-Yehuda S, Barer F et al (2003) A3 adenosine receptor activation in melanoma cells:association between receptor fate and tumor growth inhibition. J Biol Chem 278:42121–42130PubMedCrossRefPubMedCentralGoogle Scholar
  97. Madi L, Cohen S, Ochayin A et al (2007) Overexpression of A3 adenosine receptor in peripheral blood mononuclear cells in rheumatoid arthritis:involvement of nuclear factor-kappaB in mediating receptor level. J Rheumatol 34:20–26PubMedGoogle Scholar
  98. Mao J, Sung B, Ji RR et al (2002) Chronic morphine induces downregulation of spinal glutamate transporters:implications in morphine tolerance and abnormal pain sensitivity. J Neurosci 22:8312–8323PubMedCrossRefGoogle Scholar
  99. Martins DF, Mazzardo-Martins L, Soldi F et al (2013) High-intensity swimming exercise reduces neuropathic pain in an animal model of complex regional pain syndrome type I:evidence for a role of the adenosinergic system. Neuroscience 234:69–76PubMedCrossRefGoogle Scholar
  100. Mayer DJ, Mao J, Holt J et al (1999) Cellular mechanisms of neuropathic pain, morphine tolerance, and their interactions. Proc Natl Acad Sci U S A 96:7731–7736PubMedPubMedCentralCrossRefGoogle Scholar
  101. McGaraughty S, Cowart M, Jarvis MF et al (2005) Anticonvulsant and antinociceptive actions of novel adenosine kinase inhibitors. Curr Top Med Chem 5:43–58PubMedCrossRefGoogle Scholar
  102. Meller ST, Dykstra C, Grzybycki D et al (1994) The possible role of glia in nociceptive processing and hyperalgesia in the spinal cord of the rat. Neuropharmacology 33:1471–1478PubMedCrossRefGoogle Scholar
  103. Merighi S, Bencivenni S, Vincenzi F et al (2017) A2B adenosine receptors stimulate IL-6 production in primary murine microglia through p38 MAPK kinase pathway. Pharmacol Res 117:9–19PubMedCrossRefGoogle Scholar
  104. Milligan ED, Watkins LR (2009) Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci 10:23–36PubMedPubMedCentralCrossRefGoogle Scholar
  105. Moore KA, Kohno T, Karchewski LA et al (2002) Partial peripheral nerve injury promotes a selective loss of GABAergic inhibition in the superficial dorsal horn of the spinal cord. J Neurosci 22:6724–6731PubMedCrossRefGoogle Scholar
  106. Morello S, Ito K, Yamamura S et al (2006) IL-1 beta and TNF-alpha regulation of the adenosine receptor (A2A) expression:differential requirement for NF-kappa B binding to the proximal promoter. J Immunol 177:7173–7183PubMedCrossRefGoogle Scholar
  107. Moser GH, Schrader J, Deussen A (1989) Turnover of adenosine in plasma of human and dog blood. Am J Phys 256:C799–C806CrossRefGoogle Scholar
  108. Muscoli C, Cuzzocrea S, Ndengele MM et al (2007) Therapeutic manipulation of peroxynitrite attenuates the development of opiate-induced antinociceptive tolerance in mice. J Clin Invest 117:3530–3539PubMedPubMedCentralCrossRefGoogle Scholar
  109. Muscoli C, Doyle T, Dagostino C et al (2010) Counter-regulation of opioid analgesia by glial-derived bioactive sphingolipids. J Neurosci 30:15400–15408PubMedPubMedCentralCrossRefGoogle Scholar
  110. Nagata K, Imai T, Yamashita T et al (2009) Antidepressants inhibit P2X4 receptor function: a possible involvement in neuropathic pain relief. Mol Pain 5:20PubMedPubMedCentralCrossRefGoogle Scholar
  111. Ndengele MM, Cuzzocrea S, Esposito E et al (2008) Cyclooxygenases 1 and 2 contribute to peroxynitrite-mediated inflammatory pain hypersensitivity. FASEB J 22:3154–3164PubMedCrossRefGoogle Scholar
  112. Obata K, Noguchi K (2008) Contribution of primary sensory neurons and spinal glial cells to pathomechanisms of neuropathic pain. Brain Nerve 60:483–492PubMedGoogle Scholar
  113. Ochaion A, Bar-Yehuda S, Cohen S et al (2009) The anti-inflammatory target A(3) adenosine receptor is over-expressed in rheumatoid arthritis, psoriasis and Crohn's disease. Cell Immunol 258:115–122PubMedCrossRefGoogle Scholar
  114. Otsuguro KI, Tomonari Y, Otsuka S et al (2015) An adenosine kinase inhibitor, ABT-702, inhibits spinal nociceptive transmission by adenosine release via equilibrative nucleoside transporters in rat. Neuropharmacology 97:160–170PubMedCrossRefGoogle Scholar
  115. Paoletta S, Tosh DK, Finley A et al (2013) Rational design of sulfonated A3 adenosine receptor-selective nucleosides as pharmacological tools to study chronic neuropathic pain. J Med Chem 56:5949–5963PubMedCrossRefGoogle Scholar
  116. Parsons M, Young L, Lee JE et al (2000) Distinct cardioprotective effects of adenosine mediated by differential coupling of receptor subtypes to phospholipases C and D. FASEB J 14:1423–1431PubMedPubMedCentralCrossRefGoogle Scholar
  117. Peng L, Huang R, Yu AC et al (2005) Nucleoside transporter expression and function in cultured mouse astrocytes. Glia 52:25–35PubMedCrossRefGoogle Scholar
  118. Petrelli R, Scortichini M, Kachler S et al (2017) Exploring the role of N(6)-substituents in potent dual acting 5′-C-Ethyltetrazolyladenosine derivatives:synthesis, binding, functional assays, and antinociceptive effects in mice nabla. J Med Chem 60:4327–4341PubMedPubMedCentralCrossRefGoogle Scholar
  119. Pizzo PA, Clark NM (2012) Alleviating suffering 101--pain relief in the United States. N Engl J Med 366:197–199PubMedCrossRefGoogle Scholar
  120. Poderoso JJ, Carreras MC, Lisdero C et al (1996) Nitric oxide inhibits electron transfer and increases superoxide radical production in rat heart mitochondria and submitochondrial particles. Arch Biochem Biophys 328:85–92PubMedCrossRefGoogle Scholar
  121. Poon A, Sawynok J (1998) Antinociception by adenosine analogs and inhibitors of adenosine metabolism in an inflammatory thermal hyperalgesia model in the rat. Pain 74:235–245PubMedCrossRefGoogle Scholar
  122. Poulsen SA, Quinn RJ (1998) Adenosine receptors:new opportunities for future drugs. Bioorg Med Chem 6:619–641PubMedCrossRefGoogle Scholar
  123. Price TJ, Cervero F, de Koninck Y (2005) Role of cation-chloride-cotransporters (CCC) in pain and hyperalgesia. Curr Top Med Chem 5:547–555PubMedPubMedCentralCrossRefGoogle Scholar
  124. Prus AJ, James JR, Rosecrans JA (2009) Conditioned place preference. In: Buccafusco JJ (ed) Methods of behavior analysis in neuroscience, 2nd edn. CRC Press/Taylor Francis, Boca RatonGoogle Scholar
  125. Rausaria S, Ghaffari MM, Kamadulski A et al (2011) Retooling manganese(III) porphyrin-based peroxynitrite decomposition catalysts for selectivity and oral activity:a potential new strategy for treating chronic pain. J Med Chem 54:8658–8669PubMedPubMedCentralCrossRefGoogle Scholar
  126. Rebola N, Canas PM, Oliveira CR et al (2005) Different synaptic and subsynaptic localization of adenosine A2A receptors in the hippocampus and striatum of the rat. Neuroscience 132:893–903PubMedCrossRefGoogle Scholar
  127. Robson SC, Sevigny J, Zimmermann H (2006) The E-NTPDase family of ectonucleotidases:structure function relationships and pathophysiological significance. Purinergic Signal 2:409–430PubMedPubMedCentralCrossRefGoogle Scholar
  128. Romagnoli R, Baraldi PG, Tabrizi MA et al (2010) Allosteric enhancers of A1 adenosine receptors:state of the art and new horizons for drug development. Curr Med Chem 17:3488–3502PubMedCrossRefGoogle Scholar
  129. Ru F, Surdenikova L, Brozmanova M et al (2011) Adenosine-induced activation of esophageal nociceptors. Am J Physiol Gastrointest Liver Physiol 300:G485–G493PubMedCrossRefGoogle Scholar
  130. Sajjadi FG, Takabayashi K, Foster AC et al (1996) Inhibition of TNF-alpha expression by adenosine:role of A3 adenosine receptors. J Immunol 156:3435–3442PubMedGoogle Scholar
  131. Salvatore CA, Tilley SL, Latour AM et al (2000) Disruption of the A(3) adenosine receptor gene in mice and its effect on stimulated inflammatory cells. J Biol Chem 275:4429–4434PubMedCrossRefGoogle Scholar
  132. Salvemini D, Neumann W (2010) Targeting peroxynitrite driven nitroxidative stress with synzymes:a novel therapeutic approach in chronic pain management. Life Sci 86:604–614PubMedCrossRefGoogle Scholar
  133. Sawynok J (1998) Adenosine receptor activation and nociception. Eur J Pharmacol 347:1–11PubMedCrossRefGoogle Scholar
  134. Sawynok J (2013) Adenosine and pain. In: Boison D, Masino SA (eds) Adenosine: a key link between metabolism and brain activity. Springer, Berlin, pp 343–360CrossRefGoogle Scholar
  135. Sawynok J (2016) Adenosine receptor targets for pain. Neuroscience 338:1–18PubMedCrossRefGoogle Scholar
  136. Sawynok J, Zarrindast MR, Reid AR et al (1997) Adenosine A3 receptor activation produces nociceptive behaviour and edema by release of histamine and 5-hydroxytryptamine. Eur J Pharmacol 333:1–7PubMedCrossRefGoogle Scholar
  137. Sawynok J, Reid A, Liu XJ (1999) Acute paw oedema induced by local injection of adenosine A(1), A(2) and A(3) receptor agonists. Eur J Pharmacol 386:253–261PubMedCrossRefGoogle Scholar
  138. Sebastian-Serrano A, de Diego-Garcia L, Martinez-Frailes C et al (2015) Tissue-nonspecific alkaline phosphatase regulates purinergic transmission in the central nervous system during development and disease. Comput Struct Biotechnol J 13:95–100PubMedCrossRefGoogle Scholar
  139. Sebastiao AM, Ribeiro JA (1996) Adenosine A2 receptor-mediated excitatory actions on the nervous system. Prog Neurobiol 48:167–189PubMedCrossRefGoogle Scholar
  140. Shneyvays V, Nawrath H, Jacobson KA et al (1998) Induction of apoptosis in cardiac myocytes by an A3 adenosine receptor agonist. Exp Cell Res 243:383–397PubMedCrossRefPubMedCentralGoogle Scholar
  141. Shneyvays V, Mamedova L, Zinman T et al (2001) Activation of A(3) adenosine receptor protects against doxorubicin-induced cardiotoxicity. J Mol Cell Cardiol 33:1249–1261PubMedCrossRefGoogle Scholar
  142. Sjolund KF, von Heijne M, Hao JX et al (1998) Intrathecal administration of the adenosine A1 receptor agonist R-phenylisopropyl adenosine reduces presumed pain behaviour in a rat model of central pain. Neurosci Lett 243:89–92PubMedCrossRefGoogle Scholar
  143. Smith PA (2014) BDNF:no gain without pain? Neuroscience 283C:107–123CrossRefGoogle Scholar
  144. Sowa NA, Street SE, Vihko P et al (2010) Prostatic acid phosphatase reduces thermal sensitivity and chronic pain sensitization by depleting phosphatidylinositol 4,5-bisphosphate. J Neurosci 30:10282–10293PubMedPubMedCentralCrossRefGoogle Scholar
  145. Spychala J, Datta NS, Takabayashi K et al (1996) Cloning of human adenosine kinase cDNA:sequence similarity to microbial ribokinases and fructokinases. Proc Natl Acad Sci U S A 93:1232–1237PubMedPubMedCentralCrossRefGoogle Scholar
  146. Stiller CO, Cui JG, O’Connor WT et al (1996) Release of gamma-aminobutyric acid in the dorsal horn and suppression of tactile allodynia by spinal cord stimulation in mononeuropathic rats. Neurosurgery 39:367–374PubMedCrossRefGoogle Scholar
  147. Studer FE, Fedele DE, Marowsky A et al (2006) Shift of adenosine kinase expression from neurons to astrocytes during postnatal development suggests dual functionality of the enzyme. Neuroscience 142:125–137PubMedCrossRefGoogle Scholar
  148. Svenningsson P, Hall H, Sedvall G et al (1997) Distribution of adenosine receptors in the postmortem human brain:an extended autoradiographic study. Synapse 27:322–335PubMedCrossRefGoogle Scholar
  149. Sweitzer SM, Schubert P, DeLeo JA (2001) Propentofylline, a glial modulating agent, exhibits antiallodynic properties in a rat model of neuropathic pain. J Pharmacol Exp Ther 297:1210–1217PubMedGoogle Scholar
  150. Szabo C, Scott GS, Virag L et al (1998) Suppression of macrophage inflammatory protein (MIP)-1alpha production and collagen-induced arthritis by adenosine receptor agonists. Br J Pharmacol 125:379–387PubMedPubMedCentralCrossRefGoogle Scholar
  151. Taiwo YO, Levine JD (1990) Direct cutaneous hyperalgesia induced by adenosine. Neuroscience 38:757–762PubMedCrossRefGoogle Scholar
  152. Thourani VH, Nakamura M, Ronson RS et al (1999a) Adenosine A(3)-receptor stimulation attenuates postischemic dysfunction through K(ATP) channels. Am J Phys 277:H228–H235Google Scholar
  153. Thourani VH, Ronson RS, Jordan JE et al (1999b) Adenosine A3 pretreatment before cardioplegic arrest attenuates postischemic cardiac dysfunction. Ann Thorac Surg 67:1732–1737PubMedCrossRefGoogle Scholar
  154. Tosh DK, Deflorian F, Phan K et al (2012) Structure-guided design of A(3) adenosine receptor-selective nucleosides:combination of 2-arylethynyl and bicyclo[ 3 10]hexane substitutions. J Med Chem 55:4847–4860PubMedPubMedCentralCrossRefGoogle Scholar
  155. Tosh DK, Finley A, Paoletta S et al (2014) In vivo phenotypic screening for treating chronic neuropathic pain:modification of C2-arylethynyl group of conformationally constrained A3 adenosine receptor agonists. J Med Chem 57:9901–9914PubMedPubMedCentralCrossRefGoogle Scholar
  156. Tosh DK, Paoletta S, Chen Z et al (2015) Structure-based design, synthesis by click chemistry and in vivo activity of highly selective A3 adenosine receptor agonists. Med Chem Commun 6:555–563CrossRefGoogle Scholar
  157. Tracey WR, Magee W, Masamune H et al (1997) Selective adenosine A3 receptor stimulation reduces ischemic myocardial injury in the rabbit heart. Cardiovasc Res 33:410–415PubMedCrossRefGoogle Scholar
  158. Vallon V, Osswald H (2009) Adenosine receptors and the kidney. Handb Exp Pharmacol 193:443–470CrossRefGoogle Scholar
  159. Varani K, Vincenzi F, Tosi A et al (2010) Expression and functional role of adenosine receptors in regulating inflammatory responses in human synoviocytes. Br J Pharmacol 160:101–115PubMedPubMedCentralCrossRefGoogle Scholar
  160. Varani K, Padovan M, Vincenzi F et al (2011) A2A and A3 adenosine receptor expression in rheumatoid arthritis:upregulation, inverse correlation with disease activity score and suppression of inflammatory cytokine and metalloproteinase release. Arthritis Res Ther 13:R197PubMedPubMedCentralCrossRefGoogle Scholar
  161. Varani K, Vincenzi F, Targa M et al (2013) The stimulation of A(3) adenosine receptors reduces bone-residing breast cancer in a rat preclinical model. Eur J Cancer 49:482–491PubMedCrossRefGoogle Scholar
  162. Varani K, Vincenzi F, Merighi S et al (2017) Biochemical and pharmacological role of A1 adenosine receptors and their modulation as novel therapeutic strategy. Adv Exp Med Biol 1051:193–232PubMedCrossRefGoogle Scholar
  163. Vincenzi F, Targa M, Romagnoli R et al (2014) TRR469, a potent A(1) adenosine receptor allosteric modulator, exhibits anti-nociceptive properties in acute and neuropathic pain models in mice. Neuropharmacology 81:6–14PubMedCrossRefGoogle Scholar
  164. Wahlman C, Doyle TM, Little JW et al (2018) Chemotherapy-induced pain is promoted by enhanced spinal adenosine kinase levels via astrocyte-dependent mechanisms. Pain, in press. https://doi.org/10.1097/j.pain.0000000000001177
  165. Watkins LR, Martin D, Ulrich P et al (1997) Evidence for the involvement of spinal cord glia in subcutaneous formalin induced hyperalgesia in the rat. Pain 71:225–235PubMedCrossRefGoogle Scholar
  166. Watkins LR, Milligan ED, Maier SF (2001) Glial activation: a driving force for pathological pain. Trends Neurosci 24:450–455PubMedCrossRefGoogle Scholar
  167. Watkins LR, Hutchinson MR, Rice KC et al (2009) The “toll” of opioid-induced glial activation:improving the clinical efficacy of opioids by targeting glia. Trends Pharmacol Sci 30:581–591PubMedPubMedCentralCrossRefGoogle Scholar
  168. Wei CJ, Li W, Chen JF (2011) Normal and abnormal functions of adenosine receptors in the central nervous system revealed by genetic knockout studies. Biochim Biophys Acta 1808:1358–1379PubMedCrossRefGoogle Scholar
  169. Wittendorp MC, Boddeke HW, Biber K (2004) Adenosine A3 receptor-induced CCL2 synthesis in cultured mouse astrocytes. Glia 46:410–418PubMedCrossRefGoogle Scholar
  170. Wu WP, Hao JX, Halldner-Henriksson L et al (2002) Decreased inflammatory pain due to reduced carrageenan-induced inflammation in mice lacking adenosine A3 receptors. Neuroscience 114:523–527PubMedCrossRefGoogle Scholar
  171. Wu WP, Hao JX, Halldner L et al (2005) Increased nociceptive response in mice lacking the adenosine A1 receptor. Pain 113:395–404PubMedCrossRefGoogle Scholar
  172. Xu X, Wang P, Zou X et al (2010) The effects of sympathetic outflow on upregulation of vanilloid receptors TRPV(1) in primary afferent neurons evoked by intradermal capsaicin. Exp Neurol 222:93–107PubMedCrossRefGoogle Scholar
  173. Yamaoka G, Horiuchi H, Morino T et al (2013) Different analgesic effects of adenosine between postoperative and neuropathic pain. J Orthop Sci 18:130–136PubMedCrossRefGoogle Scholar
  174. Yeo JF, Ling SF, Tang N et al (2008) Antinociceptive effect of CNS peroxynitrite scavenger in a mouse model of orofacial pain. Exp Brain Res 184:435–438PubMedCrossRefGoogle Scholar
  175. Yoon MH, Choi JI, Park HC et al (2004) Interaction between intrathecal gabapentin and adenosine in the formalin test of rats. J Korean Med Sci 19:581–585PubMedPubMedCentralCrossRefGoogle Scholar
  176. Yoon MH, Bae HB, Choi JI (2005) Antinociception of intrathecal adenosine receptor subtype agonists in rat formalin test. Anesth Analg 101:1417–1421PubMedCrossRefGoogle Scholar
  177. Yoon MH, Bae HB, Choi JI et al (2006) Roles of adenosine receptor subtypes in the antinociceptive effect of intrathecal adenosine in a rat formalin test. Pharmacology 78:21–26PubMedCrossRefGoogle Scholar
  178. Zahn PK, Straub H, Wenk M et al (2007) Adenosine A1 but not A2a receptor agonist reduces hyperalgesia caused by a surgical incision in rats:a pertussis toxin-sensitive G protein-dependent process. Anesthesiology 107:797–806PubMedCrossRefGoogle Scholar
  179. Zeilhofer HU, Wildner H, Yevenes GE (2012) Fast synaptic inhibition in spinal sensory processing and pain control. Physiol Rev 92:193–235PubMedPubMedCentralCrossRefGoogle Scholar
  180. Zhang G, Franklin PH, Murray TF (1993) Manipulation of endogenous adenosine in the rat prepiriform cortex modulates seizure susceptibility. J Pharmacol Exp Ther 264:1415–1424PubMedGoogle Scholar
  181. Zhang X, Zhang M, Laties AM et al (2006) Balance of purines may determine life or death of retinal ganglion cells as A3 adenosine receptors prevent loss following P2X7 receptor stimulation. J Neurochem 98:566–575PubMedCrossRefGoogle Scholar
  182. Zhang M, Hu H, Zhang X et al (2010) The A3 adenosine receptor attenuates the calcium rise triggered by NMDA receptors in retinal ganglion cells. Neurochem Int 56:35–41PubMedCrossRefGoogle Scholar
  183. Zhang H, Yoon SY, Dougherty PM (2012) Evidence that spinal astrocytes but not microglia contribute to the pathogenesis of Paclitaxel-induced painful neuropathy. J Pain 13:293–303PubMedPubMedCentralCrossRefGoogle Scholar
  184. Zhang Y, Chen K, Sloan SA et al (2014) An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci 34:11929–11947PubMedPubMedCentralCrossRefGoogle Scholar
  185. Zimmermann H (2000) Extracellular metabolism of ATP and other nucleotides. Naunyn Schmiedeberg's Arch Pharmacol 362:299–309CrossRefGoogle Scholar
  186. Zylka MJ (2011) Pain-relieving prospects for adenosine receptors and ectonucleotidases. Trends Mol Med 17:188–196PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Daniela Salvemini
    • 1
  • Timothy M. Doyle
    • 1
  • Tally M. Largent-Milnes
    • 2
  • Todd W. Vanderah
    • 2
  1. 1.Department of Pharmacology and PhysiologySaint Louis UniversitySt. LouisUSA
  2. 2.Department of PharmacologyUniversity of ArizonaTucsonUSA

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