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The Adenosine-Receptor Axis in Chronic Pain

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The Adenosine Receptors

Part of the book series: The Receptors ((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.

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References

  • 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 241:297–304

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 575:555–571

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 436:136–144

    Article  PubMed  CAS  Google Scholar 

  • 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 142:97–103

    Article  CAS  PubMed  Google Scholar 

  • 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 6:88

    Google Scholar 

  • 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 6:44

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Blackburn MR, Kellems RE (1996) Regulation and function of adenosine deaminase in mice. Prog Nucleic Acid Res Mol Biol 55:195–226

    Article  PubMed  CAS  Google Scholar 

  • Boison D (2008a) Adenosine as a neuromodulator in neurological diseases. Curr Opin Pharmacol 8:2–7

    Article  PubMed  CAS  Google Scholar 

  • Boison D (2008b) The adenosine kinase hypothesis of epileptogenesis. Prog Neurobiol 84:249–262

    Article  PubMed  CAS  Google Scholar 

  • Boison D (2013) Adenosine kinase:exploitation for therapeutic gain. Pharmacol Rev 65:906–943

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Boison D (2016) Adenosinergic signaling in epilepsy. Neuropharmacology 104:131–139

    Article  PubMed  CAS  Google Scholar 

  • Boison D, Chen JF, Fredholm BB (2010) Adenosine signaling and function in glial cells. Cell Death Differ 17:1071–1082

    Article  PubMed  CAS  Google Scholar 

  • Bonan CD (2012) Ectonucleotidases and nucleotide/nucleoside transporters as pharmacological targets for neurological disorders. CNS Neurol Disord Drug Targets 11:739–750

    Article  PubMed  CAS  Google Scholar 

  • Borea PA, Varani K, Vincenzi F et al (2015) The A3 adenosine receptor:history and perspectives. Pharmacol Rev 67:74–102

    Article  PubMed  CAS  Google Scholar 

  • Bradesi S, Eutamene H, Theodorou V et al (2001) Effect of ovarian hormones on intestinal mast cell reactivity to substance P. Life Sci 68:1047–1056

    Article  PubMed  CAS  Google Scholar 

  • Brundege JM, Dunwiddie TV (1998) Metabolic regulation of endogenous adenosine release from single neurons. Neuroreport 9:3007–3011

    Article  PubMed  CAS  Google Scholar 

  • 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 230:178–182

    Article  PubMed  CAS  Google Scholar 

  • Cao H, Zhang YQ (2008) Spinal glial activation contributes to pathological pain states. Neurosci Biobehav Rev 32:972–983

    Article  PubMed  Google Scholar 

  • Chen Z, Muscoli C, Doyle T et al (2010) NMDA-receptor activation and nitroxidative regulation of the glutamatergic pathway during nociceptive processing. Pain 149:100–106

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chen Z, Janes K, Chen C et al (2012) Controlling murine and rat chronic pain through A3 adenosine receptor activation. FASEB J 26:1855–1865

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chen JF, Eltzschig HK, Fredholm BB (2013) Adenosine receptors as drug targets--what are the challenges? Nat Rev 12:265–286

    CAS  Google Scholar 

  • Choi JS, Berdis AJ (2012) Nucleoside transporters: biological insights and therapeutic applications. Future Med Chem 4:1461–1478

    Article  PubMed  CAS  Google Scholar 

  • 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 179:2042–2052

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 424:938–942

    Article  PubMed  CAS  Google Scholar 

  • 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–H1568

    CAS  Google Scholar 

  • 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 223:173–176

    Article  PubMed  CAS  Google Scholar 

  • 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 38:107–125

    Article  PubMed  CAS  Google Scholar 

  • Cunha RA (2005) Neuroprotection by adenosine in the brain:from A(1) receptor activation to A (2A) receptor blockade. Purinergic Signal 1:111–134

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 52:65–72

    Article  PubMed  CAS  Google Scholar 

  • 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:e1539

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Deussen A, Stappert M, Schafer S et al (1999) Quantification of extracellular and intracellular adenosine production: understanding the transmembranous concentration gradient. Circulation 99:2041–2047

    Article  PubMed  CAS  Google Scholar 

  • Dias RB, Rombo DM, Ribeiro JA et al (2013) Adenosine: setting the stage for plasticity. Trends Neurosci 36:248–257

    Article  PubMed  CAS  Google Scholar 

  • Dickenson AH, Suzuki R, Reeve AJ (2000) Adenosine as a potential analgesic target in inflammatory and neuropathic pains. CNS Drugs 13:77–85

    Article  CAS  Google Scholar 

  • 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 32:6149–6160

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dunwiddie TV, Masino SA (2001) The role and regulation of adenosine in the central nervous system. Annu Rev Neurosci 24:31–55

    Article  PubMed  CAS  Google Scholar 

  • 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 16:57–72

    Article  PubMed  CAS  Google Scholar 

  • 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 56:69–75

    Article  PubMed  CAS  Google Scholar 

  • Engler RL (1991) Adenosine. The signal of life? Circulation 84:951–954

    Article  PubMed  CAS  Google Scholar 

  • 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 23:431–447

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Feoktistov I, Biaggioni I (2011) Role of adenosine A(2B) receptors in inflammation. Adv Pharmacol 61:115–144

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ferrini F, De Koninck Y (2013) Microglia control neuronal network excitability via BDNF signalling. Neural Plast 2013:429815

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 56:254–263

    Article  PubMed  CAS  Google Scholar 

  • Fishman P, Bar-Yehuda S, Madi L et al (2002) A3 adenosine receptor as a target for cancer therapy. Anti-Cancer Drugs 13:437–443

    Article  PubMed  CAS  Google Scholar 

  • 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:R33

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fishman P, Bar-Yehuda S, Synowitz M et al (2009) Adenosine receptors and cancer. Handb Exp Pharmacol 193:399–441

    Google Scholar 

  • Fishman P, Bar-Yehuda S, Liang BT et al (2012) Pharmacological and therapeutic effects of A3 adenosine receptor agonists. Drug Discov Today 17:359–366

    Article  PubMed  CAS  Google Scholar 

  • 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 35:6057–6067

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fredholm BB, AP IJ, Jacobson KA et al (2001) International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 53:527–552

    PubMed  CAS  Google Scholar 

  • 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 63:1–34

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 37:636–646

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gan TJ, Habib AS (2007) Adenosine as a non-opioid analgesic in the perioperative setting. Anesth Analg 105:487–494

    Article  PubMed  CAS  Google Scholar 

  • Gao ZG, Jacobson KA (2007) Emerging adenosine receptor agonists. Expert Opin Emerg Drugs 12:479–492

    Article  PubMed  CAS  Google Scholar 

  • Gao ZG, Jacobson KA (2011) Emerging adenosine receptor agonists:an update. Expert Opin Emerg Drugs 16:597–602

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 5:31–37

    Article  PubMed  CAS  Google Scholar 

  • Gessi S, Merighi S, Varani K et al (2011) Adenosine receptors in health and disease. Adv Pharmacol 61:41–75

    Article  PubMed  CAS  Google Scholar 

  • Giannaccini G, Betti L, Palego L et al (2008) Species comparison of adenosine receptor subtypes in brain and testis. Neurochem Res 33:852–860

    Article  PubMed  CAS  Google Scholar 

  • Goldberg DS, McGee SJ (2011) Pain as a global public health priority. BMC Public Health 11:770

    Article  PubMed  PubMed Central  Google Scholar 

  • Gomes CV, Kaster MP, Tomé AR et al (2011) Adenosine receptors and brain diseases: neuroprotection and neurodegeneration. Biochim Biophys Acta Biomembr 1808:1380–1399

    Article  CAS  Google Scholar 

  • 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 1361:23–30

    Article  PubMed  CAS  Google Scholar 

  • 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 108:340

    Article  PubMed  CAS  Google Scholar 

  • 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 109:1085–1091

    Article  PubMed  CAS  Google Scholar 

  • 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 42:928–939

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 53:147–155

    Article  PubMed  CAS  Google Scholar 

  • 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) 25:1206–1217

    Article  CAS  Google Scholar 

  • 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 157:4634–4640

    PubMed  CAS  Google Scholar 

  • 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 358:261–268

    Article  PubMed  CAS  Google Scholar 

  • Hayashida M, Fukuda K, Fukunaga A (2005) Clinical application of adenosine and ATP for pain control. J Anesth 19:225–235

    Article  PubMed  Google Scholar 

  • Headrick JP, Peart J (2005) A3 adenosine receptor-mediated protection of the ischemic heart. Vasc Pharmacol 42:271–279

    Article  CAS  Google Scholar 

  • Headrick JP, Peart JN, Reichelt ME et al (2011) Adenosine and its receptors in the heart:regulation, retaliation and adaptation. Biochim Biophys Acta 1808:1413–1428

    Article  PubMed  CAS  Google Scholar 

  • 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 53:639–645

    Article  PubMed  CAS  Google Scholar 

  • 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, DC

    Google Scholar 

  • Jacobson KA (1998) Adenosine A3 receptors:novel ligands and paradoxical effects. Trends Pharmacol Sci 19:184–191

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jacobson KA, Gao ZG (2006) Adenosine receptors as therapeutic targets. Nat Rev Drug Discov 5:247–264

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jacobson KA, Nikodijevic O, Shi D et al (1993) A role for central A3-adenosine receptors. Mediation of behavioral depressant effects. FEBS Lett 336:57–60

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jajoo S, Mukherjea D, Watabe K et al (2009) Adenosine A(3) receptor suppresses prostate cancer metastasis by inhibiting NADPH oxidase activity. Neoplasia 11:1132–1145

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 154:2432–2440

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 155:2560–2567

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 289:21082–21097

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 44:91–99

    Article  PubMed  CAS  Google Scholar 

  • 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 49:650–658

    Article  PubMed  CAS  Google Scholar 

  • 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 285:312–323

    Article  PubMed  CAS  Google Scholar 

  • 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–PL176

    Article  PubMed  Google Scholar 

  • Kiesman WF, Elzein E, Zablocki J (2009) A1 adenosine receptor antagonists, agonists, and allosteric enhancers. Handb Exp Pharmacol 193:25–58

    Article  CAS  Google Scholar 

  • Klaasse EC, Ijzerman AP, de Grip WJ et al (2008) Internalization and desensitization of adenosine receptors. Purinergic Signal 4:21–37

    Article  PubMed  CAS  Google Scholar 

  • 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 63:83–91

    Article  PubMed  CAS  Google Scholar 

  • 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 295:1165–1174

    PubMed  CAS  Google Scholar 

  • Latini S, Pedata F (2001) Adenosine in the central nervous system:release mechanisms and extracellular concentrations. J Neurochem 79:463–484

    Article  PubMed  CAS  Google Scholar 

  • Ledent C, Vaugeois JM, Schiffmann SN et al (1997) Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2a receptor. Nature 388:674–678

    Article  PubMed  CAS  Google Scholar 

  • 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 90:10086–10090

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lee JE, Bokoch G, Liang BT (2001) A novel cardioprotective role of RhoA: new signaling mechanism for adenosine. FASEB J 15:1886–1894

    Article  PubMed  CAS  Google Scholar 

  • Li Y, Zhang H, Kosturakis AK et al (2014) Toll-like receptor 4 signaling contributes to paclitaxel-induced peripheral neuropathy. J Pain 15:712–725

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Little JW, Ford A, Symons-Liguori AM et al (2015) Endogenous adenosine A3 receptor activation selectively alleviates persistent pain states. Brain 138:28–35

    Article  PubMed  Google Scholar 

  • Lopes LV, Rebola N, Pinheiro PC et al (2003) Adenosine A3 receptors are located in neurons of the rat hippocampus. Neuroreport 14:1645–1648

    Article  PubMed  CAS  Google Scholar 

  • 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 29:14015–14025

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Luongo L, Guida F, Imperatore R et al (2014) The A1 adenosine receptor as a new player in microglia physiology. Glia 62:122–132

    Article  PubMed  CAS  Google Scholar 

  • 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 278:42121–42130

    Article  PubMed  CAS  Google Scholar 

  • 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 34:20–26

    PubMed  CAS  Google Scholar 

  • 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 22:8312–8323

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • 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 234:69–76

    Article  PubMed  CAS  Google Scholar 

  • 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 96:7731–7736

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • McGaraughty S, Cowart M, Jarvis MF et al (2005) Anticonvulsant and antinociceptive actions of novel adenosine kinase inhibitors. Curr Top Med Chem 5:43–58

    Article  PubMed  CAS  Google Scholar 

  • 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 33:1471–1478

    Article  PubMed  CAS  Google Scholar 

  • 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 117:9–19

    Article  PubMed  CAS  Google Scholar 

  • Milligan ED, Watkins LR (2009) Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci 10:23–36

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 22:6724–6731

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • 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 177:7173–7183

    Article  PubMed  CAS  Google Scholar 

  • Moser GH, Schrader J, Deussen A (1989) Turnover of adenosine in plasma of human and dog blood. Am J Phys 256:C799–C806

    Article  CAS  Google Scholar 

  • 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 117:3530–3539

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Muscoli C, Doyle T, Dagostino C et al (2010) Counter-regulation of opioid analgesia by glial-derived bioactive sphingolipids. J Neurosci 30:15400–15408

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Nagata K, Imai T, Yamashita T et al (2009) Antidepressants inhibit P2X4 receptor function: a possible involvement in neuropathic pain relief. Mol Pain 5:20

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ndengele MM, Cuzzocrea S, Esposito E et al (2008) Cyclooxygenases 1 and 2 contribute to peroxynitrite-mediated inflammatory pain hypersensitivity. FASEB J 22:3154–3164

    Article  PubMed  CAS  Google Scholar 

  • Obata K, Noguchi K (2008) Contribution of primary sensory neurons and spinal glial cells to pathomechanisms of neuropathic pain. Brain Nerve 60:483–492

    PubMed  CAS  Google Scholar 

  • 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 258:115–122

    Article  PubMed  CAS  Google Scholar 

  • 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 97:160–170

    Article  PubMed  CAS  Google Scholar 

  • 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 56:5949–5963

    Article  PubMed  CAS  Google Scholar 

  • 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 14:1423–1431

    Article  PubMed  CAS  Google Scholar 

  • Peng L, Huang R, Yu AC et al (2005) Nucleoside transporter expression and function in cultured mouse astrocytes. Glia 52:25–35

    Article  PubMed  Google Scholar 

  • 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 60:4327–4341

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Pizzo PA, Clark NM (2012) Alleviating suffering 101--pain relief in the United States. N Engl J Med 366:197–199

    Article  PubMed  CAS  Google Scholar 

  • 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 328:85–92

    Article  PubMed  CAS  Google Scholar 

  • Poon A, Sawynok J (1998) Antinociception by adenosine analogs and inhibitors of adenosine metabolism in an inflammatory thermal hyperalgesia model in the rat. Pain 74:235–245

    Article  PubMed  CAS  Google Scholar 

  • Poulsen SA, Quinn RJ (1998) Adenosine receptors:new opportunities for future drugs. Bioorg Med Chem 6:619–641

    Article  PubMed  CAS  Google Scholar 

  • Price TJ, Cervero F, de Koninck Y (2005) Role of cation-chloride-cotransporters (CCC) in pain and hyperalgesia. Curr Top Med Chem 5:547–555

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 Raton

    Google Scholar 

  • 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 54:8658–8669

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 132:893–903

    Article  PubMed  CAS  Google Scholar 

  • Robson SC, Sevigny J, Zimmermann H (2006) The E-NTPDase family of ectonucleotidases:structure function relationships and pathophysiological significance. Purinergic Signal 2:409–430

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 17:3488–3502

    Article  PubMed  CAS  Google Scholar 

  • Ru F, Surdenikova L, Brozmanova M et al (2011) Adenosine-induced activation of esophageal nociceptors. Am J Physiol Gastrointest Liver Physiol 300:G485–G493

    Article  PubMed  CAS  Google Scholar 

  • Sajjadi FG, Takabayashi K, Foster AC et al (1996) Inhibition of TNF-alpha expression by adenosine:role of A3 adenosine receptors. J Immunol 156:3435–3442

    PubMed  CAS  Google Scholar 

  • 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 275:4429–4434

    Article  PubMed  CAS  Google Scholar 

  • Salvemini D, Neumann W (2010) Targeting peroxynitrite driven nitroxidative stress with synzymes:a novel therapeutic approach in chronic pain management. Life Sci 86:604–614

    Article  PubMed  CAS  Google Scholar 

  • Sawynok J (1998) Adenosine receptor activation and nociception. Eur J Pharmacol 347:1–11

    Article  PubMed  CAS  Google Scholar 

  • Sawynok J (2013) Adenosine and pain. In: Boison D, Masino SA (eds) Adenosine: a key link between metabolism and brain activity. Springer, Berlin, pp 343–360

    Chapter  Google Scholar 

  • Sawynok J (2016) Adenosine receptor targets for pain. Neuroscience 338:1–18

    Article  PubMed  CAS  Google Scholar 

  • 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 333:1–7

    Article  PubMed  CAS  Google Scholar 

  • 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 386:253–261

    Article  PubMed  CAS  Google Scholar 

  • 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 13:95–100

    Article  PubMed  CAS  Google Scholar 

  • Sebastiao AM, Ribeiro JA (1996) Adenosine A2 receptor-mediated excitatory actions on the nervous system. Prog Neurobiol 48:167–189

    Article  PubMed  CAS  Google Scholar 

  • Shneyvays V, Nawrath H, Jacobson KA et al (1998) Induction of apoptosis in cardiac myocytes by an A3 adenosine receptor agonist. Exp Cell Res 243:383–397

    Article  PubMed  CAS  Google Scholar 

  • Shneyvays V, Mamedova L, Zinman T et al (2001) Activation of A(3) adenosine receptor protects against doxorubicin-induced cardiotoxicity. J Mol Cell Cardiol 33:1249–1261

    Article  PubMed  CAS  Google Scholar 

  • 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 243:89–92

    Article  PubMed  CAS  Google Scholar 

  • Smith PA (2014) BDNF:no gain without pain? Neuroscience 283C:107–123

    Article  CAS  Google Scholar 

  • 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 30:10282–10293

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 93:1232–1237

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 39:367–374

    Article  PubMed  CAS  Google Scholar 

  • 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 142:125–137

    Article  PubMed  CAS  Google Scholar 

  • Svenningsson P, Hall H, Sedvall G et al (1997) Distribution of adenosine receptors in the postmortem human brain:an extended autoradiographic study. Synapse 27:322–335

    Article  PubMed  CAS  Google Scholar 

  • 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 297:1210–1217

    PubMed  CAS  Google Scholar 

  • 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 125:379–387

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Taiwo YO, Levine JD (1990) Direct cutaneous hyperalgesia induced by adenosine. Neuroscience 38:757–762

    Article  PubMed  CAS  Google Scholar 

  • 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–H235

    CAS  Google Scholar 

  • Thourani VH, Ronson RS, Jordan JE et al (1999b) Adenosine A3 pretreatment before cardioplegic arrest attenuates postischemic cardiac dysfunction. Ann Thorac Surg 67:1732–1737

    Article  PubMed  CAS  Google Scholar 

  • 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 55:4847–4860

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 57:9901–9914

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 6:555–563

    Article  CAS  Google Scholar 

  • Tracey WR, Magee W, Masamune H et al (1997) Selective adenosine A3 receptor stimulation reduces ischemic myocardial injury in the rabbit heart. Cardiovasc Res 33:410–415

    Article  PubMed  CAS  Google Scholar 

  • Vallon V, Osswald H (2009) Adenosine receptors and the kidney. Handb Exp Pharmacol 193:443–470

    Article  CAS  Google Scholar 

  • 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 160:101–115

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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:R197

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 49:482–491

    Article  PubMed  CAS  Google Scholar 

  • 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 1051:193–232

    Article  PubMed  Google Scholar 

  • 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 81:6–14

    Article  PubMed  CAS  Google Scholar 

  • 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

  • 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 71:225–235

    Article  PubMed  CAS  Google Scholar 

  • Watkins LR, Milligan ED, Maier SF (2001) Glial activation: a driving force for pathological pain. Trends Neurosci 24:450–455

    Article  PubMed  CAS  Google Scholar 

  • 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 30:581–591

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 1808:1358–1379

    Article  PubMed  CAS  Google Scholar 

  • Wittendorp MC, Boddeke HW, Biber K (2004) Adenosine A3 receptor-induced CCL2 synthesis in cultured mouse astrocytes. Glia 46:410–418

    Article  PubMed  Google Scholar 

  • 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 114:523–527

    Article  PubMed  CAS  Google Scholar 

  • Wu WP, Hao JX, Halldner L et al (2005) Increased nociceptive response in mice lacking the adenosine A1 receptor. Pain 113:395–404

    Article  PubMed  CAS  Google Scholar 

  • 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 222:93–107

    Article  PubMed  CAS  Google Scholar 

  • Yamaoka G, Horiuchi H, Morino T et al (2013) Different analgesic effects of adenosine between postoperative and neuropathic pain. J Orthop Sci 18:130–136

    Article  PubMed  CAS  Google Scholar 

  • 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 184:435–438

    Article  PubMed  CAS  Google Scholar 

  • 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 19:581–585

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Yoon MH, Bae HB, Choi JI (2005) Antinociception of intrathecal adenosine receptor subtype agonists in rat formalin test. Anesth Analg 101:1417–1421

    Article  PubMed  CAS  Google Scholar 

  • 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 78:21–26

    Article  PubMed  CAS  Google Scholar 

  • 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 107:797–806

    Article  PubMed  CAS  Google Scholar 

  • Zeilhofer HU, Wildner H, Yevenes GE (2012) Fast synaptic inhibition in spinal sensory processing and pain control. Physiol Rev 92:193–235

    Article  PubMed  CAS  Google Scholar 

  • Zhang G, Franklin PH, Murray TF (1993) Manipulation of endogenous adenosine in the rat prepiriform cortex modulates seizure susceptibility. J Pharmacol Exp Ther 264:1415–1424

    PubMed  CAS  Google Scholar 

  • 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 98:566–575

    Article  PubMed  CAS  Google Scholar 

  • 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 56:35–41

    Article  PubMed  CAS  Google Scholar 

  • 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 13:293–303

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 34:11929–11947

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zimmermann H (2000) Extracellular metabolism of ATP and other nucleotides. Naunyn Schmiedeberg's Arch Pharmacol 362:299–309

    Article  CAS  Google Scholar 

  • Zylka MJ (2011) Pain-relieving prospects for adenosine receptors and ectonucleotidases. Trends Mol Med 17:188–196

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacology and Physiology, Saint Louis University, St. Louis, MO, USA

    Daniela Salvemini & Timothy M. Doyle

  2. Department of Pharmacology, University of Arizona, Tucson, AZ, USA

    Tally M. Largent-Milnes & Todd W. Vanderah

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  1. Daniela Salvemini
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  2. Timothy M. Doyle
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  3. Tally M. Largent-Milnes
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  4. Todd W. Vanderah
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Correspondence to Daniela Salvemini .

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Editors and Affiliations

  1. Department of Medical Sciences, University of Ferrara, Ferrara, Italy

    Pier Andrea Borea

  2. Department of Medical Sciences, University of Ferrara, Ferrara, Italy

    Katia Varani

  3. Department of Medical Sciences, University of Ferrara, Ferrara, Italy

    Stefania Gessi

  4. Department of Medical Sciences, University of Ferrara, Ferrara, Italy

    Stefania Merighi

  5. Department of Medical Sciences, University of Ferrara, Ferrara, Italy

    Fabrizio Vincenzi

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Salvemini, D., Doyle, T.M., Largent-Milnes, T.M., Vanderah, T.W. (2018). The Adenosine-Receptor Axis in Chronic Pain. In: Borea, P., Varani, K., Gessi, S., Merighi, S., Vincenzi, F. (eds) The Adenosine Receptors. The Receptors, vol 34. Humana Press, Cham. https://doi.org/10.1007/978-3-319-90808-3_16

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