{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T13:21:36Z","timestamp":1791638496786,"version":"4.3.4"},"reference-count":37,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2012,11,22]],"date-time":"2012-11-22T00:00:00Z","timestamp":1353542400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>This study was undertaken in order to investigate the effect of chronic treatment with 5\u2032-chloro-5\u2032-deoxy-(\u00b1)-ENBA, a potent and highly selective agonist of human adenosine A1 receptor, on thermal hyperalgesia and mechanical allodynia in a mouse model of neuropathic pain, the Spared Nerve Injury (SNI) of the sciatic nerve. Chronic systemic administration of 5\u2032-chloro-5\u2032-deoxy-(\u00b1)-ENBA (0.5 mg\/kg, i.p.) reduced both mechanical allodynia and thermal hyperalgesia 3 and 7 days post-SNI, in a way prevented by DPCPX (3 mg\/kg, i.p.), a selective A1 adenosine receptor antagonist, without exerting any significant change on the motor coordination or arterial blood pressure. In addition, a single intraperitoneal injection of 5\u2032-chloro-5\u2032-deoxy-(\u00b1)-ENBA (0.5 mg\/kg, i.p.) 7 days post-SNI also reduced both symptoms for at least two hours. SNI was associated with spinal changes in microglial activation ipsilaterally to the nerve injury. Activated, hypertrophic microglia were significantly reduced by 5\u2032-chloro-5\u2032-deoxy-(\u00b1)-ENBA chronic treatment. Our results demonstrated an involvement of adenosine A1 receptor in the amplified nociceptive thresholds and in spinal glial and microglial changes occurred in neuropathic pain, without affecting motor coordination or blood pressure. Our data suggest a possible use of adenosine A1 receptor agonist in neuropathic pain symptoms.<\/jats:p>","DOI":"10.3390\/molecules171213712","type":"journal-article","created":{"date-parts":[[2012,11,22]],"date-time":"2012-11-22T11:02:55Z","timestamp":1353582175000},"page":"13712-13726","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["5'-Chloro-5'-deoxy-(\u00b1)-ENBA, a Potent and Selective Adenosine A1 Receptor Agonist, Alleviates Neuropathic Pain in Mice Through Functional Glial and Microglial Changes without Affecting Motor or Cardiovascular Functions"],"prefix":"10.3390","volume":"17","author":[{"given":"Livio","family":"Luongo","sequence":"first","affiliation":[{"name":"Section of Pharmacology \u201cL. Donatelli\u201d, Department of Experimental Medicine, Faculty of Medicine and Surgery, II University of Naples, via Costantinopoli 16, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4760-1204","authenticated-orcid":false,"given":"Riccardo","family":"Petrelli","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa","family":"Gatta","sequence":"additional","affiliation":[{"name":"Section of Pharmacology \u201cL. Donatelli\u201d, Department of Experimental Medicine, Faculty of Medicine and Surgery, II University of Naples, via Costantinopoli 16, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catia","family":"Giordano","sequence":"additional","affiliation":[{"name":"Section of Pharmacology \u201cL. Donatelli\u201d, Department of Experimental Medicine, Faculty of Medicine and Surgery, II University of Naples, via Costantinopoli 16, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Guida","sequence":"additional","affiliation":[{"name":"Section of Pharmacology \u201cL. Donatelli\u201d, Department of Experimental Medicine, Faculty of Medicine and Surgery, II University of Naples, via Costantinopoli 16, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrizia","family":"Vita","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Palmarisa","family":"Franchetti","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. 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Agostino 1, 62032 Camerino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabatino","family":"Maione","sequence":"additional","affiliation":[{"name":"Section of Pharmacology \u201cL. Donatelli\u201d, Department of Experimental Medicine, Faculty of Medicine and Surgery, II University of Naples, via Costantinopoli 16, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2012,11,22]]},"reference":[{"key":"ref_1","first-page":"567","article-title":"Pain-basic principles of management","volume":"69","author":"Bonica","year":"1970","journal-title":"Northwest Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0301-0082(98)00048-3","article-title":"The induction of pain: An integrative review","volume":"57","author":"Millan","year":"1999","journal-title":"Prog. Neurobiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1710","DOI":"10.1002\/glia.21042","article-title":"Cathepsin S release from primary cultured microglia is regulated by the P2X7 receptor","volume":"58","author":"Clark","year":"2010","journal-title":"Glia"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"10655","DOI":"10.1073\/pnas.0610811104","article-title":"Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain","volume":"104","author":"Clark","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"6945","DOI":"10.1523\/JNEUROSCI.0828-09.2009","article-title":"The liberation of fractalkine in the dorsal horn requires microglial cathepsin S","volume":"29","author":"Clark","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.nbd.2009.09.021","article-title":"1-(2',4'-dichlorophenyl)-6-methyl-N-cyclohexylamine-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamide, a novel CB2 agonist, alleviates neuropathic pain through functional microglial changes in mice","volume":"37","author":"Luongo","year":"2010","journal-title":"Neurobiol. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/S0031-6997(24)01511-4","article-title":"International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors","volume":"53","author":"Fredholm","year":"2001","journal-title":"Pharmacol. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4634","DOI":"10.4049\/jimmunol.157.10.4634","article-title":"Adenosine receptor agonists differentially regulate IL-10, TNF-alpha, and nitric oxide production in RAW 264.7 macrophages and in endotoxemic mice","volume":"157","author":"Kvetan","year":"1996","journal-title":"J. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.pain.2008.07.012","article-title":"A2A adenosine receptor regulates glia proliferation and pain after peripheral nerve injury","volume":"140","author":"Bura","year":"2008","journal-title":"Pain"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1124\/jpet.103.056036","article-title":"Antinociceptive effects of novel A2B adenosine receptor antagonists","volume":"308","author":"Hayallah","year":"2004","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"878","DOI":"10.2174\/156802610791268729","article-title":"A1 receptors ligands: Past, present and future trends","volume":"10","author":"Schenone","year":"2010","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1708","DOI":"10.1021\/jm9707737","article-title":"2'-C-Methyl analogues of selective adenosine receptor agonists: Synthesis and binding studies","volume":"41","author":"Franchetti","year":"1998","journal-title":"J. Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1021\/jm049408n","article-title":"Synthesis, biological evaluation and molecular modeling of ribose-modified adenosine analogues as adenosine receptors agonists","volume":"48","author":"Cappellacci","year":"2005","journal-title":"J. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1016\/j.bmc.2007.09.035","article-title":"5'-Carbamoyl derivatives of 2'-C-methyl-purine nucleosides as selective A1 adenosine receptor agonists: Affinity, efficacy, and selectivity for A1 receptor from different species","volume":"16","author":"Cappellacci","year":"2008","journal-title":"Bioorg. Med. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2393","DOI":"10.1021\/jm801456g","article-title":"N6-Cycloalkyl- and N6-bicycloalkyl-C5'(C2')-modified adenosine derivatives as high-affinity and selective agonists at the human A1 adenosine receptor with antinociceptive effects in mice","volume":"52","author":"Franchetti","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2235","DOI":"10.1523\/JNEUROSCI.5324-09.2010","article-title":"Ecto-5'-nucleotidase (CD73) inhibits nociception by hydrolyzing AMP to adenosine in nociceptive circuits","volume":"30","author":"Sowa","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/1744-8069-6-20","article-title":"Recombinant ecto-5'-nucleotidase (CD73) has long lasting antinociceptive effects that are dependent on adenosine A1 receptor activation","volume":"6","author":"Sowa","year":"2010","journal-title":"Mol. Pain"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.pain.2007.01.013","article-title":"The antinociceptive effect of 2-chloro-2'-C-methyl-N6-cyclopentyladenosine (2'-Me-CCPA), a highly selective adenosine A1 receptor agonist, in the rat","volume":"131","author":"Maione","year":"2007","journal-title":"Pain"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/j.pain.2004.11.020","article-title":"Increased nociceptive response in mice lacking the adenosine A1 receptor","volume":"113","author":"Wu","year":"2005","journal-title":"Pain"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1016\/j.pbb.2005.11.014","article-title":"The antinociceptive effects of the systemic adenosine A1 receptor agonist CPA in the absence and in the presence of spinal cord sensitization","volume":"82","author":"Herrero","year":"2005","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1016\/0024-3205(93)90497-Q","article-title":"Cardiovascular effects of adenosine and its analogs in anaesthetized rats","volume":"53","author":"Stella","year":"1993","journal-title":"Life Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1038\/sj.bjp.0706043","article-title":"Role of central and peripheral adenosine receptors in the cardiovascular responses to intraperitoneal injections of adenosine A1 and A2A subtype receptor agonists","volume":"144","author":"Schindler","year":"2005","journal-title":"Br. J. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1523\/JNEUROSCI.4271-03.2004","article-title":"A1 adenosine receptor upregulation and activation attenuates neuroinflammation and demyelination in a model of multiple sclerosis","volume":"24","author":"Tsutsui","year":"2004","journal-title":"J. Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"8550","DOI":"10.1158\/0008-5472.CAN-06-0365","article-title":"A1 adenosine receptors in microglia control glioblastoma-host interaction","volume":"66","author":"Synowitz","year":"2006","journal-title":"Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1002\/ana.1007","article-title":"Diminished adenosine A1 receptor expression on macrophages in brain and blood of patients with multiple sclerosis","volume":"49","author":"Johnston","year":"2001","journal-title":"Ann. Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4857","DOI":"10.1073\/pnas.82.14.4857","article-title":"Adenosine-activated potassium conductance in cultured striatal neurons","volume":"82","author":"Trussell","year":"1985","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1113\/jphysiol.1986.sp015923","article-title":"Adenosine agonists reduce voltage-dependent calcium conductance of mouse sensory neurones in cell culture","volume":"370","author":"MacDonald","year":"1986","journal-title":"J. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.molmed.2010.12.006","article-title":"Pain-relieving prospects for adenosine receptors and ectonucleotidases","volume":"17","author":"Zylka","year":"2011","journal-title":"Trends Mol. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"6467","DOI":"10.1021\/jm3004834","article-title":"Orally active adenosine A1 receptor agonists with antinociceptive effects in mice","volume":"14","author":"Korboukh","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1067\/S1526-5900(03)00781-8","article-title":"Spared nerve injury model of neuropathic pain in the mouse: a behavioral and anatomic analysis","volume":"4","author":"Shields","year":"2003","journal-title":"J. Pain"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4308","DOI":"10.1523\/JNEUROSCI.0003-06.2006","article-title":"Activated microglia contribute to the maintenance of chronic pain after spinal cord injury","volume":"26","author":"Hains","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1189\/jlb.0505249","article-title":"Differential expression of adenosine receptors in human neutrophils: Up-regulation by specific Th1 cytokines and lipopolysaccharide","volume":"79","author":"Fortin","year":"2006","journal-title":"J. Leuk. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1007\/978-1-4615-2584-4_89","article-title":"The antiinflammatory effects of methotrexate are mediated by adenosine","volume":"370","author":"Cronstein","year":"1994","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"14415","DOI":"10.1523\/JNEUROSCI.4569-09.2009","article-title":"T-cell infiltration and signaling in the adult dorsal spinal cord is a major contributor to neuropathic pain-like hypersensitivity","volume":"29","author":"Costigan","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"15558","DOI":"10.1073\/pnas.0807419105","article-title":"CD4+ T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS","volume":"105","author":"Beers","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.pain.2006.09.018","article-title":"Spinal microglia and neuropathic pain in young rats","volume":"128","author":"Moss","year":"2007","journal-title":"Pain"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1111\/j.1600-065X.2009.00791.x","article-title":"Regulation of Notch signaling during T- and B-cell development by O-fucose glycans","volume":"230","author":"Stanley","year":"2009","journal-title":"Immunol. Rev."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/17\/12\/13712\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:53:46Z","timestamp":1760219626000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/17\/12\/13712"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,11,22]]},"references-count":37,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2012,12]]}},"alternative-id":["molecules171213712"],"URL":"https:\/\/doi.org\/10.3390\/molecules171213712","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,11,22]]}}}