{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T10:08:02Z","timestamp":1784801282840,"version":"3.55.0"},"reference-count":27,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and Objectives: Neuropathic pain presents a significant therapeutic challenge, often due to resistance to opioids. This study examined how selective adenosine receptor agonists and allopurinol modulate spinal mu-opioid receptor (MOR) mRNA expression in a rat model of neuropathic pain, aiming to develop a novel strategy for restoring opioid homeostasis. Materials and Methods: Male Sprague-Dawley rats were subjected to L5 spinal nerve ligation (SNL). The animals received treatment with selective A1AR (CCPA, 1 mg\/kg) or A3AR (IB-MECA, 1 mg\/kg) agonists, or allopurinol (10 or 50 mg\/kg) for three days. Spinal MOR mRNA expression was measured on day 7 post-SNL using qRT-PCR. Results: SNL resulted in a non-significant upward trend in MOR transcription. Selective agonists (CCPA and IB-MECA) appeared to enhance or maintain MOR levels compared to the vehicle-treated group, but the most pronounced trend toward recovery of MOR mRNA expression was observed with high-dose allopurinol (50 mg\/kg). Effect size analysis revealed large Cohen\u2019s d values for high-dose allopurinol (d = 1.05) and CCPA (d = 0.90) versus sham, supporting the biological relevance of these preliminary trends. Conclusions: These preliminary findings suggest that augmenting endogenous adenosine bioavailability with allopurinol may be more effective than targeting individual receptor subtypes in modulating the spinal opioid system. As this is an exploratory pilot investigation, these results should be interpreted as hypothesis-generating rather than confirmatory. Since allopurinol is already a clinically established drug, these findings offer a mechanistic rationale warranting further investigation of its potential as an adjuvant for opioid resistance in chronic pain management.<\/jats:p>","DOI":"10.3390\/medicina62081429","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T09:11:26Z","timestamp":1784797886000},"page":"1429","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Modulation of Spinal Mu-Opioid Receptor Expression by Selective Adenosine A1 and A3 Receptor Agonists and Allopurinol in a Rat Model of Neuropathic Pain"],"prefix":"10.3390","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9255-6994","authenticated-orcid":false,"given":"Jaesuk","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine, St. Vincent\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul 16247, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4393-7951","authenticated-orcid":false,"given":"Noh Hyun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine, St. Vincent\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul 16247, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4365-7091","authenticated-orcid":false,"given":"Jin Deok","family":"Joo","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine, St. Vincent\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul 16247, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0249-4190","authenticated-orcid":false,"given":"So Young","family":"Kwon","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine, St. Vincent\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul 16247, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"277","DOI":"10.4097\/kjae.2009.57.3.277","article-title":"The use of intra-cellular signaling pathways in anesthesiology and pain medicine field","volume":"57","author":"Joo","year":"2009","journal-title":"Korean J. Anesthesiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1007\/s00415-017-8641-6","article-title":"Advances in understanding nociception and neuropathic pain","volume":"265","year":"2018","journal-title":"J. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1016\/j.pain.2013.11.013","article-title":"Neuropathic pain in the general population: A systematic review of epidemiological studies","volume":"155","author":"Austin","year":"2014","journal-title":"Pain"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neuroscience.2015.10.031","article-title":"Adenosine receptor targets for pain","volume":"338","author":"Sawynok","year":"2016","journal-title":"Neuroscience"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/S1474-4422(14)70251-0","article-title":"Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis","volume":"14","author":"Finnerup","year":"2015","journal-title":"Lancet Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/S1474-4422(25)00068-7","article-title":"Pharmacotherapy and non-invasive neuromodulation for neuropathic pain: A systematic review and meta-analysis","volume":"24","author":"Soliman","year":"2025","journal-title":"Lancet Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1212\/CON.0000000000000462","article-title":"Neuropathic pain","volume":"23","author":"Zilliox","year":"2017","journal-title":"Contin. Lifelong Learn. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Li, L., Chen, J., and Li, Y.-Q. (2023). The Downregulation of Opioid Receptors and Neuropathic Pain. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24065981"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1038\/nrn.2018.2","article-title":"Microglia in neuropathic pain: Cellular and molecular mechanisms and therapeutic potential","volume":"19","author":"Inoue","year":"2018","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/S0166-2236(00)01854-3","article-title":"Glial activation: A driving force for pathological pain","volume":"24","author":"Watkins","year":"2001","journal-title":"Trends Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1580","DOI":"10.1097\/j.pain.0000000000001246","article-title":"Downregulation of adenosine and adenosine A1 receptor contributes to neuropathic pain in resiniferatoxin neuropathy","volume":"159","author":"Kan","year":"2018","journal-title":"Pain"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Borea, P.A., Varani, K., Gessi, S., Merighi, S., and Vincenzi, F. (2018). The Adenosine Receptors, Springer.","DOI":"10.1007\/978-3-319-90808-3"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1124\/pr.110.003285","article-title":"International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and Classification of Adenosine Receptors\u2014An Update","volume":"63","author":"Fredholm","year":"2011","journal-title":"Pharmacol. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Haddad, M., Cherchi, F., Alsalem, M., Al-saraireh, Y.M., and Madae\u2019en, S. (2023). Adenosine Receptors as Potential Therapeutic Analgesic Targets. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241713160"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1038\/nrd1983","article-title":"Adenosine receptors as therapeutic targets","volume":"5","author":"Jacobson","year":"2006","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1093\/brain\/awu330","article-title":"Endogenous adenosine A3 receptor activation selectively alleviates persistent pain states","volume":"138","author":"Little","year":"2015","journal-title":"Brain"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Vincenzi, F., Pasquini, S., Contri, C., Cappello, M., Nigro, M., Travagli, A., Merighi, S., Gessi, S., Borea, P.A., and Varani, K. (2023). Pharmacology of adenosine receptors: Recent advancements. Biomolecules, 13.","DOI":"10.3389\/fphar.2022.1030895"},{"key":"ref_18","first-page":"1857","article-title":"Role of adenosine receptors in the anti-nociceptive effects of allopurinol in mice","volume":"17","author":"Essawy","year":"2013","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1111\/j.1476-5381.2008.00025.x","article-title":"Anti-nociceptive properties of the xanthine oxidase inhibitor allopurinol in mice: Role of A1 adenosine receptors","volume":"156","author":"Schmidt","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1124\/pr.58.1.6","article-title":"Therapeutic effects of xanthine oxidase inhibitors: Renaissance half a century after the discovery of allopurinol","volume":"58","author":"Pacher","year":"2006","journal-title":"Pharmacol. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"60","DOI":"10.4097\/kja.d.18.00022","article-title":"Amitriptyline inhibits the MAPK\/ERK and CREB pathways and proinflammatory cytokines through A3AR activation in rat neuropathic pain models","volume":"72","author":"Kim","year":"2019","journal-title":"Korean J. Anesthesiol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Percie du Sert, N., Hurst, V., Ahluwalia, A., Alam, S., Avey, M.T., Baker, M., Browne, W.J., Clark, A., Cuthill, I.C., and Dirnagl, U. (2020). The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research. PLoS Biol., 18.","DOI":"10.1371\/journal.pbio.3000410"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/0304-3959(92)90041-9","article-title":"An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat","volume":"50","author":"Kim","year":"1992","journal-title":"Pain"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/j.neuroscience.2004.06.086","article-title":"Rapid upregulation of \u03bc opioid receptor mRNA in dorsal root ganglia in response to peripheral inflammation depends on neuronal conduction","volume":"129","author":"Puehler","year":"2004","journal-title":"Neuroscience"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2\u2212\u0394\u0394CT method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_26","unstructured":"Cohen, J. (1988). Statistical Power Analysis for the Behavioral Sciences, Lawrence Erlbaum Associates. [2nd ed.]."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1678","DOI":"10.1007\/s43440-025-00779-6","article-title":"The xanthine oxidase inhibitor allopurinol prevents thermal and mechanical hyperalgesia in a mouse model of peripheral mononeuropathy","volume":"77","author":"Fagundes","year":"2025","journal-title":"Pharmacol. Rep."}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/62\/8\/1429\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T09:58:29Z","timestamp":1784800709000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/62\/8\/1429"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,23]]},"references-count":27,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["medicina62081429"],"URL":"https:\/\/doi.org\/10.3390\/medicina62081429","relation":{},"ISSN":["1648-9144"],"issn-type":[{"value":"1648-9144","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,23]]}}}