{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T02:49:57Z","timestamp":1788922197805,"version":"build-2803163510"},"reference-count":47,"publisher":"Maad Rayan Publishing Company","content-domain":{"domain":["ahj.kmu.ac.ir"],"crossmark-restriction":false},"short-container-title":["Addict Health"],"published-print":{"date-parts":[[2025,12,29]]},"abstract":"<jats:p>Background: Combination analgesic therapy is a widely employed strategy for pain management worldwide. This study investigated the potential synergistic interaction between caffeine and morphine using the hot-plate test and isobolographic analysis in male NMRI mice. The interaction between caffeine and morphine in pain modulation was evaluated, and it was determined whether the combination produces a synergistic effect. Methods: Mice were treated with morphine (0.135, 1.25, 5, and 20 mg\/Kg, s.c.) or caffeine (20, 40, 80, and 160 mg\/Kg, i.p.) to obtain the ED50 values of each agent in the hot-plate test, then, an isobolographic analysis was used to evaluate the nature of interaction between the two drugs in mice. Findings: Morphine significantly increased pain thresholds in a dose-dependent manner (ED\u2085\u2080=2.49 mg\/kg; P&lt;0.001). Caffeine at a lower dose (46.13 mg\/kg) potentiated morphine\u2019s analgesic effect, indicating a synergistic interaction (P&lt;0.001). In contrast, a higher caffeine dose (138.3 mg\/kg) reversed this effect, demonstrating an antagonistic interaction (P&lt;0.001) in the mouse hot-plate test. Conclusion: A low dose of caffeine synergistically enhanced morphine-induced analgesia in the mouse hot-plate test; this effect was absent at a higher dose. Consequently, only low-dose caffeine administration effectively reduced the required dosage of morphine for acute pain management in the mouse hot-plate test.<\/jats:p>","DOI":"10.34172\/ahj.1717","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T07:55:12Z","timestamp":1786002912000},"page":"1717","update-policy":"https:\/\/doi.org\/10.34172\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Dose-Dependent Interaction Between Caffeine and Morphine in Analgesia in the Hot-Plate in Mice"],"prefix":"10.34172","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5147-9208","authenticated-orcid":true,"given":"Mohaddeseh","family":"Ebrahimi-Ghiri","sequence":"first","affiliation":[{"name":"Department of Biology, Faculty of Sciences, University of Zanjan, Zanjan, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9064-2458","authenticated-orcid":true,"given":"Marjan","family":"Aminian","sequence":"additional","affiliation":[{"name":"Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0688-5378","authenticated-orcid":true,"given":"Mohammad Reza","family":"Zarrindast","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7558-0351","authenticated-orcid":true,"given":"Mohammad Reza","family":"Jafari","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"20123","published-online":{"date-parts":[[2025,12,29]]},"reference":[{"key":"R1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-024-01845-w"},{"key":"R2","doi-asserted-by":"publisher","DOI":"10.1007\/s11010-023-04810-3"},{"key":"R3","doi-asserted-by":"publisher","DOI":"10.1038\/bjp.2008.175"},{"key":"R4","doi-asserted-by":"publisher","DOI":"10.2741\/3596"},{"key":"R5","doi-asserted-by":"publisher","DOI":"10.3390\/ph16050730"},{"key":"R6","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2019.00607"},{"key":"R7","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpain.2013.06.003"},{"key":"R8","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.25603"},{"key":"R9","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1213\/00000539-198509000-00002","article-title":"Morphine--caffeine analgesic interaction in rats","volume":"64","author":"Person DL","year":"1985","journal-title":"Anesth Analg"},{"key":"R10","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1985.tb17372.x"},{"key":"R11","doi-asserted-by":"publisher","DOI":"10.5812\/aapm.33193"},{"key":"R12","doi-asserted-by":"publisher","DOI":"10.1016\/s0014-2999(01)00718-x"},{"key":"R13","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.103.056036"},{"key":"R14","doi-asserted-by":"publisher","DOI":"10.1111\/j.2042-7158.1994.tb03758.x"},{"key":"R15","doi-asserted-by":"publisher","DOI":"10.22037\/ijps.v7.41345"},{"key":"R16","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(86)90635-7"},{"key":"R17","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/S0022-3565(25)05180-8","article-title":"Synthetic analgesics II Dithienylbutenyl- and dithienylbutylamines","volume":"107","author":"Eddy NB","year":"1953","journal-title":"J Pharmacol Exp Ther"},{"key":"R18","doi-asserted-by":"publisher","DOI":"10.1016\/s0022-3565(25)21463-x"},{"key":"R19","doi-asserted-by":"publisher","DOI":"10.30466\/vrf.2010.33108"},{"key":"R20","doi-asserted-by":"crossref","first-page":"350","DOI":"10.55782\/ane-2021-034","article-title":"Synergistic analgesic effect of morphine and tramadol in non-sensitized and morphine-sensitized mice: an isobolographic study","volume":"81","author":"Khakpai F","year":"2021","journal-title":"Acta Neurobiol Exp (Wars)"},{"key":"R21","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2023.176173"},{"key":"R22","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbb.2010.09.005"},{"key":"R23","doi-asserted-by":"publisher","DOI":"10.1139\/y04-027"},{"key":"R24","first-page":"223","article-title":"The effect of methylxanthines on morphine analgesia in mice and rats","volume":"40","author":"Malec D","year":"1988","journal-title":"Pol J Pharmacol Pharm"},{"key":"R25","doi-asserted-by":"publisher","DOI":"10.1007\/pl00005094"},{"key":"R26","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2006.03.065"},{"key":"R27","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3959(94)00169-f"},{"key":"R28","first-page":"33","article-title":"Analgesic effect of caffeine and clomipramine: a possible interaction between adenosine and serotonin systems","volume":"53","author":"Bach-Rojecky L","year":"2003","journal-title":"Acta Pharm"},{"key":"R29","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/976764"},{"key":"R30","first-page":"303","article-title":"Time dependent antinociceptive effects of morphine and tramadol in the hot plate test: using different methods of drug administration in female rats","volume":"14","author":"Gholami M","year":"2015","journal-title":"Iran J Pharm Res"},{"key":"R31","doi-asserted-by":"publisher","DOI":"10.1186\/s12929-019-0513-1"},{"key":"R32","doi-asserted-by":"publisher","DOI":"10.25083\/rbl\/27.2\/3429.3433"},{"key":"R33","doi-asserted-by":"publisher","DOI":"10.1016\/s1043-6618(02)00126-3"},{"key":"R34","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/88.2.199"},{"key":"R35","doi-asserted-by":"publisher","DOI":"10.1089\/jcr.2013.0014"},{"key":"R36","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbb.2010.09.004"},{"key":"R37","doi-asserted-by":"publisher","DOI":"10.30539\/8qhqgn78"},{"key":"R38","first-page":"245","article-title":"Comparison of the analgesic effects of ketorolac, morphine and aspirin in the rat","volume":"36","author":"Granados-Soto V","year":"1993","journal-title":"Proc West Pharmacol Soc"},{"key":"R39","doi-asserted-by":"publisher","DOI":"10.1111\/j.2042-7158.1993.tb05666.x"},{"key":"R40","first-page":"241","article-title":"[Synergism of caffeine on antinociceptive effects of metamizole]","volume":"76","author":"D\u00edaz-Reval MI","year":"2008","journal-title":"Cir Cir"},{"key":"R41","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/S0031-6997(25)00450-8","article-title":"Caffeine as an analgesic adjuvant: a review of pharmacology and mechanisms of action","volume":"45","author":"Sawynok J","year":"1993","journal-title":"Pharmacol Rev"},{"key":"R42","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2011.10.036"},{"key":"R43","doi-asserted-by":"publisher","DOI":"10.1038\/nrd1983"},{"key":"R44","doi-asserted-by":"publisher","DOI":"10.1124\/pr.113.008540"},{"key":"R45","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2015.10.031"},{"key":"R46","doi-asserted-by":"publisher","DOI":"10.1007\/s11302-023-09964-9"},{"key":"R47","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2020.113862"}],"container-title":["Addiction and Health"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ahj.kmu.ac.ir\/article_93032_395260b90910c384c058c05891d62235.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ahj.kmu.ac.ir\/article_93032_395260b90910c384c058c05891d62235.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T07:55:15Z","timestamp":1786002915000},"score":1,"resource":{"primary":{"URL":"https:\/\/ahj.kmu.ac.ir\/article_93032.html"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,29]]},"references-count":47,"URL":"https:\/\/doi.org\/10.34172\/ahj.1717","relation":{},"ISSN":["2008-4633","2008-8469"],"issn-type":[{"value":"2008-4633","type":"print"},{"value":"2008-8469","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,29]]},"assertion":[{"value":"Kerman University of Medical Sciences","name":"journal_owner","label":"Journal Owner"},{"value":"Kerman University of Medical Sciences","name":"journal_publisher","label":"Journal Publisher"},{"value":"2025-07-02","order":1,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-12","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-29","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}