{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T20:30:55Z","timestamp":1791664255375,"version":"4.3.4"},"reference-count":92,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T00:00:00Z","timestamp":1755129600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Instituto de Ciencia, Tecnolog\u00eda e Innovaci\u00f3n de Michoac\u00e1n","award":["ICTI-PICIR23-058"],"award-info":[{"award-number":["ICTI-PICIR23-058"]}]},{"name":"Instituto de Ciencia, Tecnolog\u00eda e Innovaci\u00f3n de Michoac\u00e1n","award":["ICTI-PICIR22-075-C"],"award-info":[{"award-number":["ICTI-PICIR22-075-C"]}]},{"name":"Instituto de Ciencia, Tecnolog\u00eda e Innovaci\u00f3n de Michoac\u00e1n","award":["CIC-UMSNH 18096"],"award-info":[{"award-number":["CIC-UMSNH 18096"]}]},{"name":"Instituto de Ciencia, Tecnolog\u00eda e Innovaci\u00f3n de Michoac\u00e1n","award":["CIC-UMSNH 18099"],"award-info":[{"award-number":["CIC-UMSNH 18099"]}]},{"name":"Universidad Michoacana de San Nicol\u00e1s de Hidalgo","award":["ICTI-PICIR23-058"],"award-info":[{"award-number":["ICTI-PICIR23-058"]}]},{"name":"Universidad Michoacana de San Nicol\u00e1s de Hidalgo","award":["ICTI-PICIR22-075-C"],"award-info":[{"award-number":["ICTI-PICIR22-075-C"]}]},{"name":"Universidad Michoacana de San Nicol\u00e1s de Hidalgo","award":["CIC-UMSNH 18096"],"award-info":[{"award-number":["CIC-UMSNH 18096"]}]},{"name":"Universidad Michoacana de San Nicol\u00e1s de Hidalgo","award":["CIC-UMSNH 18099"],"award-info":[{"award-number":["CIC-UMSNH 18099"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Pain is a growing public health concern worldwide, and the use of combinations of drugs can improve their analgesic effects while minimizing their adverse effects. Drugs such as metformin (antidiabetic) and melatonin (sleep regulator) have analgesic potential in combination. In this study, we evaluated the pharmacological interaction between metformin and melatonin when orally administered in a rat model, using the formalin test. Methods: Female Wistar rats (220\u2013350 g) were injected with 50 \u00b5L of 1% formalin in the dorsal surface of the right hind paw. Formalin produces pain-related flinching behavior, and antinociception was evaluated as the reduction in this response. The percentage of the antinociceptive effect was determined after the oral administration of metformin (30\u20131000 mg\/kg), melatonin (10\u2013150 mg\/kg), and their combination (MMC). To establish the nature of the interaction, isobolographic analysis was performed in a fixed-dose ratio (0.5:0.5), based on the effective dose 50 (ED50) values for each drug: metformin (947.46 \u00b1 242.60 mg\/kg) and melatonin (126.86 \u00b1 37.98 mg\/kg). To evaluate the mechanism of action, the receptor antagonist for metformin compound C (dorsomorphin) for AMPK inhibition, MT1 and MT2 melatonin receptor antagonists (4-P-PDOT, luzindole), and an opioid antagonist (naloxone) were employed. The rotarod test was used to evaluate the safety profile of the combination. Results: The metformin\u2013melatonin combination significantly reduced the number of flinches in the second phase of the formalin test. The theoretical ED50 for the combination (ED50 T) was 537.15 \u00b1 122.76 mg\/kg. Experimentally, the ED50 (ED50 E) was significantly lower (360.83 \u00b1 23.36 mg\/kg), indicating a synergistic interaction for the combination involving opioidergic pathways, MT2 receptors, and AMPK activation. Conclusions: Oral metformin\u2013melatonin coadministration could provide a therapeutic alternative for inflammatory pain.<\/jats:p>","DOI":"10.3390\/pharmaceutics17081057","type":"journal-article","created":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T14:51:46Z","timestamp":1755183106000},"page":"1057","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Preclinical Assessment of a Metformin\u2013Melatonin Combination: Antinociceptive Synergism"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2431-0471","authenticated-orcid":false,"given":"Marcia Yvette","family":"Gauthereau-Torres","sequence":"first","affiliation":[{"name":"Divisi\u00f3n de Estudios de Posgrado, Facultad de Ciencias M\u00e9dicas y Biol\u00f3gicas \u201cDr. Ignacio Ch\u00e1vez\u201d, Universidad Michoacana de San Nicol\u00e1s de Hidalgo, Morelia 58020, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny Selene","family":"Mart\u00ednez-Guillen","sequence":"additional","affiliation":[{"name":"Divisi\u00f3n de Estudios de Posgrado, Facultad de Ciencias M\u00e9dicas y Biol\u00f3gicas \u201cDr. Ignacio Ch\u00e1vez\u201d, Universidad Michoacana de San Nicol\u00e1s de Hidalgo, Morelia 58020, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Cervantes-Dur\u00e1n","sequence":"additional","affiliation":[{"name":"Escuela Nacional de Estudios Superiores, Unidad Morelia, Universidad Nacional Aut\u00f3noma de M\u00e9xico (UNAM), Morelia 58000, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4910-2676","authenticated-orcid":false,"given":"Carmen Judith","family":"Guti\u00e9rrez-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Departamento de Estudios de Posgrado e Investigaci\u00f3n, Tecnol\u00f3gico Nacional de M\u00e9xico\/Instituto Tecnol\u00f3gico de Morelia, Morelia 58190, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8789-8789","authenticated-orcid":false,"given":"Daniel","family":"God\u00ednez-Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones Qu\u00edmico-Biol\u00f3gicas, Universidad Michoacana de San Nicol\u00e1s de Hidalgo, Morelia 58030, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0326-2068","authenticated-orcid":false,"given":"Asdr\u00fabal","family":"Aguilera M\u00e9ndez","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones Qu\u00edmico-Biol\u00f3gicas, Universidad Michoacana de San Nicol\u00e1s de Hidalgo, Morelia 58030, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1830-7468","authenticated-orcid":false,"given":"Luis Fernando","family":"Ortega-Varela","sequence":"additional","affiliation":[{"name":"Divisi\u00f3n de Estudios de Posgrado, Facultad de Ciencias M\u00e9dicas y Biol\u00f3gicas \u201cDr. Ignacio Ch\u00e1vez\u201d, Universidad Michoacana de San Nicol\u00e1s de Hidalgo, Morelia 58020, Mexico"},{"name":"Facultad de Salud P\u00fablica y Enfermer\u00eda, Universidad Michoacana de San Nicol\u00e1s de Hidalgo, Morelia 58020, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Goldberg, D.S., and McGee, S.J. 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