{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T22:53:29Z","timestamp":1791240809007,"version":"4.1.0"},"reference-count":57,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,3,19]],"date-time":"2025-03-19T00:00:00Z","timestamp":1742342400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Council for Scientific and Technological Development (CNPQ)","award":["28\/2018"],"award-info":[{"award-number":["28\/2018"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Chronic pain significantly impacts quality of life and is often accompanied by inflammation, a natural bodily response that can become harmful when excessive. The orofacial region is commonly affected, making effective treatment crucial. However, current drugs often cause undesirable side effects, highlighting the need for new pharmacological alternatives. 4-hydroxycoumarin (4-HC), a natural compound, has shown promising antinociceptive and anti-inflammatory effects, but studies confirming its specific properties are limited. In silico analyses suggest that 4-HC exhibits favorable pharmacokinetic characteristics, not interacting with P-glycoprotein and successfully crossing the blood\u2013brain barrier. Molecular docking studies indicate that its effects may be mediated through NMDAR or by inhibiting iNOS. Our study assessed the antinociceptive and anti-inflammatory effects of 4-HC in animal models at doses of 25, 50, and 75 mg\/kg. 4-HC significantly reduced abdominal contortions induced by acetic acid and decreased nociceptive rubbing in orofacial pain models induced by formalin, glutamate, and capsaicin. Interactions with opioid receptors were not observed, suggesting that 4-HC\u2019s antinociceptive effect does not involve this pathway. Additionally, 4-HC reduced paw edema induced by carrageenan and significantly decreased leukocyte migration and TNF-\u03b1 levels. These findings highlight the therapeutic potential of 4-HC and warrant further investigation into its mechanisms.<\/jats:p>","DOI":"10.3390\/ijms26062788","type":"journal-article","created":{"date-parts":[[2025,3,20]],"date-time":"2025-03-20T05:03:59Z","timestamp":1742447039000},"page":"2788","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["4-Hydroxycoumarin Exhibits Antinociceptive and Anti-Inflammatory Effects Through Cytokine Modulation: An Integrated In Silico and In Vivo Study"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7869-7061","authenticated-orcid":false,"given":"Diogo Vilar","family":"da Fons\u00eaca","sequence":"first","affiliation":[{"name":"Postgraduate Program in Biosciences, Federal University of the S\u00e3o Francisco Valley (UNIVASF), Pernambuco 56304-917, PE, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliana Sousa","family":"Rocha","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Biosciences, Federal University of the S\u00e3o Francisco Valley (UNIVASF), Pernambuco 56304-917, PE, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8354-3198","authenticated-orcid":false,"given":"Pablo R.","family":"da Silva","sequence":"additional","affiliation":[{"name":"Postgraduate Program of Dentistry (PPGO), Health Sciences Center, Federal University of Para\u00edba, Jo\u00e3o Pessoa 58051-900, PB, Brazil"},{"name":"Psychopharmacology Laboratory, Institute of Drugs and Medicines Research, Federal University of Para\u00edba, Jo\u00e3o Pessoa 58051-900, PB, Brazil"},{"name":"Postgraduate Program in Natural Synthetic and Bioactive Products, Health Sciences Center, Federal University of Para\u00edba, Jo\u00e3o Pessoa 58051-900, PB, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugo Natan","family":"de S\u00e1 Novaes Pereira","sequence":"additional","affiliation":[{"name":"Department of Medicine, Federal University of the S\u00e3o Francisco Valley (UNIVASF), Paulo Afonso 48605-560, BA, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas Vinicius Novaes","family":"dos Santos","sequence":"additional","affiliation":[{"name":"Department of Medicine, Faculdade Est\u00e1cio IDOMED, Juazeiro 48924-999, BA, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9110-6294","authenticated-orcid":false,"given":"Melquisedec Abiar\u00e9 Dantas","family":"de Santana","sequence":"additional","affiliation":[{"name":"Departament of Morphology, Biosciences Center, Federal University of Rio Grande do Norte, Natal 59078-970, RN, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6042-1075","authenticated-orcid":false,"given":"Alan F.","family":"Alves","sequence":"additional","affiliation":[{"name":"Cheminformatics Laboratory, Institute of Drugs and Medicines Research, Federal University of Para\u00edba, Jo\u00e3o Pessoa 58051-900, PB, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adiel H. O.","family":"Pontes","sequence":"additional","affiliation":[{"name":"Cheminformatics Laboratory, Institute of Drugs and Medicines Research, Federal University of Para\u00edba, Jo\u00e3o Pessoa 58051-900, PB, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo\u00e1s","family":"de Souza Gomes","sequence":"additional","affiliation":[{"name":"Cheminformatics Laboratory, Institute of Drugs and Medicines Research, Federal University of Para\u00edba, Jo\u00e3o Pessoa 58051-900, PB, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00edcero F. 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