{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T20:19:18Z","timestamp":1771013958831,"version":"3.50.1"},"reference-count":41,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2023,1,13]],"date-time":"2023-01-13T00:00:00Z","timestamp":1673568000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Science, Sports and Culture of Japan","doi-asserted-by":"crossref","award":["26462335"],"award-info":[{"award-number":["26462335"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100007312","name":"National Center for Geriatrics and Gerontology","doi-asserted-by":"publisher","award":["19-21"],"award-info":[{"award-number":["19-21"]}],"id":[{"id":"10.13039\/501100007312","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Tramadol is a useful analgesic which acts as a serotonin and noradrenaline reuptake inhibitor in addition to \u03bc-opioid receptor agonist. Cytoplasmic serotonin modulates the small GTPase activity through serotonylation, which is closely related to the human platelet activation. We recently reported that the combination of subthreshold collagen and CXCL12 synergistically activates human platelets. We herein investigated the effect and the mechanism of tramadol on the synergistic effect. Tramadol attenuated the synergistically stimulated platelet aggregation (300 \u03bcM of tramadol, 64.3% decrease, p&lt;0.05). Not morphine or reboxetine, but duloxetine, fluvoxamine and sertraline attenuated the synergistic effect of the combination on the platelet aggregation (30 \u03bcM of fluvoxamine, 67.3% decrease, p&lt;0.05; 30 \u03bcM of sertraline, 67.8% decrease, p&lt;0.05). The geranylgeranyltransferase inhibitor GGTI-286 attenuated the aggregation of synergistically stimulated platelet (50 \u03bcM of GGTI-286, 80.8% decrease, p&lt;0.05), in which GTP-binding Rac was increased. The Rac1-GEF interaction inhibitor NSC23766 suppressed the platelet activation and the phosphorylation of p38 MAPK and HSP27 induced by the combination of collagen and CXCL12. Tramadol and fluvoxamine almost completely attenuated the levels of GTP-binding Rac and the phosphorylation of both p38 MAPK and HSP27 stimulated by the combination. Suppression of the platelet aggregation after the duloxetine administration was observed in 2 of 5 patients in pain clinic. These results suggest that tramadol negatively regulates the combination of subthreshold collagen and CXCL12-induced platelet activation via Rac upstream of p38 MAPK.<\/jats:p>","DOI":"10.1371\/journal.pone.0279011","type":"journal-article","created":{"date-parts":[[2023,1,13]],"date-time":"2023-01-13T18:38:52Z","timestamp":1673635132000},"page":"e0279011","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["Tramadol regulates the activation of human platelets via Rac but not Rho\/Rho-kinase"],"prefix":"10.1371","volume":"18","author":[{"given":"Hiroki","family":"Iida","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takashi","family":"Onuma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daiki","family":"Nakashima","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daisuke","family":"Mizutani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8673-7868","authenticated-orcid":true,"given":"Takamitsu","family":"Hori","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyohei","family":"Ueda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoyuki","family":"Hioki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Woo","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yukiko","family":"Enomoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoaki","family":"Doi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rie","family":"Matsushima-Nishiwaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinobu","family":"Yamaguchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junko","family":"Tachi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kumiko","family":"Tanabe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinji","family":"Ogura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toru","family":"Iwama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4834-6073","authenticated-orcid":true,"given":"Osamu","family":"Kozawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haruhiko","family":"Tokuda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2023,1,13]]},"reference":[{"key":"pone.0279011.ref001","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1002\/ejp.1196","article-title":"Comparative pharmacology and toxicology of tramadol and tapentadol","volume":"22","author":"J. 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