Tramadol regulates the activation of human platelets via Rac but not Rho/Rho-kinase.
Humans
Tramadol
/ pharmacology
HSP27 Heat-Shock Proteins
/ metabolism
rho-Associated Kinases
Duloxetine Hydrochloride
/ pharmacology
Fluvoxamine
Serotonin
/ pharmacology
Sertraline
/ pharmacology
Blood Platelets
/ metabolism
Platelet Aggregation
Collagen
/ metabolism
p38 Mitogen-Activated Protein Kinases
/ metabolism
Guanosine Triphosphate
Phosphorylation
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2023
2023
Historique:
received:
11
01
2022
accepted:
29
11
2022
entrez:
13
1
2023
pubmed:
14
1
2023
medline:
18
1
2023
Statut:
epublish
Résumé
Tramadol is a useful analgesic which acts as a serotonin and noradrenaline reuptake inhibitor in addition to μ-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 μM of tramadol, 64.3% decrease, p<0.05). Not morphine or reboxetine, but duloxetine, fluvoxamine and sertraline attenuated the synergistic effect of the combination on the platelet aggregation (30 μM of fluvoxamine, 67.3% decrease, p<0.05; 30 μM of sertraline, 67.8% decrease, p<0.05). The geranylgeranyltransferase inhibitor GGTI-286 attenuated the aggregation of synergistically stimulated platelet (50 μM of GGTI-286, 80.8% decrease, p<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.
Identifiants
pubmed: 36638092
doi: 10.1371/journal.pone.0279011
pii: PONE-D-22-00906
pmc: PMC9838859
doi:
Substances chimiques
Tramadol
39J1LGJ30J
HSP27 Heat-Shock Proteins
0
rho-Associated Kinases
EC 2.7.11.1
Duloxetine Hydrochloride
9044SC542W
Fluvoxamine
O4L1XPO44W
Serotonin
333DO1RDJY
Sertraline
QUC7NX6WMB
Collagen
9007-34-5
p38 Mitogen-Activated Protein Kinases
EC 2.7.11.24
Guanosine Triphosphate
86-01-1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0279011Informations de copyright
Copyright: © 2023 Iida et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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