title: Morphine-potentiated platelet aggregation in in vitro and platelet plug formation in in vivo experiments.
abstract: The detailed mechanisms underlying morphine-signaling pathways in platelets remain obscure. Therefore, we systematically examined the influence of morphine on washed human platelets. In this study, washed human platelet suspensions were used for in vitro studies. Furthermore, platelet thrombus formation induced by irradiation of mesenteric venules with filtered light in mice pretreated with fluorescein sodium was used for an in vivo thrombotic study. Morphine concentration dependently (0.6, 1, and 5 microM) potentiated platelet aggregation and the ATP release reaction stimulated by agonists (i.e., collagen and U46619) in washed human platelets. Yohimbine (0.1 microM), a specific alpha(2)-adrenoceptor antagonist, markedly abolished the potentiation of morphine in platelet aggregation stimulated by agonists. Morphine also potentiated phosphoinositide breakdown and intracellular Ca(2+) mobilization in human platelets stimulated by collagen (1 microg/ml). Moreover, morphine (0.6-5 microM) markedly inhibited prostaglandin E(1) (10 microM)-induced cyclic AMP formation in human platelets, while yohimbine (0.1 microM) significantly reversed the inhibition of cyclic AMP by morphine (0.6 and 1 microM) in this study. The thrombin-evoked increase in pH(i) was markedly potentiated in the presence of morphine (1 and 5 microM). Morphine (2 and 5 mg/g) significantly shortened the time require to induce platelet plug formation in mesenteric venules. We concluded that morphine may exert its potentiation in platelet aggregation by binding to alpha(2)-adrenoceptors in human platelets, with a resulting inhibition of adenylate cyclase, thereby reducing intracellular cyclic AMP formation followed by increased activation of phospholipase C and the Na(+)/H(+) exchanger. This leads to increased intracellular Ca(2+) mobilization, and finally potentiation of platelet aggregation and of the ATP release reaction.
authors.affiliation: Department of Pharmacology, Taipei Medical University, No. 250 Wu-Hsing Street, Taipei 110, Taiwan.
authors.forename: George
authors.initials: G
authors.lastname: Hsiao
authors.forename: Ming-Yi
authors.initials: MY
authors.lastname: Shen
authors.forename: Chiao-Ling
authors.initials: CL
authors.lastname: Fang
authors.forename: Duen-Suey
authors.initials: DS
authors.lastname: Chou
authors.forename: Chien-Huang
authors.initials: CH
authors.lastname: Lin
authors.forename: Tzeng-Fu
authors.initials: TF
authors.lastname: Chen
authors.forename: Joen-Rong
authors.initials: JR
authors.lastname: Sheu
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists; D000704:Analysis of Variance; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D002118:Calcium / Q000097:blood; D000242:Cyclic AMP / Q000097:blood; D004357:Drug Synergism; D019793:Fluorescein / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D009020:Morphine / Q000819:agonists / Q000494:pharmacology*; D009391:Nephelometry and Turbidimetry; D010716:Phosphatidylinositols / Q000097:blood; D010974:Platelet Aggregation / Q000187:drug effects*; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013050:Spectrometry, Fluorescence; D015016:Yohimbine / Q000494:pharmacology
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D010716:Phosphatidylinositols; D018341:Receptors, Adrenergic, alpha-2; D015016:Yohimbine; D009020:Morphine; D000242:Cyclic AMP; D002118:Calcium; D019793:Fluorescein