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The antinociceptive effect of tramadol in the formalin test is mediated by the serotonergic component

The antinociceptive effect of tramadol in the formalin test is mediated by the serotonergic component. Oliva, Patrizia; Aurilio, Caterina; Massimo, Francesco; Grella, Antonio; Maione, Sabatino; Grella, Elisa; Scafuro, Mariantonietta; Rossi, Francesco; Berrino, Liberato (Section of Pharmacology "L.In this study， 148229-78-1 and 27203-92-5 are also used. Donatelli", Department of Experimental Medicine, Second University of Naples, Naples 80138, Italy). European Journal of Pharmacology, 445(3), 179-185 (English) 2002 Elsevier Science B.V. CODEN: EJPHAZ. ISSN: 0014-2999. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) The aim of this study was to investigate the neurotransmissions involved in the antinociceptive effect of tramadol in the formalin test, which is an animal model of acute and tonic pain. A s.c. injection of formalin produces a biphasic nociceptive response: phase 1 (0-10 min-acute pain) and phase 2 (21-60 min-tonic pain). Nociceptive activity is reduced greatly during the 10 min between these two phases. We measured in mice the effects of (±)-tramadol, and of (+)- and (-)-tramadol administered before the induction of pain by formalin, in the presence and absence of drugs that act on the opioidergic, serotonergic and noradrenergic systems (naloxone, ketanserin, fluoxetine, maprotiline). With respect to animals treated with formalin alone, (±)-tramadol and its enantiomers significantly reduced the duration of nociceptive behaviors (lifting, licking, favoring, shaking, and flinching of the formalin-treated paw) during phase 2. This effect was prevented by the 5-HT2 receptor antagonist ketanserin, but not by naloxone which, on the contrary, was able to prevent the antinociceptive effect of morphine. Naloxone and ketanserin did not affect the duration of nociceptive behavior in animals not treated with tramadol. Fluoxetine (a selective 5-hydroxytryptamine (5-HT) reuptake inhibitor), but not maprotiline (a selective norepinephrine reuptake inhibitor), potentiated the antinociceptive effect of (±)-tramadol. In conclusion, we demonstrate that the serotonergic pathway is responsible for the antinociceptive effect of tramadol in phase 2 of the formalin test, and that this effect is mediated by 5-HT2 receptors. .

Enantioselective pharmacokinetics of tramadol in CYP2D6 extensive and poor metabolizers

All Rights Reserved. Enantioselective pharmacokinetics of tramadol in CYP2D6 extensive and poor metabolizers. Pedersen, Rasmus Steen; Damkier, Per; Brosen, Kim (Institute of Public Health, Clinical Pharmacology, University of Southern Denmark, Odense C 5000, Den.). European Journal of Clinical Pharmacology, 62(7), 513-521 (English) 2006 Springer. CODEN: EJCPAS. ISSN: 0031-6970. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) Section cross-reference(s): 63 Objective: To describe in detail the i.v., single oral and multiple oral dose enantioselective pharmacokinetics of tramadol in CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs). Methods: Eight EMs and eight PMs conducted three phases as an open-label cross-over trial with different formulations; 150 mg single oral tramadol hydrochloride, 50 mg single oral tramadol hydrochloride every 8 h for 48 h (steady state), 100 mg i.v. tramadol hydrochloride. Urine and plasma concns. of (+/-)-tramadol and (+/-)-M1 were detd. for 48 h after administration. Results: In all three phases, there were significant differences between EMs and PMs in AUC and t1/2 of (+)-tramadol (P￡0.0015), (-)-tramadol (P￡0.0062), (+)-M1 (P￡0.0198) and (-)-M1 (P￡0.0370), and significant differences in Cmax of (+)-M1 (P<0.0001) and (-)-M1 (P￡0.0010). In Phase A and C, significant differences in tmax were seen for (+)-M1 (P￡0.0200). There were no statistical differences between the abs. bioavailability of tramadol in EMs and PMs. The urinary recoveries of (+)-tramadol, (-)-tramadol, (+)-M1 and (-)-M1 were statistically significantly different in EMs and PMs (P<0.05).There are some commonly used reagents with their cas registry numbers 144830-14-8 and 148229-78-1 in this article. Median antimodes of the urinary metabolic ratios of (+)-tramadol / (+)-M1 and (-)-M1 were 5.0 and 1.5, resp., hereby clearly sepg. EMs and PMs in all three phases. Conclusion: The impact of CYP2D6 phenotype on tramadol pharmacokinetics was similar after single oral, multiple oral and i.v. administration displaying significant pharmacokinetic differences between EMs and PMs of (+)-tramadol, (-)-tramadol, -(+)-M1 and (-)-M1. The O-demethylation of tramadol was catalyzed stereospecific by CYP2D6 in the way that very little (+)-M1 was produced in PMs. .