Induction of 5-hydroxytryptamine release by tramadol, fenfluramine and reserpine.

Schneider F.

Grunenthal, Abteilung Pharmakologie, Aachen, Germany.

Tramadol is a centrally acting analgesic with several modes of action. Enhancement of 5-hydroxytryptamine release contributes to its actions. We investigated in which way tramadol induces 5-hydroxytryptamine release. Rat brain frontal cortex slices were preincubated with [3H]5-hydroxytryptamine, then superfused using conditions which impaired either carrier mediated release or exocytosis. Tramadol (10 and 100 microM), fenfluramine (1 microM) and reserpine (10 microM) enhanced the basal release of [3H]5-hydroxytryptamine. In the presence of a high concentration of 6-nitroquipazine effects of tramadol were reduced and those of fenfluramine abolished. Effects by reserpine were enhanced, indicating that [3H]5-hydroxytryptamine depletion was counteracted by reuptake. When NaCl was replaced by LiCl, tramadol did not affect [3H]5-hydroxytryptamine release, fenfluramine induced a small and reserpine a marked facilitation. Omission of CaCl2 did not alter fenfluramine and reserpine effects while those by tramadol were reduced. It is concluded that tramadol induces both carrier mediated 5-hydroxytryptamine release as well as exocytosis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9671098&dopt=Abstract tramadol



Tramadol, a centrally acting opioid: anticonvulsant effect against maximal electroshock seizure in mice.

Mediratta PK.

Department of Pharmacology, University College of Medical Sciences and GTB Hospital, Delhi.

The present study was designed to investigate the pro- or anticonvulsant effect of tramadol using maximal electroshock (MES) test. An attempt was also made to determine the possible opioid receptor mechanism involved. MES seizures were induced through transauricular electrodes (60 mA, 0.2s) and the seizure severity was assessed by the duration of tonic hindlimb extensor phase. Intraperitoneal (i.p.) administration of tramadol resulted in a dose-dependent anticonvulsant action; the ED50 for the effect was 33 mg/kg. The anti-MES effect of tramadol was antagonized by the low doses (0.05 and 0.1 mg/kg, s.c.) of MR 2266, a selective kappa receptor antagonist and also by the high doses (1.0 and 5.0 mg/kg, i.p.) but not the low doses (0.1 and 0.25 mg/kg) of naloxone. The results suggest that the anti-MES effect of tramadol is mediated by kappa receptors, since MR 2266 and naloxone (in high doses) are known to block these receptors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9741657&dopt=Abstract tramadol



Tramadol induces antidepressant-type effects in mice.

Mico JA.

Department of Neuroscience, Faculty of Medicine, University of Cadiz, Spain.

Tramadol is a clinically-effective, centrally-acting analgesic. This drug is a racemic mixture of two enantiomers, each one displaying different mechanisms: (+)tramadol displays opioid agonist properties and inhibits serotonin reuptake while (-)tramadol inhibit preferentially noradrenaline reuptake. The action of tramadol on the monoaminergic reuptake is similar to that of antidepressant drugs. Therefore, we have examined the effects of (+/-)tramadol, (+)tramadol and (-)tramadol in a test predictive of antidepressant activity, the forced swimming test in mice. Both (+/-)tramadol and its (-) enantiomer displayed a dose-dependent reduction on immobility; while the effect induced by the (+) enantiomer was not significant. Inhibition of noradrenaline synthesis, but not of serotonin synthesis, was capable of blocking the effect of (+/-)tramadol. The alpha-adrenoceptor antagonist phentolamine, as well as the alpha2-adrenergic antagonist yohimbine, and the beta-adrenoceptor blocker propranolol countered the immobility-reducing action of (+/-)tramadol. Moreover, neither the serotoninergic blocker methysergide nor the opioid antagonist naloxone antagonized the effect of (+/-)tramadol. Our results show that (+/-)tramadol and (-)tramadol have antidepressant-like effect in mice, probably mediated by the noradrenergic system rather than the serotoninergic or opioidergic ones.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9749830&dopt=Abstract tramadol



Antinociception, tolerance, and physical dependence comparison between morphine and tramadol.

Pinardi G.

Department of Pharmacology, Faculty of Medicine, Universidad de Chile, Santiago.

The mechanism of action of tramadol includes the activation of opioid receptors, and the potential ability of the drug to induce tolerance and physical dependence has been evaluated in different animal species and humans. This work was designed to study the involvement of opioid receptors in the antinociceptive activity and the potential ability to develop tolerance, crosstolerance, and/or physical dependence of tramadol. The writhes induced by acetic acid administration was used as algesiometric test. After chronic administration of tramadol, tolerance was evaluated by measuring the antinociceptive activity, and physical dependence was measured by naloxone administration. Morphine was used as drug of comparison. The i.p. administration of tramadol produced a dose-dependent antinociception with an ED50 value of 7.82 +/- 1.16 mg/kg, which was unchanged after chronic administration of either tramadol (39.1 or 100 mg/kg) or morphine (1.05 or 100 mg/kg). By contrast, the ED50 for morphine (0.21 +/- 0.08 mg/kg) was significantly reduced only by chronic pretreatment with both doses of morphine (tolerance). Physical dependence was developed only in mice pretreated with morphine, as evidenced by the presence of jumps, wet-dog shakes, tachypnea, piloerection, seizures, diarrhea, and urination after the administration of naloxone (1 mg/kg). These findings suggest that the antinociceptive activity of tramadol in mice is due to activation of opioid and nonopioid mechanisms, and as opposed to morphine, is not likely to induce tolerance and physical dependence.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9802828&dopt=Abstract tramadol