Influence of tramadol on neurotransmitter systems of the rat brain.

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Frink MC, Hennies HH, Englberger W, Haurand M, Wilffert B

Influence of tramadol on neurotransmitter systems of the rat brain.

Arzneimittelforschung. 1996 Nov;46(11):1029-36.

PubMed ID

8955860 [ View in PubMed

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Abstract

In in vitro receptor binding and synaptosomal uptake experiments the (+)-enantiomer of tramadol (CAS 148229-78-1) is specific for the mu-opioid receptor site and for the serotonin (5-HT) carrier, whereas the (-)-enantiomer (CAS 148229-79-2) has a higher affinity to the noradrenaline (NA) transporter. The antinociceptive active tramadol metabolite O-demethyltramadol (M1) shows a pronounced mu-selectivity. With respect to in vitro receptor binding experiments, the affinity of (+)-M1 to this opioid receptor subtype is more than two orders of magnitude higher than that of (+)-tramadol and approximately 1/10 that of morphine. Tramadol and M1 (and the enantiomers thereof) have no affinity to other receptor or uptake sites tested, e.g. 5-HT1A, 5-HT2, 5-HT3, NMDA (ligand: MK801), dopamine (DA)-D1, DA-D2, benzodiazepine, muscarine M1 and DA uptake (Ki > or = 2 x 10(-5) mol/l). Ex vivo neurotransmitter determinations show that tramadol (46.4 mg/kg i.p.) elevates the DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid and enhances DA release in definite brain areas. The active enantiomer of the racemic tramadol is the (+)-enantiomer. (+)-Tramadol significantly enhances the turnover rate of DA. The enantioselective elevation of DOPAC by (+)-tramadol is antagonized by naloxone (2 x 5 mg/kg i.p.). Morphine (21.5 mg/kg i.p.) enhances the turnover of NA in definite brain areas. Neither the NA-specific uptake inhibition nisoxetine (31.6 mg/kg i.p.) nor tramadol (or its (+)- and (-)-enantiomers) have any influence on the NA turnover. Tramadol reduces the levels of 5-HT and its metabolite 5-hydroxyindoleacetic acid. Morphine enhances, whereas tramadol reduces, 5-HT utilisation in the brain areas under assay. The 5-HT specific uptake inhibitor fluoxetine (20 mg/kg i.p.) shows the same influence on 5-HT turnover as tramadol. The results indicate that tramadol enhances DA turnover via an opioid mechanism. The interaction with the noradrenergic and serotonergic neurotransmission is clearly different from that of an opioid receptor agonist and closely resembles that of NA and 5-HT uptake inhibitors.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Tramadol	Mu-type opioid receptor	Protein	Humans	Yes	Agonist	Details
Tramadol	Sodium-dependent noradrenaline transporter	Protein	Humans	Yes	Inhibitor	Details
Tramadol	Sodium-dependent serotonin transporter	Protein	Humans	Yes	Inhibitor	Details