INHIBITION OF SPINAL NORADRENALINE UPTAKE IN RATS BY THE CENTRALLY ACTING ANALGESIC TRAMADOL

Tramadol is a centrally acting analgesic with low affinity to opioid r eceptors. A further mode of action is inhibition of noradrenaline upta ke as measured in standard assays. Since tramadol shows antinociceptio n at the spinal site, it was to be tested whether uptake blockade coul d be verified in spinal tissue. Therefore, synaptosomes and slices had to be prepared from the dorsal half of the spinal cord and the uptake of [H-3]noradrenaline into synaptosomes to be characterized. The upta ke was linear for at least 3 min. The apparent K-m was 0.16 mu M and V -max was 7.9 pmol/min/mg protein. Tramadol inhibited the uptake compet itively as analysed with Dixon plots with a K-i of 0.6 mu M. Uptake in hibition was effected in order of potency by (+)-oxaprotiline > nisoxe tine > (-)-tramadol > (-)-oxaprotiline = tramadol > (+)-tramadol. Slic es were preincubated with [H-3]noradrenaline then superfused and stimu lated electrically. Nisoxetine, tramadol and its (-)-enantiomer enhanc ed mainly the stimulation-evoked overflow indicating uptake inhibition without releasing effects. Experiments with inclusion of the noradren aline uptake inhibitor desipramine provide evidence that tramadol inte rfered with the noradrenaline transporter. The results show that spina l synaptosomes and slices are valid preparations to study local noradr enaline uptake and release. Tramadol enhances extraneuronal noradrenal ine levels in the spinal cord by competitive interference with the nor adrenaline uptake mechanism.