Inhibition of spinal noradrenaline uptake in rats by the centrally acting analgesic tramadol.

Tramadol is a centrally acting analgesic with low affinity to opioid receptors. A further mode of action is inhibition of noradrenaline uptake as measured in standard assays. Since tramadol shows antinociception at the spinal site, it was to be tested whether uptake blockade could 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 [3H]noradrenaline into synaptosomes to be characterized. The uptake was linear for at least 3 min. The apparent Km was 0.16 microM and Vmax was 7.9 pmol/min/mg protein. Tramadol inhibited the uptake competitively as analysed with Dixon plots with a Ki of 0.6 microM. Uptake inhibition was effected in order of potency by (+)-oxaprotiline > nisoxetine > (-)-tramadol > (-)-oxaprotiline = tramadol > (+)-tramadol. Slices were preincubated with [3H]noradrenaline then superfused and stimulated electrically. Nisoxetine, tramadol and its (-)-enantiomer enhanced mainly the stimulation-evoked overflow indicating uptake inhibition without releasing effects. Experiments with inclusion of the noradrenaline uptake inhibitor desipramine provided evidence that tramadol interfered with the noradrenaline transporter. The results show that spinal synaptosomes and slices are valid preparations to study local noradrenaline uptake and release. Tramadol enhances extraneuronal noradrenaline levels in the spinal cord by competitive interference with the noradrenaline uptake mechanism.