Effects of narcotic analgesics on the uptake and release of 5-hydroxytryptamine in rat synaptosomal preparations

1 The effects of various narcotic analgesics on the uptake and release of labelled 5-hydroxytryptamine (5-HT) in brain and spinal cord synaptosomes were investigated.2 Methadone was most active in inhibiting 5-HT uptake (IC(50) 2.5 x 10(-7) M). Levorphanol also inhibited 5-HT uptake to a large extent (IC(50) 8.8 x 10(-7) M) while dextrophan, pethidine and pentazocine showed much less activity. Etorphine and morphine had virtually no such activity, with IC(50)S higher than 10(-4) and 10(-3) M respectively.3 The same order of potency as ;5-HT releasers' was found when radioactivity was measured in [(3)H]-5-HT preloaded synaptosomal pellets incubated for 20 min with the various narcotics. Methadone, like chlorimipramine, showed a significant effect at a concentration of 10(-7) M while morphine, at a concentration of 10(-4) M, had no effect.4 When 5-HT release was studied by a perfusion technique, which largely prevents reuptake of the released amine, only fenfluramine, an anorectic agent proposed as a 5-HT releaser, significantly increased spontaneous 5-HT release. These data suggest that the apparent 5-HT release induced by various narcotics in traditional incubation techniques may largely depend on their ability to interfere with neurotransmitter reuptake mechanisms.5 The effects of the various narcotics on 5-HT uptake have no relationship to their relative potency as analgesics in the rat. In the light of their poor effectiveness as 5-HT releasers, it can be concluded that mechanisms other than 5-HT uptake inhibition and release are probably involved in the analgesic effects of these compounds in intact animals.