Release studies with rat brain cortical synaptosomes indicate that tramadol is a 5-hydroxytryptamine uptake blocker and not a 5-hydroxytryptamine releaser

Eur J Pharmacol. 1999 Apr 1;370(1):23-6. doi: 10.1016/s0014-2999(99)00123-5.


Tramadol is a centrally acting opioid analgesic whose mechanism of action could also involve an increase in central serotoninergic transmission. Thus, tramadol inhibits synaptosomal serotonin (5-hydroxytryptamine, 5-HT) reuptake and induces tritium release from [3H]5-HT-preloaded slices. We investigated the effect of (+/-)-tramadol in release studies with superfused rat brain cortex synaptosomes preloaded with [3H]5-HT. Tramadol had no releasing effect up to 30 microM, whereas at 10 microM tramadol significantly inhibited by 45% D-fenfluramine-induced [3H]5-HT release. At 100 microM, tramadol showed a slight releasing effect in the absence or in the presence of pargyline, which was not augmented in synaptosomes pre-exposed to Ro 04-1284 (2-ethyl-1,3,4,6,7,11b-hexahydro-3-isobutyl-9,10-dimethoxy-2H-benzo [a]quinolizin-2-ol hydrochloride), a reserpine-like compound that enhances cytoplasmic 5-HT levels. In summary, (+/-)-tramadol behaved as a classical 5-HT uptake blocker (like citalopram) and not as a substrate of the 5-HT carrier with indirect 5-HT mimetic properties (like D-fenfluramine).

MeSH terms

  • 2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-hexahydro-3-isobutyl-9,10-dimethoxy- / pharmacology
  • Analgesics, Opioid / pharmacology*
  • Animals
  • Cells, Cultured
  • Cerebral Cortex / drug effects*
  • Cerebral Cortex / metabolism
  • Fenfluramine / pharmacology
  • Male
  • Rats
  • Selective Serotonin Reuptake Inhibitors / pharmacology*
  • Serotonin / metabolism*
  • Synaptosomes / drug effects*
  • Synaptosomes / metabolism
  • Tramadol / pharmacology*


  • Analgesics, Opioid
  • Serotonin Uptake Inhibitors
  • Fenfluramine
  • 2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-hexahydro-3-isobutyl-9,10-dimethoxy-
  • Serotonin
  • Tramadol