The atypical analgesic tramadol has strong structural similarities to the antidepressant venlafaxine and is a mixed noradrenaline (NA) and serotonin (5-HT) uptake inhibitor. Because tramadol has been found active in the forced swim test, a common predictor of antidepressant efficacy, we therefore examined the effects of chronic tramadol on various pre- and post-synaptic monoamine measures. Male Wistar rats (150–200 g) received tramadol (20 mg/kg i.p.) or vehicle for 21 days and were sacrificed 24 h after the last dose. Quantitative autoradiography revealed that specific frontocortical [³H]dihydroalprenolol and [³H]ketanserin binding was lower in the chronic tramadol group than controls (β: 37 ± 8 and 217 ± 56 fmol/mg; 5-HT_2A: 23 ± 3 and 44 ± 7 fmol/mg, respectively, p < 0.05). Chronic tramadol had no effect on the magnitude of electrically stimulated noradrenaline (NA) efflux or uptake in locus coeruleus (LC) slices. Although dexmedetomidine (10 nM) decreased LC NA efflux equally (by approximately 60%) in chronic tramadol and vehicle groups, desipramine (50 nM) increased LC NA efflux more in vehicle (to 164 ± 7%) than tramadol-treated rats (144 ± 6%; p< 0.05). Chronic tramadol had no effect on dorsal raphé (DRN) or median raphé (MRN) 5-HT efflux. However, 5-HT uptake in tramadol-treated rats was slower (p < 0.05) in MRN and nearly so (p= 0.055) in DRN. The selective 5-HT_1A agonist 8-OH-DPAT reduced 5-HT efflux in both DRN and MRN. Its effect in DRN was greater in rats given chronic tramadol than in vehicle controls (54 ± 2 versus 32 ± 6% reduction in 5-HT efflux, respectively). In conclusion, we suggest that tramadol has many of the pre and postsynaptic neurochemical features of a conventional antidepressant, as might be predicted from its pharmacology.

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Effects of chronic tramadol on pre- and post-synaptic measures of monoamine function