EFFECT OF ACUTE AND CHRONIC TRAMADOL ON [H-3] 5-HT UPTAKE IN RAT CORTICAL SYNAPTOSOMES

1 Tramadol hydrochloride is a centrally acting opioid analgesic, the e fficacy and potency of which is only five to ten times lower than that of morphine. Opioid, as well as non-opioid mechanisms, may participat e in the analgesic activity of tramadol. 2 [H-3]-5-hydroxytryptamine ( 5-HT) uptake in rat isolated cortical synaptosomes was studied in the presence of tramadol, desipramine, fluoxetine, methadone and morphine. Methadone and tramadol inhibited synaptosomal [H-3]-5-HT uptake with apparent K(i)s of 0.27 +/- 0.04 and 0.76 +/- 0.04 mu M, respectively. Morphine essentially failed to inhibit [H-3]-5-HT uptake (K-i 0.50 +/- 0.30 M). 3 Methadone, morphine and tramadol were active in the hot pl ate test with ED(50)s of 3.5, 4.3 and 31 mg kg(-1), respectively. At t he highest tested dose (80 mg kg(-1)) tramadol produced only 77 +/- 5. 3% of the maximal possible effect.4 When [H-3]-5-HT uptake was examine d in synaptosomes prepared from rats 30 min after a single dose of mor phine, methadone or tramadol, only tramadol (31 mg kg(-1) s.c., equal to the ED50 in the hot plate test) and methadone (35 mg kg(-1), s.c., equal to the ED90 in the hot plate test) decreased uptake. 5 Animals w ere chronically treated for 15 days with increasing doses of tramadol or methadone (5 to 40 mg kg(-1) and 15 to 120 mg kg(-1), s.c., respect ively). Twenty-four hours after the last drug injection, a challenge d ose of methadone (35 mg kg(-1), s.c.) or tramadol (31 mg kg(-1), s.c.) was administered. [H-3]-5-HT uptake was not affected in synaptosomes prepared from rats chronically-treated with methadone, whereas chronic tramadol was still able to reduce this parameter by 42%. 6 Rats chron ically-treated with methadone showed a significant increase in [H-3]-5 -HT uptake (190%) 72 h after drug withdrawal. In contrast, [H-3]-5-HT uptake in rats chronically-treated with tramadol (110%) did not differ significantly from control animals. 7 These results further support t he hypothesis that [H-3]-5-HT uptake inhibition may contribute to the antinociceptive effects of tramadol. The lack of tolerance development of [H-3]-5-HT uptake, together with the absence of behavioural altera tions after chronic tramadol treatment, suggest that tramadol has an a dvantage over classical opioids in the treatment of pain disorders.