Effect of acute and chronic tramadol on [3H]-norepinephrine-uptake in rat cortical synaptosomes

1. Tramadol hydrochloride is a centrally acting opioid analgesic whose efficacy and potency is only five to ten times lower than that of morphine. Opioid, as well as non-opioid mechanisms, may participate in the analgesic activity of tramadol. 2. [H-3]-NE uptake in isolated rat cortical synaptosomes was studied in the presence of tramadol, desipramine, methadone, and morphine. Desipramine and tramadol inhibited synaptosomal [H-3]-NE uptake with apparent K(i)s of 7.3 +/- 0.66 and 1.4 +/- 0.0045 mu M, respectively. Methadone was active at a 10-fold higher concentration (Ki: 87 +/- 5.6 mu M) In contrast, morphine essentially failed to inhibit [H-3]-5-HT uptake (K-i: 0.75 +/- 0.40 M). 3. 3. Methadone, morphine, and tramadol were active in the hot plate test with ED(50)s of 6.2, 9.3, and 40 mg kg(-1), respectively. 4. [H-3]-NE uptake was examined in synaptosomes prepared from rats 30 min after receiving a single dose of morphine, methadone or tramadol. Only tramadol (31 mg kg(-1), i.p.) decreased uptake of the transmitter, with an ED50 equal to that in the hot plate test. 5. Animals were chronically treated for 15 days with increasing doses of tramadol (20 to 125 mg kg(-1), i.p.). Twenty-four hours after the last drug injection, a challenge dose of tramadol (40 mg kg(-1), i.p.) was administered. Chronic tramadol was still able to reduce [H-3]-NE uptake by 35%. 6. These results further support the hypothesis that [H-3]-NE uptake inhibition may contribute to the antinociceptive effects of tramadol. The lack of tolerance in [H-3]-NE uptake, together with the absence of behavioural alteration after chronic tramadol treatment proposes that tramadol holds potential over classical opioids in the treatment of pain disorders.