Attenuation of Pethidine‐induced Antinociception by Zimelidine, an Inhibitor of 5‐hydroxytryptamine Reuptake

Abstract

1 The effect of selective inhibition of 5-hydroxytryptamine (5-HT) re-uptake by fluoxetine and zimelidine on morphine-and pethidine-induced antinociception was studied in rats. The hot plate (55°C) and tail flick test procedures for measurement of analgesia were employed to assess antinociception. 2 Pretreatment with fluoxetine and zimelidine potentiated the antinociceptive effect of morphine (4.5 mg/kg, as base); zimelidine was without effect on a lesser dose of morphine (3.0 mg/kg, as base). 3 Pretreatment with zimelidine but not fluoxetine, significantly attenuated pethidine-induced antinociception (24 mg/kg, as base) and prevented the expression of pethidine-induced antinociception at a lesser 10 mg/kg (as base) dose of pethidine. 4 These and other results support (a) a role for 5-HT in the expression of morphine-induced antinociception, and (b) a different mode of antinociceptive action of morphine and pethidine. The role of 5-HT in pethidine-induced antinociception remains unclear.

Zimelidine attenuates the development of tolerance to morphine-induced antinociception

“…However, the effect of zimelidine pretreatment on pethidine-induced antinociception revealed a significant attenuation of antinociception by pethidine in the hot plate test. [ 31 ] These data support a role for 5-HT in the expression of morphine-induced antinociception, and a different mode of antinociceptive action of morphine and pethidine.…”

Involvement of 5‐hydroxytryptamine in the Analgesic Action of Pethidine and Morphine in Mice

“…Details are as in the footnotes to Table 5. nuclei (Samanin et al, 1973;Vogt, 1974;Chance et al, 1978;Miranda et al, 1979), or systemic administration of PCPA (Tenen, 1968;Vogt, 1974) inhibit the antinociceptive action of morphine. Conversely, raising the 5-HT concentration with fluoxetine or zimelidine potentiated morphine analgesia but was without effect on pethidine analgesia (Sugrue & McIndewar, 1976;Sugrue, 1979;Gebhart & Lorens, 1980). In conclusion, pretreatment with the 5-HT depletors, fenfluramine or PCPA did not alter the antinociceptive action of pethidine in mice.…”

“…Drug treatments that tend to increase brain 5-HT concentrations can potentiate morphine-induced analgesia. For example, pretreatment with the 5-HT reuptake inhibitors, fluoxetine or zimelidine (Sugrue & McIndewar, 1976;Sugrue, 1979;Gebhart & Lorens, 1980), or intracerebroventricular (i.c.v.) injection of 5-HT (Sparkes & Spencer, 1971) increase morphine analgesia.…”