Antinociceptive effects of monoamine reuptake inhibitors administered alone or in combination with mu opioid agonists in rhesus monkeys

Cocaine, which non-selectively blocks the re-uptake of the monoamines serotonin, dopamine and norepinephrine, produces weak antinociceptive effects and increases the antinociceptive effects of low- to intermediate-efficacy mu opioid agonists in rhesus monkeys. In the present study, the antinociceptive effects of more selective monoamine re-uptake inhibitors administered alone and in combination with mu opioid agonists were evaluated in rhesus monkeys using a warm-water tail-withdrawal assay of thermal nociception. Like cocaine, the selective serotonin re-uptake inhibitors clomipramine (0.01-3.2 mg/kg) and fluoxetine (0.1-10 mg/kg) produced weak antinociceptive effects. Pretreatment with the serotonin receptor antagonist mianserin (0.032-0.32 mg/kg) produced rightward and downward shifts in the clomipramine dose-effect curve, suggesting that the effects of clomipramine were mediated by serotonin receptors. Combination of clomipramine with the low efficacy mu agonist nalbuphine or the intermediate efficacy mu agonist morphine produced more antinociception than did the mu agonists alone. Fluoxetine also produced a small leftward shift in the morphine dose-effect curve. The selective norepinephrine re-uptake inhibitors nisoxetine (0.1-10 mg/kg) and tomoxetine (0.1-10 mg/kg) and the selective dopamine re-uptake inhibitors bupropion (0.032-3.2 mg/kg) and GBR 12909 (0.1-10 mg/kg) did not produce antinociception or increase antinociception induced by nalbuphine or morphine. In fact, GBR 12909 produced dose-dependent allodynia and reduced the maximal antinociceptive effects of morphine. These results suggest that inhibition of serotonin re-uptake is sufficient to produce weak antinociceptive effects and enhance the antinociceptive effects of low efficacy mu opioid agonists. These results also suggest that the effects of cocaine on serotonin re-uptake may contribute to cocaine's antinociceptive effects in rhesus monkeys.