ANTINOCICEPTIVE EFFECTS OF MONOAMINE REUPTAKE INHIBITORS ADMINISTEREDALONE OR IN COMBINATION WITH MU-OPIOID AGONISTS IN RHESUS-MONKEYS

Cocaine, which non-selectively blocks the reuptake of the monoamines s erotonin, dopamine and norepinephrine, produces weak antinociceptive e ffects and increases the antinociceptive effects of low- to intermedia te-efficacy mu opioid agonists in rhesus monkeys. In the present study , the antinociceptive effects of more selective monoamine reuptake inh ibitors administered alone and in combination with mu opioid agonists were evaluated in rhesus monkeys using a warm-water tail-withdrawal as say of thermal nociception. Like cocaine, the selective serotonin reup take inhibitors clomipramine (0.01-3.2 mg/kg) and fluoxetine (0.1-10 m g/kg) produced weak antinociceptive effects. Pretreatment with the ser otonin receptor antagonist mianserin (0.032-0.32 mg/kg) produced right ward and downward shifts in the clomipramine dose-effect curve, sugges ting that the effects of clomipramine were mediated by serotonin recep tors. Combination of clomipramine with the low efficacy mu agonist nal buphine or the intermediate efficacy mu agonist morphine produced more antinociception than did the mu agonists alone. Fluoxetine also produ ced a small leftward shift in the morphine dose-effect curve. The sele ctive norepinephrine reuptake inhibitors nisoxetine (0.1-10 mg/kg) and tomoxetine (0.1-10 mg/kg) and the selective dopamine reuptake inhibit ors bupropion (0.032-3.2 mg/kg) and GBR 12909 (0.1-10 mg/kg) did not p roduce antinociception or increase antinociception induced by nalbuphi ne or morphine. In fact, GBR 12909 produced dose-dependent allodynia a nd reduced the maximal antinociceptive effects of morphine. These resu lts suggest that inhibition of serotonin reuptake is sufficient to pro duce weak antinociceptive effects and enhance the antinociceptive effe cts of low efficacy mu opioid agonists. These results also suggest tha t the effects of cocaine on serotonin reuptake may contribute to cocai ne's antinociceptive effects in rhesus monkeys.