The blockade of serotonin uptake into synaptosomes:relationship to an interaction with monoamine oxidase inhibitors.
To test the hypothesis that the hyperpyrexia produced by meperidine and detromethorphan in rabbits pretreated with a monoamine oxidase inhibitor is related to inhibition of neuronal uptake of serotonin (5-hydroxytryptamine (5-HT)), fluoxetine (Lilly 110140) was studied. This potent and specific 5-HT neuronal uptake blocker was administered to phenelzine-pretreated rabbits and found to produce a lethal hyperpyrexia in doses equal to or greater than 2.5 mg/kg. The order of potency in blocking 5-[14C]HT uptake into synaptosomes prepared from rabbits was: fluoxetine greater than meperidine = dextromethorphan = levorphanol greater than anileridine greater than alphaprodine greater than morphine. Since fluoxetine, meperidine, and dextromethorphan produce hyperpyrexia in phenelzine-pretreated rabbits, whereas anileridine, alphaprodine, and morphine do not, there appears to be some correlation between the hyperpyrexic response and inhibition of 5-HT uptake. The exception is levorphanol, which is not hyperpyrexic despite being equipotent with meperidine and dextromethorphan in inhibiting 5-HT uptake. The ineffectiveness of levorphanol in producing hyperpyrexia may be due to its marked depressant properties, since the addition of another depressant drug (pentobarbital) antagonized the hyperpyrexic effect of meperidine.
D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000648:ultrastructure; D003864:Depression, Chemical; D003915:Dextromethorphan / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D010624:Phenelzine / Q000494:pharmacology*; D010647:Phenyl Ethers / Q000494:pharmacology; D011437:Propylamines / Q000494:pharmacology; D011817:Rabbits; D012701:Serotonin / Q000378:metabolism*; D012890:Sleep / Q000187:drug effects; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors
D000701:Analgesics, Opioid; D010647:Phenyl Ethers; D011437:Propylamines; D012701:Serotonin; D003915:Dextromethorphan; D010624:Phenelzine; D009638:Norepinephrine