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.

[1]  J. Leander,et al.  Pethidine interaction with clorgyline, pargyline, or 5‐hydroxytryptophan: lack of enhanced pethidine lethality or hyperpyrexia in mice , 1978, The Journal of pharmacy and pharmacology.

[2]  D. Wong,et al.  A new selective inhibitor for uptake of serotonin into synaptosomes of rat brain: 3-(p-trifluoromethylphenoxy). N-methyl-3-phenylpropylamine. , 1975, The Journal of pharmacology and experimental therapeutics.

[3]  R. Fuller,et al.  Inhibition of serotonin uptake and the toxic interaction between meperidine and monoamine oxidase inhibitors. , 1975, Toxicology and applied pharmacology.

[4]  E. Anderson,et al.  Paradoxical blockade by p-chlorophenylalanine of 5-hydroxytryptophan facilitatory actions on spinal reflexes. , 1973, The Journal of pharmacology and experimental therapeutics.

[5]  P. Gessner,et al.  A study of the tranylcypromine-meperidine interaction: effects of p-chlorophenylalanine and l-5-hydroxytryptophan. , 1973, The Journal of pharmacology and experimental therapeutics.

[6]  K. Rogers,et al.  Role of brain monoamines in the fatal hyperthermia induced by pethidine or imipramine in rabbits pretreated with a monoamine oxidase inhibitor , 1973, British journal of pharmacology.

[7]  J. Sinclair.  The effects of meperidine and morphine in rabbits pretreated with phenelzine. , 1972, Toxicology and applied pharmacology.

[8]  K. Rogers,et al.  Comparison of the effects of morphine, pethidine and pentazocine in rabbits pretreated with a monoamine oxidase inhibitor , 1971, British journal of pharmacology.

[9]  S. J. Shamsie,et al.  The hazards of use of monoamine oxidase inhibitors in disturbed adolescents. , 1971, Canadian Medical Association journal.

[10]  K. Rogers.  Role of brain monoamines in the interaction between pethidine and tranylcypromine. , 1971, European journal of pharmacology.

[11]  N. Rivers,et al.  Possible lethal reaction between nardil and dextromethorphan. , 1970, Canadian Medical Association journal.

[12]  J. A. Thornton,et al.  The interaction between monoamine oxidase inhibitors and narcotic analgesics in mice , 1969, British journal of pharmacology.

[13]  B. Clark.  The in vitro inhibition of the N-demethylation of pethidine by phenelzine (Phenethylhydrazine). , 1967, Biochemical pharmacology.

[14]  D. Maxwell,et al.  A comparison of the effects of imipramine, trimipramine, and some other drugs in rabbits treated with a monoamine oxidase inhibitor. , 1965, British journal of pharmacology and chemotherapy.

[15]  P. Denton,et al.  Dangers of Monoamine Oxidase Inhibitors , 1962 .

[16]  N. C. Reid,et al.  Pethidine and Phenelzine , 1962 .

[17]  H. Palmer.  Potentiation of Pethidine , 1960 .

[18]  J. Shee.  Dangerous Potentiation of Pethidine by Iproniazid, and its Treatment , 1960, British medical journal.

[19]  A. Horita,et al.  The pyretogenic effect of 5-hydroxytryptophan and its comparison with that of ISD. , 1958, The Journal of pharmacology and experimental therapeutics.

[20]  Oliver H. Lowry,et al.  Protein measurement with the Folin phenol reagent. , 1951, The Journal of biological chemistry.

[21]  L. Saarnivaara,et al.  Interactions of some analgesics and antidepressants with phenelzine or reserpine in the mouse. , 1974, Pharmacology.

[22]  Jounela Aj.  Effect of phenelzine on the rate of metabolism of pethidine. , 1968 .

[23]  V. P. Whittaker,et al.  The isolation of nerve endings from brain: an electron-microscopic study of cell fragments derived by homogenization and centrifugation. , 1962, Journal of anatomy.