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Abstract
Nefopam antagonized 6-hydroxydopamine-induced depletion of heart norepinephrine in
mice with an ED50 value of 12 mg/kg. Nefopam was ineffective in antagonizing p-chloroamphetamine-induced
depletion of brain serotonin in our standard assay in mice, apparently due to a short
duration of action. Brain concentrations of the serotonin metabolite 5-hydroxyindoleacetic
acid (5-HIAA) were decreased after a 32 mg/kg, i.p., dose of nefopam at 1 and 2 hr
but not at 4 hr. When nefopam was injected simultaneously with p-chloroamphetamine,
it prevented brain serotonin depletion initially, but by 6 hr the protective effect
was essentially lost, suggesting that p-chloroamphetamine persisted in mouse brain
longer than did nefopam. Nefopam caused a dose-related antagonism of brain serotonin
depletion at 2 hr after injection of a low dose of p-chloroamphetamine hydrochloride
(10 mg/kg, i.p.), with a calculated ED50 value of 11 mg/kg. The lowering of brain
5-HIAA concentration 2 hr after nefopam injection occurred after a 32 mg/kg dose but
not after a 3 or 10 mg/kg dose. These data suggest that nefopam is effective as an
inhibitor of norepinephrine and serotonin uptake at doses previously shown to be analgesic
in mice, consistent with uptake inhibition being a postulated mechanism important
in its analgesic effect. Nonetheless, nefopam is a relatively weak inhibitor of monoamine
uptake with a short duration of action in mice.