Evaluation of nefopam as a monoamine uptake inhibitor in vivo in mice.
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.
Fuller
R W
RW
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285.
Snoddy
H D
HD
D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009206:Myocardium / Q000378:metabolism; D009340:Nefopam / Q000494:pharmacology*; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism; D016627:Oxidopamine / Q000037:antagonists & inhibitors; D012701:Serotonin / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D010133:p-Chloroamphetamine / Q000037:antagonists & inhibitors
D015306:Biogenic Monoamines; D006897:Hydroxyindoleacetic Acid; D009340:Nefopam; D014179:Neurotransmitter Uptake Inhibitors; D009638:Norepinephrine; D016627:Oxidopamine; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D010133:p-Chloroamphetamine