Dextromethorphan and its metabolite dextrorphan block alpha3beta4 neuronal nicotinic receptors.
Dextromethorphan (DM), a structural analog of morphine and codeine, has been widely used as a cough suppressant for more than 40 years. DM is not itself a potent analgesic, but it has been reported to enhance analgesia produced by morphine and nonsteroidal anti-inflammatory drugs. Although DM is considered to be nonaddictive, it has been reported to reduce morphine tolerance in rats and to be useful in helping addicted subjects to withdraw from heroin. Here we studied the effects of DM on neuronal nicotinic receptors stably expressed in human embryonic kidney cells. Studies were carried out to examine the effects of DM on nicotine-stimulated whole cell currents and nicotine-stimulated (86)Rb(+) efflux. We found that both DM and its metabolite dextrorphan block nicotinic receptor function in a noncompetitive but reversible manner, suggesting that both drugs block the receptor channel. Consistent with blockade of the receptor channel, neither drug competed for the nicotinic agonist binding sites labeled by [(3)H]epibatidine. Although DM is approximately 9-fold less potent than the widely used noncompetitive nicotinic antagonist mecamylamine in blocking nicotinic receptor function, the block by DM appears to reverse more slowly than that by mecamylamine. These data indicate that DM is a useful antagonist for studying nicotinic receptor function and suggest that it might prove to be a clinically useful neuronal nicotinic receptor antagonist, possibly helpful as an aid for helping people addicted to nicotine to refrain from smoking, as well as in other conditions where blockade of neuronal nicotinic receptors would be helpful.
Hernandez
S C
SC
Department of Pharmacology, Georgetown University School of Medicine, Washington, DC 20007, USA.
Bertolino
M
M
Xiao
Y
Y
Pringle
K E
KE
Caruso
F S
FS
Kellar
K J
KJ
D000818:Animals; D000996:Antitussive Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D003915:Dextromethorphan / Q000494:pharmacology*; D003917:Dextrorphan / Q000494:pharmacology*; D006801:Humans; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012414:Rubidium Radioisotopes / Q000378:metabolism
D000996:Antitussive Agents; D018733:Nicotinic Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D012414:Rubidium Radioisotopes; D003917:Dextrorphan; D003915:Dextromethorphan