Effect of dextrometorphan and dextrorphan on nicotine and neuronal nicotinic receptors: in vitro and in vivo selectivity.
The effects of dextrometorphan and its metabolite dextrorphan on nicotine-induced antinociception in two acute thermal pain assays after systematic administration were evaluated in mice and compared with that of mecamylamine. Dextrometorphan and dextrorphan were found to block nicotine's antinociception in the tail-flick and hot-plate tests with different potencies (dextrometorphan is 10 times more potent than its metabolite). This blockade was not due to antagonism of N-methyl-d-aspartate receptors and/or interaction with opiate receptors, since selective drugs of these receptors failed to block nicotine's analgesic effects. Our results with the tail-flick and hot-plate tests showed an interesting in vivo functional selectivity for dextrometorphan over dextrorphan. In oocytes expressing various neuronal acetylcholine nicotinic receptors (nAChR), dextrometorphan and dextrorphan blocked nicotine activation of expressed alpha(3)beta(4), alpha(4)beta(2), and alpha(7) subtypes with a small degree of selectivity. However, the in vivo antagonistic potency of dextrometorphan and dextrorphan in the pain tests does not correlate well with their in vitro blockade potency at expressed nAChR subtypes. Furthermore, the apparent in vivo selectivity of dextrometorphan over dextrorphan is not related to its in vitro potency and does suggest the involvement of other mechanisms. In that respect, dextrometorphan seems to behave as another mecamylamine, a noncompetitive nicotinic receptor antagonist with a preferential activity to alpha(3)beta(4)(*) neuronal nAChR subtypes.
Damaj
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MI
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Box 980613, Richmond, VA 23298-0613, USA. mdamaj@hsc.vcu.edu
Flood
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Ho
K K
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May
E L
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Martin
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BR
D000818:Animals; D003915:Dextromethorphan / Q000494:pharmacology*; D003917:Dextrorphan / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006358:Hot Temperature; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D010147:Pain Measurement / Q000187:drug effects; D011930:Reaction Time / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D014982:Xenopus laevis; D064569:alpha7 Nicotinic Acetylcholine Receptor
C579166:Chrna7 protein, mouse; D018691:Excitatory Amino Acid Antagonists; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403530:nicotinic receptor alpha3beta4; C403531:nicotinic receptor alpha4beta2; D003917:Dextrorphan; D008464:Mecamylamine; D016291:Dizocilpine Maleate; D009538:Nicotine; D003915:Dextromethorphan