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 ␣ 3 ␤ 4 , ␣ 4 ␤ 2 , and ␣ 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 ␣ 3 ␤ 4 * neuronal nAChR subtypes.Dextrometorphan is structurally related to the morphinan opioid levorphanol and is widely known as a centrally acting non-narcotic antitussive agent. Although dextromethorphan produces little analgesia by itself, it was found to potentiate the antinociceptive effects of opiates and reduce tolerance and physical dependence to morphine (Mao et al., 1996). In addition, Glick et al. (2001) have shown that both dextrometorphan and its major metabolite, dextrorphan, decreased nicotine, methamphetamine, and morphine self-administration in rats after s.c. administration. These multiple pharmacological and behavioral effects may be related to the ability of dextrometorphan and dextrorphan to interact with various receptor systems. Dextrometorphan has little or no opioid activity but binds with high affinity to sites (Klein and Musacchio, 1989). It binds, along with dextrorphan, with low affinity to the phencyclidine site of the NMDA receptor with dextrorphan having a 10-fold higher affinity at the site (Franklin and Murray, 1992). In addition, dextrometorphan and dextrorphan are both antagonists at NMDA glutamate receptors (Murray and Leid, 1984). They were also recently shown to block ␣ 3 ␤ 4 neuronal nicotinic receptors in a noncompetitive fashion (Hernandez et al., 2000) with dextrometorphan 3-fold less potent than dextrorphan. These reports suggest that dextrometorphan and/or dextrorphan may hold promise for understanding nicotine pharmacology and nicotine dependence. However, further st...

Conservative mutation of a single amino acid in the extracellular transmembrane segment 2 domain induces resistance to ketamine inhibition in the alpha7 nicotinic receptor and sensitivity to inhibition in the 5HT3A receptor. This region may represent a ketamine binding site in the alpha7 nicotinic receptor, or it may be an important transduction site for ketamine action.