Codeine produces a cholinergically mediated analeptic effect in rats and rabbits.

The intravenous administration of codeine to diazepam-narcotized rabbits resulted in a shortened duration of loss of righting reflex. Coadministration of naltrexone plus codeine enhanced this analeptic effect and was also effective in shortening the duration of pentobarbital narcosis. The analeptic effect was blocked by atropine, but not by methylatropine, indicating involvement of a central cholinergic mechanism. In rats the analeptic activity correlated with the reversal of the diazepam-induced fall in sodium dependent high affinity choline uptake in hippocampal and cortical synaptosomes. These findings may represent the pharmacological basis of the recently reported antinarcoleptic action of codeine in man.