The ability of proglumide to modulate changes in morphine's aversive properties during chronic morphine exposure

Just as chronic exposure to morphine alters its antinociceptive properties, chronic exposure to morphine has been shown to alter the strength of its aversive effects. As cholecystokinin (CCK) antagonists have been shown to prevent or reverse tolerance to morphine's analgesic effects, such compounds could potentially modulate morphine's aversive properties. The current experiment assessed the ability of the CCK antagonist proglumide to block the development of tolerance to the aversive properties of morphine in rats utilizing a conditioned taste aversion (CTA) design. Specifically, animals were preexposed to vehicle, morphine (5 mg/kg), proglumide (5 mg/kg) or a combination of proglumide administered either immediately or 15 min before morphine. On subsequent conditioning days, saccharin was presented followed immediately by administration of either morphine (10 mg/kg) or vehicle. Over conditioning, control animals increased saccharin consumption, regardless of preexposure condition. Animals preexposed to vehicle or proglumide and injected with morphine during conditioning acquired a morphine-induced saccharin aversion. Animals preexposed to morphine and conditioned with morphine acquired an attenuated morphine-induced saccharin aversion. Animals preexposed to the combination of proglumide and morphine and injected with morphine during conditioning also acquired an attenuated morphine-induced saccharin aversion. Importantly, saccharin consumption in animals preexposed to either proglumide-morphine combination was not different from animals preexposed to morphine, indicating that proglumide had no effect on the development of tolerance to the aversive properties of morphine in a CTA design. In order to assess whether the inability of proglumide to block the development of tolerance was due to the specific parameters of Experiment 1, Experiment 2 examined the effects of 5 mg/kg proglumide administered either immediately, 5 or 15 min before CCK (3 or 10 mug/kg) on CCK-induced suppression of feeding. When proglumide was administered immediately before 3 mug/kg CCK, it attenuated the CCK-induced suppression of feeding. The findings from the current study suggest that CCK may not be involved in the aversive properties of morphine.