Effects of μ- and δ-Opioid–Receptor Antagonists on the Stimulus Properties of Cholecystokinin

Abstract

Melton and Riley recently reported that the relatively selective μ-opioid–antagonist naloxone potentiated the stimulus properties of the gut peptide cholecystokinin (CCK). To assess whether such opioid potentiation is limited to activity at the μ-receptor subtype, in the present experiment the effects of the highly selective δ-antagonist naltrindole on CCK's stimulus properties were examined. Because in the initial report of naloxone's potentiation of CCK a relatively high, nonphysiologic dose of CCK (i.e., 13 μg/kg) was used as the training drug, in the current analysis subjects were trained to discriminate 5.6 μg/kg CCK from its vehicle and the assessments and comparisons of the effects of naloxone and naltrindole were based on this dose. Specifically, rats were administered 5.6 μg/kg CCK before saccharin–LiCl pairings and the CCK vehicle before saccharin alone. With such training, they rapidly acquired the drug discrimination, avoiding saccharin consumption when it was preceded by CCK and consuming the same saccharin solution when it was preceded by its vehicle. In subsequent generalization tests, doses of CCK that were ineffective in suppressing saccharin consumption (i.e., did not substitute for the training dose of CCK) did result in the suppression of saccharin consumption when combined with doses of the μ antagonist naloxone that alone had no effect on saccharin intake. On the other hand, the highly selective δ-opioid–receptor antagonist naltrindole was ineffective in potentiating the effects of CCK. Specifically, when naltrindole was combined with ineffective doses of CCK, subjects drank at control levels. The ability of naloxone to potentiate CCK's stimulus effects is consistent with a range of other demonstrations of the role of the μ-opioid–receptor subtype in CCK–opioid interactions, although the specific basis for the interaction remains unknown. Given recent findings on the effects of δ agonists and antagonists on CCK-induced activity, the failure of naltrindole to potentiate CCK's stimulus effects may be due to the absence of δ activity within this preparation, rather than the absence of δ mediation of CCK–opioid interactions in general.