ABSTRACT This study investigated the effect of delta opioid receptor blockade by naltrindole on the development of physical dependence and tolerance to the antinociceptive and respiratory depressive effects of morphine in rats. Chronic morphine was delivered either by s.c. injection of increasing amounts of morphine over 5 days or by s.c. implantation of morphine pellets. Animals were cotreated with saline or naltrindole. Antinociception and respiratory depression were assessed after administration of a challenge dose of morphine, and withdrawal signs were determined after naloxone challenge. Naltrindole significantly attenuated the development of antinociceptive tolerance after all three chronic treatment regimens. In addition, rats pretreated with naltrindole displayed significantly fewer withdrawal symptoms and less weight loss after a naloxone challenge. In contrast, naltrindole did not prevent the development of tolerance to morphine-induced respiratory depression. These results imply that tolerance to antinociception and physical dependence involves adaptations at interacting mu and delta receptor populations, whereas tolerance to respiratory depression reflects actions of independent mu and delta receptor populations. These findings suggest that delta antagonists may have potential clinical application for decreasing the rapid development of tolerance to opiate-induced analgesia, while allowing for the development of protective tolerance to respiratory depression. There is increasing evidence of interaction between mu and delta opiate receptors (see Traynor and Elliot, 1993 for review). These receptors can coexist on the same neuron, as proposed for receptor populations in the neostriatum Stimulation of delta opiate receptors modulates mu-based antinociception. Two populations of delta receptors (delta 1 and delta 2 ) have been postulated on the basis of pharmacologic evidence There is also evidence that delta receptor activation contributes to the development of morphine-induced tolerance and physical dependence. Coadministration of the delta-2 antagonist 5Ј-NTII with either 100 mg/kg of morphine or morphine pellets over 3 days prevented the normal development of tolerance and dependence in mice, whereas the delta-1-specific antagonist DALCE did not prevent the development of physical dependence in mic
