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.