Tolerance to opiate-induced depression of respiratory rate was studied in unanesthetized mice following chronic treatment with morphine or etorphine. Mice implanted subcutaneously (s.c.) with morphine pellets showed development of tolerance to morphine administered both s.c. and intracerebroventricularly (i.c.v.) and to s.c. etorphine and heroin. However, no cross-tolerance to i.c.v. etorphine or heroin was observed. In contrast, mice implanted with etorphine pellets demonstrated development of tolerance to all 3 agents given either s.c. or i.c.v. These findings on development of tolerance to opiate-induced respiratory depression differ from our previous studies measuring analgesia in which mice tolerant to s.c. morphine did not demonstrate development of tolerance to s.c. etorphine or heroin (unidirectional non-cross-tolerance). To investigate a possible mechanism for this difference in development of tolerance, apparent pA2 values for respiratory rate depression were determined for s.c. morphine-naloxone and etorphine-naloxone. The apparent pA2 values for these two opiates were similar, in contrast to the dissimilar apparent pA2 values previously found when analgesia was measured. The apparent pA2 values demonstrated differences between the respiratory depressant and analgesic effects of these opiates, but there was no obvious relationship between apparent pA2 values and the absence of unidirectional non-cross-tolerance observed for respiratory depression.