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.