Differential development of acute tolerance to analgesia, respiratory depression, gastrointestinal transit and hormone release in a morphine infusion model

To determine whether the differences in development of acute tolerance to several morphine actions correlate with the mu receptor subtype mediating them, we have examined the appearance of acute tolerance to analgesia, respiratory depression, gastrointestinal transit, and hormone release in an intravenous morphine infusion model. Analgesia, a naloxonazine-sensitive mu₁ action, peaked at 2 hr after initiation of the infusions. The log dose-response relationship of the infusion rate to peak tailflick latency was linear from 10 to 50 μg/kg/min. By 8 hr, the tailflick latencies declined nearly to baseline levels, implying the rapid development of tolerance. Tolerance to morphine-induced prolactin release, another mu₁ action, also developed rapidly over 8 hr. In contrast, two mu₂ actions, respiratory depression measured with arterial blood gas determinations and gastrointestinal transit, showed no significant tolerance over a similar 8 hr infusion. We also observed no tolerance to morphine-induced growth hormone release, a non-mu₁ action, over the same period. Thus, these results demonstrate that mu₁ actions develop tolerance in an infusion model far more rapidly than a number of naloxonazine-insensitive (non-mu₁) ones and may help explain differences in the rate of tolerance development to morphine actions.