Evidence for the dissociation of morphine analgesia, tolerance and dependence.

A single large dose of morphine produced profound analgesia accompanied by the development of tolerance and physical dependence. The tolerance developed acutely within 24 h and was further intensified, reaching a peak on the 5th day, then gradually disappeared. Partial or complete masking of morphine analgesia by naloxone inhibited the development of the acute, but could not prevent the development of the delayed, tolerance. These results suggest there are two kinds of tolerance and that the analgesic effect is separate from tolerance. Similarly, treatment with morphine produced physical dependence which was precipitated by naloxone. Unlike tolerance, dependence did not develop when morphine analgesia was completely masked by naloxone. The findings provide for the dissociation or morphine analgesia, tolerance and dependence.