Differential disappearance of tolerance to thermal, hormonal and locomotor effects of morphine in the male rat.

Development and disappearance of tolerance to various effects of morphine was studied by comparing the effect of acute morphine at 6 h and at 92 h after cessation of a 5-day regimen with increasing doses of morphine. After the 6-h lag time, tolerance manifested to the thermal, locomotor depressant and hormonal (stimulation of growth hormone and prolactin secretion) effects of morphine. The hypokinetic effect of morphine was replaced by a hyperkinetic effect and increased locomotor activity was evident following the challenge dose of morphine. Tolerance disappeared in different ways during the 92-h lag time. Tolerance persisted (hypothermic and hypokinetic effect) or disappeared considerably (prolactin secretion) during the 92-h withdrawal period. Tolerance to some effects also faded completely, and in contrast, even sensitization to various effects of morphine (growth hormone secretion, hyperthermic effect) could be seen after the 92-h withdrawal period. In addition, the original hypokinetic effect of morphine was replaced by a hyperkinetic effect (i.e., enhanced locomotor activity), which was even stronger after the 92-h lag time. The observed dissociation, which has not been seen to such an extent before, may be due to the differential modulation of the subtypes of mu-opioid receptors or differences in the adaptive mechanisms, e.g. conditioning, in various brain areas. Faster recovery of tolerance to an inhibitory than to a stimulatory effect of morphine during the withdrawal period may partially explain the sensitization to some effects of morphine.