Abstract
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 μ-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.
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