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 morph ine was studied by comparing the effect of acute morphine at 6 h and a t 92 h after cessation of a 5-day regimen with increasing doses of mor phine. After the 6-h lag time, tolerance manifested to the thermal, lo comotor depressant and hormonal (stimulation of growth hormone and pro lactin secretion) effects of morphine. The hypokinetic effect of morph ine was replaced by a hyperkinetic effect and increased locomotor acti vity was evident following the challenge dose of morphine. Tolerance d isappeared in different ways during the 92-h lag time. Tolerance persi sted (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 sensitizatio n to various effects of morphine (growth hormone secretion, hypertherm ic effect) could be seen after the 92-h withdrawal period. In addition , the original hypokinetic effect of morphine was replaced by a hyperk inetic effect (i.e., enhanced locomotor activity), which was even stro nger 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 mo dulation 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 o f morphine during the withdrawal period may partially explain the sens itization to some effects of morphine.