title: Differential disappearance of tolerance to thermal, hormonal and locomotor effects of morphine in the male rat.
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 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.
authors.affiliation: Department of Pharmacology and Toxicology, University of Helsinki, Finland.
authors.forename: P
authors.initials: P
authors.lastname: Rauhala
authors.forename: J J
authors.initials: JJ
authors.lastname: Idänpään-Heikkilä
authors.forename: R K
authors.initials: RK
authors.lastname: Tuominen
authors.forename: P T
authors.initials: PT
authors.lastname: Männistö
mesh_terms: D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D004361:Drug Tolerance; D013006:Growth Hormone / Q000378:metabolism*; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects*; D009294:Narcotics / Q000494:pharmacology*; D011388:Prolactin / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017450:Receptors, Opioid, mu / Q000502:physiology; D013997:Time Factors
chemical_list: D009294:Narcotics; D017450:Receptors, Opioid, mu; D009020:Morphine; D011388:Prolactin; D013006:Growth Hormone