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

• Published in: European journal of pharmacology Vol. 285; no. 1; pp. 69 - 77
• Main Authors: Rauhala, Pekka, Idänpään-Heikkilä, Juhana J., Tuominen, Raimo K., Männistö, Pekka T.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 04-10-1995; Elsevier
• Subjects: Analgesics; Animals; Biological and medical sciences; Body Temperature - drug effects; Drug Tolerance; Growth hormone; Growth Hormone - metabolism; Locomotor activity; Male; Medical sciences; Morphine; Morphine - pharmacology; Motor Activity - drug effects; Narcotics - pharmacology; Neuropharmacology; Pharmacology. Drug treatments; Prolactin; Prolactin - metabolism; Rats; Rats, Wistar; Receptors, Opioid, mu - physiology; Rectal temperature; Thyrotropin; Time Factors; Tolerance; Prolactin; Rectal temperature; Tolerance; Morphine; Thyrotropin; Growth hormone; Locomotor activity; Locomotion; Vertebrata; Mammalia; Rat; Animal; Body temperature; Rodentia; Hormonal regulation; Opiates; Narcotic analgesic
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/0014-2999(95)00392-X

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.