, Volume 4, Issue 4, pp 247–260

Tolerance to and physical dependence on morphine in rats

  • W. R. Martin
  • A. Wikler
  • C. G. Eades
  • F. T. Pescor
Original Investigations


The effects of large doses of morphine in nontolerant and tolerant rats as well as the effects of abruptly withdrawing morphine in rats experimentally addicted to large doses of morphine have been studied on body weight, temperature, metabolic rate, respiratory rate, water consumption and various forms of motor activity and behavior. In confirmation of many early reports, tolerance develops to certain depressant actions of large doses of morphine and the effects of morphine in the tolerant rat are primarily excitatory, consisting of an increase in body temperature, metabolic rate and motor activity. The abstinence syndrome of rats addicted to large doses of morphine seems to have two phases: (1) An early phase, which has been called “primary abstinence” consists of weight loss, an increased number of “wet dog” shakes, increased activity, and a fall in body temperature and metabolic rate. The primary abstinence syndrome becomes clearly manifest within 8 to 16 hours following the last dose of morphine and persists for approximately 72 hours. (2) The secondary abstinence syndrome emerges thereafter and consists of a rapid gain in body weight, elevated body temperature and metabolic rate and an increase in water consumption. The secondary abstinence syndrome is protracted and small differences have been seen between addicted and control animals as long as four to six months after withdrawal of morphine.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Beach, H. D.: Morphine addiction in rats. Canad. J. Psychol. 11, 104–112 (1957).PubMedGoogle Scholar
  2. Davis, W. M., and J. R. Nichols: Physical dependence and sustained opiatedirected behavior in the rat. A preliminary report. Psychopharmacologia (Berl.) 3, 139–143 (1962).Google Scholar
  3. Fichtenberg, D. G.: Study of experimental habituation to morphine. Bull. Narcot. 3, 19–42 (1951).Google Scholar
  4. George, R., and E. L. Way: Studies on the mechanism of pituitary-adrenal activation by morphine. Brit. J. Pharmacol. 10, 260–264 (1955).Google Scholar
  5. Gunne, Lars-M.: The temperature response in rats during acute and chronic morphine administration. A study of morphine tolerance. Arch. int. Pharmacodyn. 129, 416–428 (1960).PubMedGoogle Scholar
  6. Hanna, C.: A demonstration, of morphine tolerance and physical dependence in the rat. Arch. int. Pharmacodyn. 124, 326–329 (1960).PubMedGoogle Scholar
  7. Herrmann, J. B.: The pyretic action on rats of small doses of morphine. J. Pharmacol. exp. Ther. 76, 309–315 (1942).Google Scholar
  8. Himmelsbach, C. K.: Clinical studies of drug addiction: Physical dependence, withdrawal and recovery. Arch. intern. Med. 69, 766–772 (1942).Google Scholar
  9. —: With reference to physical dependence. Fed. Proc. 2, 201–203 (1943).Google Scholar
  10. —, G. H. Gerlach and E. J. Stanton: A method for testing addiction, tolerance and abstinence in the rat. J. Pharmacol. exp. Ther. 53, 179–188 (1935).Google Scholar
  11. Holtkamp, D. E., S. Ochs, C. C. Pfeiffer and A. E. Heming: Determination of the oxygen consumption of groups of rats. Endocrinology 56, 93–104 (1955).PubMedGoogle Scholar
  12. Hosoya, E.: Some withdrawal symptoms of rats to morphine. Pharmacologist 1, 77 (1959).Google Scholar
  13. Joël, E., u. A. Ettinger: Zur Pathologie der Gewöhnung. III. Mitteilung: Experimentelle Studien über Morphingewöhnung. Naunyn-Schmiedeberg's Arch. exp. Path. Pharmak. 115, 334–350 (1926).Google Scholar
  14. Kaymakcalan, S., and L. A. Woods: Nalorphine-induced “abstinence syndrome” in morphine tolerant albino rat. J. Pharmacol. exp. Ther. 117, 112–116 (1956).PubMedGoogle Scholar
  15. Lewis, J. R.: The development of tolerance in rats to some new synthetic analgesics. J. Pharmacol. exp. Ther. 96, 31–37 (1949).Google Scholar
  16. Maynert, E. W., and G. I. Klingman: Tolerance to morphine. I. Effects of catecholamines in the brain and adrenal glands. J. Pharmacol. exp. Ther. 135, 285–298 (1962).Google Scholar
  17. Nichols, J. R., C. P. Headlee and H. W. Coppock: Drug addiction. I. Addiction by escape training. J. Amer. pharm. Ass. 45, 788–791 (1956).Google Scholar
  18. Shideman, F. E., and M. H. Seevers: Effects of morphine and its derivatives on intermediary metabolism. II. The influence of thiamin deficiency on the respiration of skeletal muscle and cocarboxylase content of tissues of normal and chronically morphinized rats. J. Pharmacol. exp. Ther. 71, 383–393 (1941).Google Scholar
  19. Sloan, Jewell W., J. W. Brooks, Anna J. Eisenman and W. R. Martin: Comparison of the effects of single doses of morphine and thebaine on body temperature activity and brain and heart levels of catecholamines and serotonin. Psychopharmacologia (Berl.) 3, 291–301 (1962).Google Scholar
  20. Tanabe, T., and E. J. Cafruny: Adrenal hypertrophy in rats treated chronically with morphine. J. Pharmacol. exp. Ther. 122, 148–153 (1958).PubMedGoogle Scholar
  21. Wikler, A., P. C. Green, H. D. Smith and F. T. Pescor: Use of a benzimidazole derivative with potent morphine-like properties orally as a presumptive reinforcer in conditioning of drug seeking behavior in rats. Fed. Proc. 19, 22 (1960); also presented at the 21st meeting of Committee on on Drug Addiction and Narcotics, Natl. Res. Council, Natl. Acad. Sci., Philadelphia, 11–12 January 1960.Google Scholar
  22. - W. R. Martin, F. T. Pescor and C. G. Eades: Factors regulating oral consumption of an opioid (etonitazene) in aqueous solution by morphine-addicted rats. (In preparation.)Google Scholar

Copyright information

© Springer-Verlag 1963

Authors and Affiliations

  • W. R. Martin
    • 1
  • A. Wikler
    • 1
  • C. G. Eades
    • 1
  • F. T. Pescor
    • 1
  1. 1.National Institute of Mental Health, Addiction Research CenterPublic Health Service HospitalLexingtonUSA

Personalised recommendations