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Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the µ-opioid-receptor gene

Nature volume 383, pages 819823 (31 October 1996) | Download Citation

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Abstract

DESPITE tremendous efforts in the search for safe, efficacious and non-addictive opioids for pain treatment, morphine remains the most valuable painkiller in contemporary medicine. Opioids exert their pharmacological actions through three opioid-receptor classes1,2, µ, δ and κ, whose genes have been cloned3. Genetic approaches are now available to delineate the contribution of each receptor in opioid function in vivo. Here we disrupt the μ-opioid-receptor gene in mice by homologous recombination and find that there are no overt behavioural abnormalities or major compensatory changes within the opioid system in these animals. Investigation of the behavioural effects of morphine reveals that a lack of μ receptors abolishes the analgesic effect of morphine, as well as place-preference activity and physical dependence. We observed no behavioural responses related to δ- or κ-receptor activation with morphine, although these receptors are present and bind opioid ligands. We conclude that the µ-opioid-receptor gene product is the molecular target of morphine in vivo and that it is a mandatory component of the opioid system for morphine action.

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References

  1. 1.

    Proc. Natl Acad. Sci. USA 90, 5391–5393 (1993).

  2. 2.

    & Mol. Pharmacol. 36, 265–272 (1989).

  3. 3.

    Cell. Mol. Neurobiol. 15, 615–635 (1995).

  4. 4.

    Clin. Pharmacol. 16, 1–18 (1993).

  5. 5.

    Nature 298, 221–222 (1982).

  6. 6.

    in Handbook of Experimental Pharmacology Opioids II (ed. Herz, A.) Vol. 104, 393–414 (Springer, Berlin, 1993).

  7. 7.

    , , , & Pharmacol. Rev. 45, 87–146 (1993).

  8. 8.

    , , & J. Pharmacol. Exp. Ther. 257, 767–773 (1991).

  9. 9.

    Br. Med. Bull. 47, 690–702 (1991).

  10. 10.

    , , , & J. Med. Chem. 31, 374–383 (1988).

  11. 11.

    & Trends Pharmacol. Sci. 13, 185–193 (1992).

  12. 12.

    Trends Biochem. Sci. 13, 177–184 (1992).

  13. 13.

    & Pharmacol. Biochem. Behav. 11, 231–233 (1979).

  14. 14.

    , & Brain Res. 436, 234–239 (1987).

  15. 15.

    , , , & Brain Res. 548, 100–110 (1991).

  16. 16.

    , & Neuropharmacology 31, 1231–1241 (1992).

  17. 17.

    J. Pharmacol. Exp. Ther. 216, 12–18 (1981).

  18. 18.

    , , , & J. Pharmacol. Exp. Ther. 246, 950–955 (1988).

  19. 19.

    & Trends Pharmacol. Sci. 14, 84–85 (1993).

  20. 20.

    , , & Proc. Natl Acad. Sci USA 89, 12048–12052 (1992).

  21. 21.

    et al. Nucleic Acids Res. 19, 5755–5761 (1991).

  22. 22.

    , , , & Cell 88, 1105–1119 (1991).

  23. 23.

    et al. Biochem. Pharmacol. 37, 3843–3851 (1988).

  24. 24.

    et al. J. Pharmacol. Exp. Ther. 275, 1595–1607 (1995).

  25. 25.

    , & in Gene probes 2: A Practical Approach (eds Names, B. D. & Higgins, S.) 183–210 (Oxford Univ. Press, 1995).

  26. 26.

    et al. Eur. J. Pharmacol. 192, 253–262 (1991).

  27. 27.

    , , & Psychopharmacology 123, 119–126 (1996).

  28. 28.

    et al. Science 273, 657–650 (1996).

  29. 29.

    , , , & J. Biol. Chem. 252, 2039–2045 (1977).

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Affiliations

  1. UPR 9050 CNRS, ESBS Université Louis Pasteur, 67400 Illkirch, Strasbourg, France

    • Hans W. D. Matthes
    • , Frédéric Simonin
    • , Katia Befort
    •  & Brigitte L. Kieffer
  2. Département de Pharmacochimie Moléculaire et Structurale, INSERM U266. URA D1500 CNRS, Université René Descartes, 75270 Paris, France

    • Rafael Maldonado
    • , Olga Valverde
    •  & Bernard P. Roques
  3. Receptors and Cellular Regulation Research Group, School of Biological Sciences, University of Surrey, Guildford, Surrey GU2 5XH, UK

    • Susan Slowe
    •  & Ian Kitchen
  4. Institut de Génétique et Biologie Moléculaire et Cellulaire, BP 163, 67404 Illkirch, Strasbourg, France

    • Andrée Dierich
    • , Marianne Le Meur
    •  & Pascal Dollé
  5. Unité de Recherches INSERM U-99, Hôpital Henri Mondor, 94010 Créteil, France

    • Eleni Tzavara
    •  & Jacques Hanoune

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https://doi.org/10.1038/383819a0

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