Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1

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

    ADS  Article  Google Scholar 

  2. 2

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

    CAS  PubMed  Google Scholar 

  3. 3

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

    CAS  Article  Google Scholar 

  4. 4

    Pasternak, G. W. Clin. Pharmacol. 16, 1–18 (1993).

    CAS  Google Scholar 

  5. 5

    Rossier, J. Nature 298, 221–222 (1982).

    ADS  CAS  Article  Google Scholar 

  6. 6

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

    Google Scholar 

  7. 7

    Roques, B. P., Noble, F., Daugé, V., Fournié-Zaluski, M.-C. & Beaumont, A. Pharmacol. Rev. 45, 87–146 (1993).

    CAS  PubMed  Google Scholar 

  8. 8

    Baamonde, A., Daugé, V., Gacel, C. & Roques, B. P. J. Pharmacol. Exp. Ther. 257, 767–773 (1991).

    CAS  PubMed  Google Scholar 

  9. 9

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

    CAS  Article  Google Scholar 

  10. 10

    Gacel, G., Zajac, J. M., Delay-Goyet, P., Dauge, V. & Roques, B. P. J. Med. Chem. 31, 374–383 (1988).

    CAS  Article  Google Scholar 

  11. 11

    Di Chiara, G. & North, A. Trends Pharmacol. Sci. 13, 185–193 (1992).

    CAS  Article  Google Scholar 

  12. 12

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

    CAS  Google Scholar 

  13. 13

    Katz, R. J. & Gormezano, G. Pharmacol. Biochem. Behav. 11, 231–233 (1979).

    CAS  Article  Google Scholar 

  14. 14

    Shippenberg, T. S., Bals-Kubik, R. & Herz, A. Brain Res. 436, 234–239 (1987).

    CAS  Article  Google Scholar 

  15. 15

    Terwillinger, R. Z., Beitner-Johnson, D., Sevarino, K. A., Crain, S. M. & Nestler, E. J. Brain Res. 548, 100–110 (1991).

    Article  Google Scholar 

  16. 16

    Maldonado, R., Negus, S. & Koob, G. F. Neuropharmacology 31, 1231–1241 (1992).

    CAS  Article  Google Scholar 

  17. 17

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

    CAS  PubMed  Google Scholar 

  18. 18

    Cowan, A., Zhu, X. Z., Mosberg, H. I., Omnaas, J. R. & Porreca, F. J. Pharmacol. Exp. Ther. 246, 950–955 (1988).

    CAS  PubMed  Google Scholar 

  19. 19

    Traynor, J. R. & Elliot, J. Trends Pharmacol. Sci. 14, 84–85 (1993).

    CAS  Article  Google Scholar 

  20. 20

    Kieffer, B. L., Befort, K., Gavéeriaux-Ruff, R. C. & Hirth, C. G. Proc. Natl Acad. Sci USA 89, 12048–12052 (1992).

    ADS  CAS  Article  Google Scholar 

  21. 21

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

    CAS  Article  Google Scholar 

  22. 22

    Lufkin, T., Dierich, A., LeMeur, M., Mark, M. & Chambon, P. Cell 88, 1105–1119 (1991).

    Article  Google Scholar 

  23. 23

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

    CAS  Article  Google Scholar 

  24. 24

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

    Google Scholar 

  25. 25

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

    Google Scholar 

  26. 26

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

    CAS  Article  Google Scholar 

  27. 27

    Valverde, O., Fournier-Zaluski, M.-C., Roques, B. P. & Maldonado, R. Psychopharmacology 123, 119–126 (1996).

    CAS  Article  Google Scholar 

  28. 28

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

    ADS  CAS  Article  Google Scholar 

  29. 29

    Hanoune, J., Stengel, D., Lacombe, M. L., Fledmann, G. & Coudrier, E. J. Biol. Chem. 252, 2039–2045 (1977).

    CAS  PubMed  Google Scholar 

Download references

Author information



Rights and permissions

Reprints and Permissions

About this article

Cite this article

Matthes, H., Maldonado, R., Simonin, F. et al. Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the µ-opioid-receptor gene. Nature 383, 819–823 (1996).

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing