Mice deficient for δ- and μ-opioid receptors exhibit opposing alterations of emotional responses

Abstract

The role of the opioid system in controlling pain1, reward and addiction2,3 is well established, but its role in regulating other emotional responses is poorly documented in pharmacology4. The μ-, δ- and κ- opioid receptors (encoded by Oprm, Oprd1 and Oprk1, respectively) mediate the biological activity of opioids5. We have generated Oprd1-deficient mice and compared the behavioural responses of mice lacking Oprd1, Oprm (ref. 6) and Oprk1 (ref. 7) in several models of anxiety and depression. Our data show no detectable phenotype in Oprk1−/− mutants, suggesting that κ-receptors do not have a role in this aspect of opioid function; opposing phenotypes in Oprm−/− and Oprd1−/− mutants which contrasts with the classical notion of similar activities of μ- and δ-receptors; and consistent anxiogenic- and depressive-like responses in Oprd1−/− mice, indicating that δ-receptor activity contributes to improvement of mood states. We conclude that the Oprd1-encoded receptor, which has been proposed to be a promising target for the clinical management of pain8,9, should also be considered in the treatment of drug addiction and other mood-related disorders.

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Figure 1: Targeted disruption of Oprd1.
Figure 2: Anxiety-related behaviour.
Figure 3: Behavioural models of depression.

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Acknowledgements

We thank D. Metzger for the Neo cassette; F. Ruffenach for oligonucleotide synthesis; S. Vicaire for DNA sequencing; IGBMC for ES cell culture and microinjection services; J.P. Poirier and N. Schallon for animal care; V. Fraulob and P. Dollé for in situ hybridization; E. Borrelli for probes; A. Borsodi and G. Toth for [3H]Naltrindole; and P. Chambon, F. Pattus and J.C. Stoclet for their support. This work was funded by grants from the Mission Interministérielle de Lutte contre la Drogue et la Toxicomanie (B.L.K.), the Centre National de la Recherche Scientifique (B.L.K.), the Association de la Recherche pour le Cancer (B.L.K.), the European Commission (Biomed-2 98-2227, B.L.K. and R.M.), Dr. Esteve S. A. Laboratories (R.M.) and the Spanish Ministry of Health (FIS 99/0624, R.M.).

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Correspondence to Brigitte L. Kieffer.

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