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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Dickenson, A.H. Mechanisms of the analgesic action of opiates and opioids. Br. Med. Bull. 47, 690–702 ( 1991).
Koob, G.F. Drug of abuse: anatomy, pharmacology and function of reward pathways. Trends Pharmacol. Sci. 13, 177–184 (1992).
Wise, R.A. Neurobiology of addiction. Curr. Opin. Neurobiol. 6 , 243–251 (1996).
Naber, D. Opioids in the etiology and treatment of psychiatric disorders. in Handbook Exp Pharm: Opioids II (ed. Herz, A.) 781– 793 (Springer, Berlin, 1993).
Kieffer, B.L. Recent advances in molecular recognition and signal transduction of active peptides: receptors for opioid peptides. Cell. Mol. Neurobiol. 15, 615–635 ( 1995).
Matthes, H.W.D. 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).
Simonin, F. et al. Disruption of the κ-opioid receptor gene in mice enhances sensitivity to chemical visceral pain, impairs pharmacological actions of the selective κ-agonist U-50,488H and attenuates morphine withdrawal . EMBO J. 17, 886–897 (1998).
Rapaka, R.S. & Porreca, F. Development of δ opioid peptides as nonaddicting analgesics. Pharm. Res. 8, 1–8 (1991).
Dondio, G., Ronzoni, S. & Petrillo, P. Non-peptide δ opioid agonists and antagonists . Exp. Opin. Ther. Patents 7, 1075– 1098 (1997).
Zaki, P.A. et al. Opioid receptor types and subtypes: the δ receptor as a model. Annu. Rev. Pharmacol. Toxicol. 36, 379–401 (1996).
Zhu, Y. et al. Retention of supraspinal δ-like analgesia and loss of morphine tolerance in δ opioid receptor knockout mice. Neuron 24, 243–252 (1999).
Matthes, H.W.D. et al. Activity of the δ-opioid receptor is partially reduced while activity of the κ-receptor is maintained in mice lacking the μ-receptor . J. Neurosci. 18, 7285– 7295 (1998).
Pellow, S., Chopin, M.P., File, S.E. & Briley, M. Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J. Neurosci. Methods 14, 149–167 (1985).
Timpl, P. et al. Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1. Nature Genet. 19, 162–166 ( 1998).
König, M. et al. Pain responses, anxiety and aggression in mice deficient in pre-proenkephalin. Nature 383, 535– 538 (1996).
Calenco-Choukroun, G. et al. Opioid δ agonists and endogenous enkephalins induce different emotional reactivity than μ agonists after injection in the rat ventral tegmental area. Psychopharmacology 103, 493–502 (1991).
Asakawa, A. et al. Endomorphins have orexigenic and anxiolytic activities in mice. Neuroreport 9, 2265– 2267 (1998).
Porsolt, R.D., Bertin, A. & Jalfre, M. Behavioral despair in mice: a primary screening test for antidepressants. Arch. Int. Pharmacodyn. Ther. 229, 327–336 (1977).
Baamonde, A. et al. Antidepressant-type effects of endogenous enkephalins protected by systemic RB 101 are mediated by opioid δ and dopamine D1 receptor stimulation. Eur. J. Pharmacol. 216, 157–166 (1992).
Tejedor-Real, P. et al. Involvement of δ-opioid receptors in the effects induced by endogenous enkephalins on learned helplessness model. Eur. J. Pharmacol. 354, 1–7 ( 1998).
Kameyama, T., Nagasaka, M. & Yamada, K. Effect of antidepressant drugs on a quickly learned conditioned suppression response in mice. Neuropharmacology 24, 59–63 (1985).
Crestani, F. et al. Decreased GABAA-receptor clustering results in enhanced anxiety and a bias for threat cues. Nature Neurosci. 2, 833–839 (1999).
Rothman, R.B., Holaday, J.W. & Porreca, F. Allosteric coupling among opioid receptors: evidence for an opioid receptor complex. in Handbook of Experimental Pharmacology, Opioids I (ed. Herz, A.) 217–237 (Springer, Berlin, 1993).
Traynor, J.R. & Elliot, J. δ-opioid receptor subtypes and cross talk with μ-receptors. Trends Pharmacol. Sci. 14, 84–85 (1993).
Mansour, A., Fox, C.A., Akil, H. & Watson, S.J. Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications. Trends Neurosci. 18, 22–29 (1995).
Walsh, T.D. Antidepressants in chronic pain. Clin. Neuropharmacol. 6, 271–295 (1983).
Kieffer, B.L., Befort, K., Gaveriaux-Ruff, C. & Hirth, C.G. The δ-opioid receptor: isolation of a cDNA by expression cloning and pharmacological characterization. Proc. Natl Acad. Sci. USA 89, 12048–12052 (1992).
Lufkin, T. et al. Disruption of the Hox-1.6 homeobox gene results in defects in a region corresponding to its rostral domain of expression. Cell 88, 1105–1119 ( 1991).
Smadja, C. et al. Opposite role of CCKA and CCKB receptors in the modulation of endogenous enkephalin antidepressant-like effects. Psychopharmacology 120, 400–408 ( 1995).
Valverde, O., Fournié-Zaluski, M.C., Roques, B.P. & Maldonado, R. Eur. J. Pharmacol. 312, 15– 25 (1996).
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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