, Volume 96, Issue 3, pp 343–352 | Cite as

Comparison of the behavioural effects induced by administration in rat nucleus accumbens or nucleus caudatus of selective μ and δ opioid peptides or kelatorphan an inhibitor of enkephalin-degrading-enzymes

  • Valérie Dauge
  • Paul Rossignol
  • Bernard P. Roques
Original Investigations


The effects of selective agonists for δ opioid receptors: [D-Thr2, Leu5]-enkephalyl-Thr6 (DTLET) and μ receptors: [D-Ala2, MePhe4, Gly-ol5]-enkephalin (DAGO) and of (R)-3-(N-hydroxyl-carboxamido-2-benzylpropanoyl)-L-alanine (kelatorphan), a complete inhibitor of enkephalin degrading enzymes, on the motor activity of rats was examined after their local administration into the nucleus accumbens (NA) or nucleus caudatus (NC). In both structures DTLET dose dependently enhanced locomotor activity as measured in the open-field test. This strong effect was reversed by the selective δ antagonist: ICI 174,864. Contrastingly, DAGO induced hypoactivity followed by hyperactivity 150 min later. This biphasic effect was blocked by systemic injection of naloxone, but not by ICI 174,864. The physiological relevance of these effects was ascertained by the naloxone-reversible stimulatory responses induced by kelatorphan, supporting a role for endogenous enkephalins in the control of behavior through δ receptor stimulation.

Key words

μ, δ opioid receptors Inhibition of enkephalin catabolism Nucleus accumbens Nucleus caudatus Motor behavior Kelatorphan DAGO DTLET Rat 


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  1. Babbini M, Davis WM (1972) Time dose relationships for locomotor activity effects of morphine after acute or repeated treatment. Br J Pharmacol 46:213–224PubMedGoogle Scholar
  2. Brady LS, Holtzman SG (1981) Effects of intraventricular morphine and enkephalins on locomotor activity in non-dependent, morphine-dependent and post-dependent rats. J Pharmacol Exp Ther 218:613–620Google Scholar
  3. Broekkamp CLE, Phillips AG, Cools AT (1979) Stimulant effects of enkephalin microinjection into the dopaminergic A10 area. Nature 278:560–562Google Scholar
  4. Browne RG, Segal DS (1978) β-endorphin and opiate-induced immobility: behavioral caracterization and tolerance development. In: Van Ree JM, Terenius L (eds) Characteristics and functions of opioids. Elsevier/North-Holland Biomedical Press, Amsterdam, pp 413–414Google Scholar
  5. Buxbaum DM, Yarborough GG, Carter ME (1973) Biogenic amines and narcotic effects. I-Modification of morphine-induced analgesia and motor activity after activation of cerebral amine levels. J Pharmacol Exp Ther 185:317–327Google Scholar
  6. Costall B, Fortune DH, Naylor RJ (1978) The induction of catalepsy and hyperactivity by morphine administered directly into the nucleus accumbens of rats. Eur J Pharmacol 49:49–64Google Scholar
  7. Cotton R, Giles MG, Miller L, Show JS, Timms D (1984) ICI 174,864: a highly selective antagonist for the opioid δ receptor. Eur J Pharmacol 97:331–332Google Scholar
  8. Cowan AC, Rance MJ, Blackburn TP (1986) In vivo studies on delta opioid receptors. In: Holaday JW, Law PY, Herz A (eds) Progress in opioid research INRC. NIDA Res Monogr 75, pp 473–476Google Scholar
  9. Crawley JN, Hommer DW, Skirboll LR (1984) Behavioral and neurophysiological evidence for a facilitatory interaction between co-existing transmitters: cholecystokinin and dopamine. Neurochem Int 6:755–760Google Scholar
  10. Domino EF, Vasko MR, Wilson AE (1976) Mixed depressant and stimulant actions of morphine and their relationship to brain acetylcholine. Life Sci 18:361–376Google Scholar
  11. Esposito RU, Kornetsky C (1978) Opioids and rewarding brain stimulation. Neurosci Biobehav Rev 2:115–122Google Scholar
  12. Fournié-Zaluski MC, Chaillet P, Bouboutou R, Coulaud A, Chérot P, Waksman G, Costentin J, Roques BP (1984) Analgesic effects of kelatorphan, a new highly potent inhibitor of multiple enkephalin degrading enzymes. Eur J Pharmacol 102:525–528Google Scholar
  13. Geula C, Asdourian D (1985) Asymetric behavior induced by enkephalinergic agents in the basal ganglia. Pharmacol Biochem Behav 23:207–213Google Scholar
  14. Handa BK, Lane AC, Lord JAH, Morgan BA, Rance MJ, Smith CFC (1981) Analogues of beta-LPH 61–64 possessing selective agonists of mu-opiate receptors. Eur J Pharmacol 70:531–540Google Scholar
  15. Havemann U, Kuschinsky K (1985) Locomotor activity of rats after injection of various opioids into the nucleus accumbens and the septum medial. Naunyn Schmiedeberg's Arch Pharmacol 331:175–180Google Scholar
  16. Herkenham M, Pert CB (1980) In vitro autoradiography of opiate receptors in rat brain suggests loci of “opiatergic” pathways. Proc Natl Acad Sci USA 77:5532–5536Google Scholar
  17. Iversen SD, Iversen LL (1981) Drugs affecting mood: antidepressants and opiates. In: Iversen SD, Iversen LL (eds) Behavioral Pharmacology (2nd edn). Oxford University Press, Oxford, pp 194–230Google Scholar
  18. Joyce EM, Koob GF, Strecker R, Iversen SD, Bloom FE (1981) The bahavioural effects of enkephalin analogues injected into the ventral tegmental area and globus pallidus. Brain Res 221:359–370Google Scholar
  19. Kalivas PW, Bronson M (1985) Mesolimbic dopamine lesions produce an augmented behavioral response of enkephalin. Neuropharmacology 24:931–936Google Scholar
  20. Kalivas PW, Miller JS (1984) Neurotensin neurons in the ventral tegmental area project to the medial nucleus accumbens. Brain Res 300:157–160Google Scholar
  21. Kalivas PW, Richardson-Carlson R (1986) Endogenous enkephalin modulation of dopamine neurons in ventral tegmental area. Am J Physiol 251:R243Google Scholar
  22. Kalivas PW, Nemeroff CB, Prange AJ Jr (1982) Neuroanatomical sites of action of neurotensine. Ann NY Acad Sci 400:307–318Google Scholar
  23. Kalivas PW, Widerlöv E, Stanley D, Breese G, Prange AJ Jr (1983) Enkephalin action on the mesolimbic system. A dopamine-dependent and a dopamine-independent increase in locomotor activity. J Pharmacol Exp Ther 227:229–237Google Scholar
  24. Locke KW, Holtzman SG (1986) Behavioral effects of opioid peptides selective for mu or delta receptors. I-Morphine like discriminative stimulus effects. J Pharmacol Exp Ther 238:990–995Google Scholar
  25. Lord JAH, Waterfield AA, Hughes J, Kosterlitz HW (1977) Endogenous opioid peptides: mutliple agonists and receptors. Nature 267:495–499Google Scholar
  26. Martin WR (1983) Pharmacology of opioids. Pharmacol Rev 35:283Google Scholar
  27. Oka T, Hosoya E (1976) Effects of humoral modulators and naloxone on morphine induced changes in the spontaneous locomotor activity of the rat. Psychopharmacology 47:243–248Google Scholar
  28. Paterson SJ, Robson LE, Kosterlitz HW (1984) Opioid receptors. In: Udenfriend S, Meienhofer T (eds) The peptides. Analysis, synthesis, biology, vol 6. Academic Press, New York London, pp 147–188Google Scholar
  29. Paxinos G, Watson C (1982) The rat brain. Academic Press, New YorkGoogle Scholar
  30. Pert A, Sivit C (1977) Neuroanatomical focus for morphine and enkephalin-induced hypermotility. Nature 265:645–647Google Scholar
  31. Quirion R, Zajac JM, Morgat JL, Roques BP (1983) Autoradiographic distribution of mu and delta opiate receptors in rat brain using highly selective ligands. Life Sci 33:227–230Google Scholar
  32. Roques BP (1986) Pharmacologie des différentes classes de récepteurs opioides cérébraux. Ann Endocrinol (Paris) 47:88–96Google Scholar
  33. Roques BP, Fournié-Zaluski MC, Soroca E, Lecomte JM, Malfroy B, Llorens C, Schwartz JC (1980) The enkephalinase inhibitor thiorphan shows antinociceptive activity in mice. Nature 288:286–288Google Scholar
  34. Roques BP, Daugé V, Gacel G, Fournié-Zaluski MC (1985) Selective agonists and antagonists of delta opioid receptors and inhibitors of enkephalins metabolism. Potential use in treatment of mental illness. Biol Psychiatry 7:287–289Google Scholar
  35. Segal DS, Browne RG, Arnsten A, Derrington DC, Bloom FE, Davis AV, Guillemin R, Ling N (1979) Characterization of β-endorphin induced behavioral activation and immobilization. In: Usdin E, Bunney WE, Kline NS (eds) Endorphins in mental health research. Oxford University Press, New York, pp 307–324Google Scholar
  36. Stein L, Belluzi JD (1978) Brain endorphins and sense of well-being: A psychobiological hypothesis. In: Costa E, Trabucchi (eds) Advances in biochemical pharmacology, vol. 18. Raven Press, New York, pp 299–311Google Scholar
  37. Stinus L (1982) Interaction entre systèmes peptidergiques opioides et neurones dopaminergiques mésolimbiques: analyse comportementale. Actualités de Chimie Thérapeutique, 2ème série, Technique et Documentation Lavoisier, pp 275–284Google Scholar
  38. Stinus L, Nadaud D, Jauregui J, Kelley AE (1986) Chronic treatment with five different neuroleptics elicits behavioral supersensitivity to opiate infusion into the nucleus accumbens. Biol Psychiatry 21:34–48Google Scholar
  39. Tortella FC, Moreton JE, Khazan N (1978) Electroencephalographic and behavioral effects of D-Ala2-methionine-enkephalinamide and morphine in the rat. J Pharmacol Exp Ther 206:636–643Google Scholar
  40. Turner AJ, Matsas R, Kenny AJ (1985) Are there neuropeptide specific peptidases? Biochem Pharmacol 34:1347–1356Google Scholar
  41. Van Ree JM, Gaffori O, De Wied D (1983) In rats, the behavioral profile of CCK8 related peptides ressembles that of antipsychotic agents. Eur J Pharmacol 93:63–78Google Scholar
  42. Waksman G, Hamel E, Fournié-Zaluski MC, Roques BP (1986) Autoradiographic comparison of the distribution of the neutral endopeptidase “enkephalinase” and of μ and δ opioid receptors in rat brain. Proc Natl Acad Sci USA 83:1523–1527Google Scholar
  43. Walker JM, Berntson GG, Dandman CA, Coy DH, Schally AV, Kastin AJ (1977) An analog of enkephalin having prolonged opiate-like effects in vivo. Science 196:85–87Google Scholar
  44. Walker JM, Berntson GG, Paulucci TS, Champney TC (1980) Blockade of endogenous opiates reduces activity in the rat. Pharmacol Biochem Behav 14:113–116Google Scholar
  45. Winkler M, Havemann U, Kuschinsky K (1982) Unilateral injection of morphine into the nucleus accumbens induces akinesia and catalepsy but no spontaneous muscular rigidity in rats. Naunyn Schmiedeberg's Arch Pharmacol 318:143–147Google Scholar
  46. Zajac JM, Gacel G, Petit F, Dodey P, Rossignol P, Roques BP (1983) Deltakephalin, Tyr-D-Thr-Gly-Phe-Leu-Thr: a new highly potent and fully specific agonist for opiate delta receptors. Biochem Biophys Res Commun 111:390–397Google Scholar

Copyright information

© Springer-Verlag 1988

Authors and Affiliations

  • Valérie Dauge
    • 1
  • Paul Rossignol
    • 1
  • Bernard P. Roques
    • 2
  1. 1.Laboratoire de PharmacologieUER des Sciences Pharmaceutiques et BiologiquesParisFrance
  2. 2.Département de Chimie OrganiqueU 266 INSERM, UA 498 CNRS, UER des Sciences Pharmaceutiques et BiologiquesParisFrance

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