Abstract
The role of the different opioid receptors was studied in rats trained to discriminate SC injections of 3.0 mg/kg morphine from saline by tests for generalization to graded doses of morphine and receptor-selective peptides administered into the lateral cerebral ventricle. Dose-dependent morphine-like stimulus effects were produced over a wide range of doses (0.001–30 μg), depending upon ligand and animal, by morphine, by themu-selective peptides DAGO[d-Ala2-NMePhe4-Gly(ol)-enkephalin] and FK33824[d-Ala2,NMePhe4-Met(O)5-(ol)-enkephalin], and by thedelta-selective peptide, DADL[d-Ala2,d-Leu5enkephalin]. The order of relative potency of these substances was: FK33824>DAGO>morphine>DADL. In contrast, DPLPE[d-Pen2,l-Pen5)enkephalin], which has much greaterdelta receptor selectivity than does DADL, and dynorphin A(1-13) (0.1–10 μg), akappa-receptor agonist, engendered choice responding appropriate for saline. When 1.0 μg DADL, a dose lacking morphine-like discriminative effects, was administered concurrently with SC morphine, the stimulus effects of morphine were potentiated. Concurrent administration of 10 μg dynorphin A(1-13) and morphine attenuated the stimulus effects of morphine inconsistently. These results support previous findings thatmu-opioid receptors are of primary importance in mediating the morphine-like discriminative effects of opioid peptides. They also suggest that morphine-like discriminative effects can be modulated by other types of opioid receptors.
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References
Browne RG, Fondren B (1978) β-Endorphin and the narcotic cue. In: Colpaert FC, Rosecrans JA (eds) Stimulus properties of drugs: ten years of progress. Elsevier/North Holland, Amsterdam Oxford New York, pp 137–147
Chang K-J, Cuatrecasas P (1979) Multiple opiate receptors: enkephalins and morphine bind to receptors different specificity. J Biol Chem 254:2610–2618
Chang K-J, Wei ET, Chang JK (1983) Potent morphiceptin analogs: Structure activity relationships and morphine-like activities. J Pharmacol Exp Ther 227:403–408
Chavkin C, James IF, Goldstein A (1982) Dynorphin is a specific endogenous ligand of the k-opioid receptor. Science 215:413–415
Chipken RE, Stewart JM, Morris DH, Crowley TJ (1978) Generalization of (D-ala2)-enkephalinamide but not of substance P to the morphine cue. Pharmacol Biochem Behav 9:129–132
Colpaert FC, Niemegeers CJE, Janssen PAJ, van Ree JM (1978) Narcotic cueing properties of intraventricularly administered sufentanil, fentanyl, morphine and met-enkephalin. Eur J Pharmacol 47:115–119
Corbett AD, Paterson SJ, McKnight AT, Magnan J, Kosterlitz HW (1982) Dynorphin(1-8) and dynorphin(1-9) are ligands for the kappa subtype of opiate receptor. Nature 299:79–81
D'Amato R, Holaday JW (1984) Multiple opioid receptors in endotoxic shock: evidence for involvement and μ-interactions in vivo. Proc Natl Acad Sci USA 81:2898–2901
Dray A, Nunan L, Wire W (1986) Centrally administered β-endorphin produces prolonged changes in δ-opioid ligand activity in vivo. Eur J Pharmacol 120:359–362
Friedman HJ, Jen M-F, Chang JK, Lee NM, Loh HH (1981) Dynorphin: a possible modulatory peptide on morphine or β-endorphin analgesia in mice. Eur J Pharmacol 69:357–360
Galligan JJ, Mosberg HI, Hurst R, Hruby VJ, Burks TF (1984) Cerebral delta opioid receptors mediate analgesia but not the intestinal motility effects of intracerebroventricularly administrered opioids. J Pharmacol Exp Ther 229:641–648
Garzon J, Jen M-F, Sanchez-Blazquez P, Lee NM (1982) Dynorphin(1-13), a long-lasting inhibitor of opiate receptor binding in vitro. Life Sci 31:1789–1792
Gilbert PE, Martin WR (1976) The effects of morphine- and nalorphine-like drugs in the non-dependent, morphine-dependent and cyclazocine-dependent chronic spinal dog. J Pharmacol Exp Ther 198:66–82
Goldstein A (1964) Biostatistics: An Introductory Text. MacMillan
Handa BK, Lane AC, Lord JAH, Morgan BA, Rance JM, Smith CFC (1981) Analogues of β-LPH61-64 possessing selective agonist activity at μ-opiate receptors. Eur J Pharmacol 70:531–540
Herling S, Woods JH (1981) Discriminative stimulus effects of narcotics: evidence for multiple receptor-mediated actions. Life Sci 28:1571–1584
Herman BH, Leslie F, Goldstein A (1980) Behavioral effects and in vivo degradation of intraventricularly administered dynorphin-(1-13) andd-Ala2-dynorphin-(1-11) in rats. Life Sci 27:883–892
Holtzman SG (1982) Stimulus properties of opioids with mixed agonist and antagonist activity. Fed Proc 41:2328–2332
Holtzman SG (1983) Discriminative stimulus properties of opioid agonists and antagonists. In: Cooper SJ (ed) Theory in psychopharmacology, vol. 2. Academic Press, London, pp 1–45
James IF, Chavkin C, Goldstein A (1982) Preparation of brain membranes containing a single type of opioid receptor highly selective for dynorphin. Proc Natl Acad Sci USA 79:7570–7574
Lee NM, Landahl H (1986) Dynorphin: specific binding to opiate receptors. In: Brown RM, Clouet DH, Friedman DP (eds) Opiate receptor subtypes and brain function, National Institute on Drug Abuse Research Monograph 71, US Department of Health and Human Services, National Institute on Drug Abuse, DHHS publication number (ADM) 86-1462, US Government Printing Office, pp 19–27
Lee NM, Smith AP (1980) A protein lipid model of the opiate receptor. Life Sci 26:1459–1464
Lee NM, Smith AP (1984) Possible regulatory function of dynorphin and its clinical implications. TIPS 5:108–110
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 238:990–996
Lord JAH, Waterfield AA, Hughes J, Kosterlitz HW (1977) Endogenous opioid peptides: multiple agonists and receptors. Nature 267:495–499
Martin WR, Eades CG, Thompson JA, Huppler RE, Gilbert PE (1976) The effects of morphine- and nalorphine-like drugs in the nondependent and morphine-dependent chronic spinal dog. J Pharmacol Exp Ther 197:517–532
Mosberg HI, Hurst R, Hruby VJ, Gee K, Yamamura HI, Galligan JJ, Burks TF (1983) Bis-penicillamine enkephalins possess highly improved specificity towards delta opioid receptors. Proc Natl Acad Sci USA 80:5871–5874
Paxinos G, Watson C (1982) The rat brain in stereotaxic coordinates. Academic Press, Sydney
Roemer D, Buescher HH, Hill RC, Plexx J, Bauer W, Cordinaux F, Closse A, Hause D, Huguenin R (1977) A synthetic enkephalin analog with prolonged parenteral and oral analgesic activity. Nature 268:547–549
Rothman RB, Westfall TC (1982) Allosteric coupling between morphine and enkephalin receptors in vitro. Mol Pharmacol 21:548–557
Severs WB, Summy-Long J (1976) The role of angiotensin in thirst. Life Sci 17:1513–1526
Shannon HE, Holtzman SG (1976) Evaluation of the discriminative effects of morphine in the rat. J Pharmacol Exp Ther 198:54–65
Shannon HE, Holtzman SG (1977) Discriminative effects of morphine administered intracerebrally in the rat. Life Sci 21:585–594
Shearman GT, Herz A (1982)d-Ala2,d-Leu5-enkephalin generalizes to a discriminative stimulus produced by fentanyl but not ethylketocyclazocine. Pharmacol Biochem Behav 16:249–252
Shearman GT, Schulz R, Schiller PW, Herz A (1985) Generalization tests with intraventricularly applied pro-enkephalin β-derived peptides in rats trained to discriminate the opioid kappa receptor agonist ethylketocyclazocine. Psychopharmacology 85:440–443
Tulunay FC, Jen M-F, Chang JK, Loh HH, Lee NM (1981) Possible regulatory role of dynorphin on morphine- and β-endorphin-induced analgesia. J Pharmacol Exp Ther 219:296–298
van Ree JM, Smyth DG, Colpaert FC (1979) Dependence creating properties of lipotropin C-fragment (beta-endorphin): evidence for internal control of behavior. Life Sci 24:495–502
Vaught JL, Takemori AE (1979) Differential effects of leucine and methionine enkephalin on morphine-induced analgesia, acute tolerance and dependence. J Pharmacol Exp Ther 208:86–90
Vaught JL, Rothman RB, Westfall TC (1982) Mu and delta receptors: their role in analgesia and in the differential effects of opioid peptides on analgesia. Life Sci 30:1443–1455
Woo SK, Tulnay FC, Loh HH, Lee NM (1983) Effect of dynorphine-(1-13) and related peptides on respiratory rate and morphine-induced respiratory rate depression. Eur J Pharmacol 96:117–122
Wood PL (1982) Multiple opiate receptors: support for unique mu, delta and kappa sites. Neuropharmacology 21:487–497
Woods JH, Hein DW, Herling S, Young AM, Valentino RJ (1980a) Discriminative and reinforcing effects of some systemically active enkephalin analogues. In: Way EL (ed) Endogenous and exogenous opiate agonists and antagonists. Pergamon Press, Oxford New York, pp 443–446
Woods JH, Herling S, Valentino RJ, Hein DW, Coale EH Jr (1980b) Narcotic drug discriminations by rhesus monkeys and pigeons. In: Harris LS (ed) Problems of drug dependence 1979. National Institute on Drug Abuse Research Monograph 27, Department of Health, Education and Welfare Publication No. (ADM) 80-901, US Government Printing Office, Washington, D.C., pp 128–134
Woods JH, Herling S, Young AM (1981) Comparison of discriminative and reinforcing stimulus characteristics of morphine-like opioids and two met-enkephalin analogues. Neuropeptides 1:409–419
Young AM, Woods JH, Herling S, Hein DW (1983) Comparison of the reinforcing and discriminative stimulus properties of opioids and opioid peptides. In: Smith JE, Lane JD (eds) The neurobiology of opiate reward processes. Elsevier Press, Amsterdam Oxford New York, pp 147–174
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Ukai, M., Holtzman, S.G. Morphine-like discriminative stimulus effects of opioid peptides: possible modulatory role ofd-Ala2-d-Leu5-enkephalin (DADL) and dynorphin A(1-13). Psychopharmacology 94, 32–37 (1988). https://doi.org/10.1007/BF00735877
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DOI: https://doi.org/10.1007/BF00735877