, Volume 120, Issue 2, pp 177–185 | Cite as

The delta opioid receptor antagonist naltrindole attenuates both alcohol and saccharin intake in rats selectively bred for alcohol preference

  • S. Krishnan-Sarin
  • S. -L. Jing
  • D. L. Kurtz
  • M. Zweifel
  • P. S. Portoghese
  • T. -K. Li
  • J. C. Froehlich
Original Investigation


This study demonstrates that the selective delta receptor antagonists ICI 174864 and naltrindole (NTI) attenuate alcohol intake in a dose-dependent manner, without altering water intake, in rats selectively bred for alcohol preference. ICI 174864 had a very limited duration of action, as evidenced by the fact that suppression of alcohol intake lasted for only an hour following ICI 174864 administration. NTI, when administered in a dose of 10 mg/kg, suppressed alcohol intake by 28%. Increasing the dose of NTI to 15 mg/kg produced a 44% suppression of alcohol intake, but a further increase to 20 mg/kg did not produce greater suppression than was seen with a dose of 15 mg/kg (46% versus 44%, respectively). This suggests that NTI is maximally effective in suppressing alcohol intake at a dose of 15.0 mg/kg. NTI displayed a long duration of action, as evidenced by attenuation of alcohol drinking that lasted for at least 8 h following drug treatment. Administering the maximally effective dose of NTI (15 mg/kg) in two parts, separated by 4 h, served to prolong the duration of action of NTI and produced an attenuation of alcohol intake, but not water intake, that lasted for at least 28 h. The effect of NTI on alcohol intake was not specific for alcohol, as evidenced by the fact that NTI reduced the intake of saccharin solutions with and without alcohol.

Key words

Alcohol-preferring rats Saccharin intake Alcohol intake ICI 174864 Naltrindole Delta opioid receptor antagonists 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abdelhamid EE, Sultana M, Portoghese PS, Takemori AE (1991) Selective blockage of delta opioid receptors prevents the development of morphine tolerance and dependence in mice. J Pharmacol Exp Ther 258:299–303Google Scholar
  2. Akkok F, Manha NA, Czirr SA, Reid LD (1988) Naloxone persistently modifies water-intake. Pharmacol Biochem Behav 29:331–334Google Scholar
  3. Allan AM, Harris RA (1991) Neurochemical studies of genetic differences in alcohol action. In: Crabbe JC, Harris RA (eds) The genetic basis for alcohol and drug actions. Plenum Press, New York, pp 105–152Google Scholar
  4. Altshuler HL, Phillips PE, Feinhandler DA (1980) Alteration of alcohol self-administration by naltrexone. Life Sci 26:679–688Google Scholar
  5. Beczkowska IW, Bowen WD, Bodnar RJ (1992) Central opioid subtype antagonists differentially alter sucrose and deprivation-induced water intake in rats. Brain Res 589:291–301Google Scholar
  6. Berman RF, Lee JA, Olson KL, Goldman MS (1984) Effects of naloxone on alcohol dependence in rats. Drug Alcohol Depend 13:245–254Google Scholar
  7. Blass EM (1987) Opioids, sweets and a mechanism for positive effect: broad motivational implications. In: Dobbing J (ed) Sweetness. Springer, New York, pp 119–124Google Scholar
  8. Brown DR, Holtzman SG (1979) Suppression of deprivation-induced food and water intake in rats and mice by naloxone. Pharmacol Biochem Behav 11:567–573Google Scholar
  9. Brown DR, Holtzman SG (1981) Opiate antagonists: central sites of action in suppressing water intake of the rat. Brain Res 221:432–436Google Scholar
  10. Calcagnetti DJ, Holtzman SG (1990) Delta opioid antagonist, naltrindole, selectively blocks analgesia induced by DPDPE but not DAGO or morphine. Pharmacol Biochem Behav 38:185–190Google Scholar
  11. Chang K-J, Cuatrecasas P (1981) Heterogeneity and properties of opiate receptors. Fed Proc 40:2729–2734Google Scholar
  12. Chang K-J, Cooper BR, Hazum E, Cuatrecasas P (1979) Multiple opiate receptors: different regional distribution in the brain and differential binding of opiates and opioid peptides. Mol Pharmacol 16:91–104Google Scholar
  13. Chang K-J, Hazum E, Killian A, Cuatrecasas P (1981) Interactions of ligands with morphine and enkephalin receptors are differentially affected by guanine nucleotide. Mol Pharmacol 20:1–7Google Scholar
  14. Childers SR, Creese I, Snowman AM, Snyder SH (1979) Opiate receptor binding affected differentially by opiates and opioid peptides. Eur J Pharmacol 55:11–18Google Scholar
  15. Cooper SJ (1983) Effects of opiate agonists and antagonists on fluid intake and saccharin choice in the rat. Neuropharmacology 22:323–328Google Scholar
  16. Cooper SJ (1988) Evidence for opioid involvement in control of drinking and water balance. In: Rodgers RJ, Cooper SJ (eds) Endorphins, opiates and behavioral processes. Wiley, Chichester, pp 187–216Google Scholar
  17. Cooper SJ, Kirkham TC (1990) Basic mechanisms of opioid's effect on eating and drinking. In: Reid LD (ed) Opioids, bulimia and alcohol abuse and alcoholism. Springer, New York, pp 91–110Google Scholar
  18. Cotton R, Giles MG, Miller L (1984) ICI 174864: a highly selective antagonist for the opioid delta receptor. Eur J Pharmacol 97:331–332Google Scholar
  19. Cowan A, Zhu XZ, Porreca F (1985) Studies in vivo with ICI 174864 and (d-Pen2,d-Pen5) enkephalin. Neuropeptides 5:311–314Google Scholar
  20. Czirr SA, Reid LD (1986) Demonstrating morphine's potentiating effects on sucrose intake. Brain Res Bull 17:639–642Google Scholar
  21. Davis WM, Miya TS, Edwards LD (1956) The influence of glucose and insulin pretreatment upon morphine analgesia in rats. J Am Pharm Assoc 45:60–62Google Scholar
  22. De Waele J-P, Papachristou DN, Gianoulakis C (1992) The alcohol-preferring c57BL/6 mice present an enhanced sensitivity of the hypothalamic β-endorphin system to ethanol than the alcohol-avoiding DBA/2 mice. J Pharmacol Exp Ther 261:788–794Google Scholar
  23. DeWitte P (1984) Naloxone reduces alcohol intake in a free choice procedure even when both drinking bottles contain saccharin sodium or quinine substances. Neuropsychobiology 12:73–77Google Scholar
  24. Deitrich RA, Dunwiddie TV, Harris RA, Erwin VG (1989) Mechanism of action of alcohol: initial central nervous system actions. Pharmacol Rev 41:491–537Google Scholar
  25. DiChiara G, North RA (1992) Neurobiology of opiate abuse. Trends Pharm Sci 13:185–211Google Scholar
  26. Dum J, Gramsch Ch, Herz A (1983) Activation of hypothalamic β-endorphin pools by reward induced by highly palatable foods. Pharmacol Biochem Behav 18:443–447Google Scholar
  27. Froehlich JC (1993) Interactions between alcohol and the endogenous opioid system. In: Zakhari S (ed) Alcohol and the endocrine system. monograph 23, National Institute on Alcohol Abuse and Alcoholism Research Monograph Series. US Government Printing Office, Washington, DC, pp 21–35Google Scholar
  28. Froehlich JC, Li T-K (1990) Enkephalinergic involvement in voluntary drinking of alcohol. In: Reid LD (ed) Opioids, bulimia, alcohol abuse and alcoholism. Springer, New York, pp 217–228Google Scholar
  29. Froehlich JC, Li T-K (1991) Animal models for the study of alcoholism: utility of selected lines. J Addict Dis 10:61–71Google Scholar
  30. Froehlich JC, Li T-K (1993) Opioid peptides. In: Galantar M (ed) Recent developments in alcoholism, vol. 11: ten years of progress. Plenum, New York, pp 187–205Google Scholar
  31. Froehlich JC, Harts J, Lumeng L, Li T-K (1990) Naloxone attenuates voluntary ethanol intake in rats selectively bred for high ethanol preference. Pharmacol Biochem Behav 35:385–390Google Scholar
  32. Froehlich JC, Zweifel M, Harts J, Lumeng L, Li T-K (1991) Importance of delta opioid receptors in maintaining high alcohol drinking. Psychopharmacology 103:463–467Google Scholar
  33. Getto CJ, Fullerton DT, Carlson IH (1984) Plasma immunoreactive beta endorphin response to glucose ingestion in human obesity. Appetite 5:327–335Google Scholar
  34. Gianoulakis C (1990) Characterization of the effects of acute ethanol administration on the release of B-E peptides by the rat hypothalamus. Eur J Pharmacol 180:21–29Google Scholar
  35. Gianoulakis C, Barcomb A (1987) Effect of acute ethanol in vivo and in vitro on the β-endorphin system in the rat. Life Sci 40:19–28Google Scholar
  36. Gianoulakis C, Chan JSD, Kalant H, Cretien M (1983) Chronic ethanol treatment alters the biosynthesis of beta-endorphin by the rat neurointermediate lobe. Can J Physiol Pharmacol 61:967–976Google Scholar
  37. Gianoulakis C, Hutchison WD, Kalant H (1988) Effect of ethanol treatment and withdrawal on biosynthesis and processing of proopiomelanocortin by the rat neurointermediate lobe. Endocrinology 122:815–817Google Scholar
  38. Gianoulakis C, Beliveau D, Angelogianni P, Meaney M, Thavundayil J, Tawar V, Dumas M (1989) Different pituitary β-endorphin and adrenal cortisol response to ethanol in individuals with high and low risk for future development of alcoholism. Life Sci 45:1097–1109Google Scholar
  39. Gosnell BA, Krahn DD (1992a) The effects of continuous naltrexone infusions on diet preferences are modulated by adaptation to the diets. Physiol Behav 51:239–244Google Scholar
  40. Gosnell BA, Krahn DD (1992b) The relationship between saccharin and alcohol intake in rats. Alcohol 9:203–206Google Scholar
  41. Gosnell BA, Majchrzak MJ (1990) Effects of a selective mu opioid receptor agonist and naloxone on the intake of sodium chloride solutions. Psychopharmacology 100:66–71Google Scholar
  42. Hubbell CL, Reid LD (1990) Opioids modulate rat's intake of alcoholic beverages. In: Reid LD (ed) Opioids, bulimia and alcohol abuse and alcoholism, Springer, New York, pp 145–191Google Scholar
  43. Hubbell CL, Czirr SA, Hunter GA, Beaman CM, LeCann NC, Reid LD (1986) Consumption of ethanol solution is potentiated by morphine and attenuated by naloxone persistently across repeated daily administration. Alcohol 3:39–54Google Scholar
  44. Keith LD, Crabbe JC, Robertson LM, Kendall JW (1986) Ethanol-stimulated endorphin and corticotropin secretion in vitro. Brain Res 367:222–229Google Scholar
  45. LeMagnen J, Marfaing-Jallat P, Miceli D, Devos M (1980) Pain modulating and reward systems: a single brain mechanism? Pharmacol Biochem Behav 12:729–733Google Scholar
  46. Levine AS, Murray SS, Kneip J, Grace M, Morley JE (1982) Flavor enhances the antidipsogenic effect of naloxone. Physiol Behav 28:23–25Google Scholar
  47. Levine AS, Morley JE, Gosnell BA, Billington CJ, Bartness TJ (1985) Opioids and consummatory behavior. Brain Res Bull 14:663–672Google Scholar
  48. Li T-K, Lumeng L, McBride WJ, Waller MB (1981) Indiana selection studies on alcohol-related behaviors. In: NIAAA Research Monograph No.6: development of animals models as pharmacogenetic tools. US Department of Health and Human Services, Rockville, Md., pp 171–191Google Scholar
  49. Lipkowski AW, Tam SW, Portoghese PS (1986) Peptides as receptor selective modulators of opiate pharmacophores. J Med Chem 297:3–5Google Scholar
  50. Long JB, Ruvio BA, Glatt CE (1984) ICI 174864, a putative delta opioid antagonist, reverses endotoxemic hypotension: pretreatment with dynorphin 1–13, a kappa agonist, blocks this action. Neuropeptides 5:291–294Google Scholar
  51. Lumeng L, Penn PE, Gaff TM, Hawkins TD, Li T-K (1978) Further characterization of a new rat strain with high alcohol preference. In: Seixas FA (ed) Currents in alcoholism, biological, biochemical and clinical studies, vol. III. Grune and Stratton, New York, pp 23–35Google Scholar
  52. Lynch WC (1986) Opiate blockade inhibits saccharin intake and blocks normal preference acquisition. Pharmacol Biochem Behav 24:833–836Google Scholar
  53. Maickel RP, Braude MC, Zabik JE (1977) The effects of various narcotic agonists and antagonists on deprivation-induced fluid consumption. Neuropharmacology 16:863–866Google Scholar
  54. Marfaing-Jallat P, Miceli C, LeMagnen J (1983) Decrease in ethanol consumption by naloxone in naive and dependent rats. Pharmacol Biochem Behav 18:537–539Google Scholar
  55. Marks-Kaufman R, Plager A, Kanarek RB (1985) Central and peripheral contributions of endogenous opioid systems to nutrient selection in rats. Psychopharmacology 85:414–418Google Scholar
  56. Morabia A, Fabre J, Chee E, Zeger S, Orsat E, Robert A (1989) Diet and opiate addiction: a quantitative assessment of the diet of non-institutionalized opiate addicts. Br J Addict 84:173–180Google Scholar
  57. Myers RD, Borg S, Mossberg R (1986) Antagonism by naltrexone of voluntary alcohol selection in the chronically drinking macaque monkey. Alcohol 3:383–388Google Scholar
  58. O'Malley SS, Jaffe AJ, Chang G, Schottenfeld RS, Meyer RE, Rounsaville B (1992) Naltrexone and coping skills therapy for alcohol dependence. A controlled study. Arch Gen Psychiatry 49:881–887Google Scholar
  59. Overstreet DH, Kampov-Polevoy AB, Rezvani AH, Murrelle L, Halikas JA, Janowsky DS (1993) Saccharin intake predicts ethanol intake in genetically heterogenous rats as well as different rat strains. Alcohol Clin Exp Res 17:366–369Google Scholar
  60. Patel VA, Pohorecky LA (1988) Interaction of stress and ethanol: effect on β-endorphin and catecholamines. Alcohol Clin Exp Res 12:785–789Google Scholar
  61. Portoghese PS, Sultana M, Takemori AE (1988) Naltrindole, a highly selective and potent non-peptide delta opioid receptor antagonist. Eur J Pharmacol 146:185–186Google Scholar
  62. Portoghese PS, Sultana M, Takemori AE (1990) Design of peptidomimetic delta opioid receptor antagonists using the message-address concept. J Med Chem 33:1714–1720Google Scholar
  63. Portoghese PS, Nagase H, MaloneyHuss KE, Lin C-E, Takemori AE (1991) Role of spacer and address components in peptidomimetic delta opioid receptor antagonists related to naltrindole. J Med Chem 34:1715–1720Google Scholar
  64. Raynor K, Kong H, Yasuda K, Chen Y, Yu L (1994) Pharmacological characterization of the cloned kappa, delta, and mu opioid receptors. Mol Pharmacol 45:330–334Google Scholar
  65. Reid LD (1985) Endogenous opioid peptides and regulation of drinking and feeding. Am J Clin Nutr 42:1099–1132Google Scholar
  66. Reid LD, Hunter GA (1984) Morphine and naloxone modulate intake of ethanol. Alcohol 1:33–37Google Scholar
  67. Sanger DJ, McCarthy PS (1980) Differential effects of morphine on food and water intake in food deprived and freely-feeding rats. Psychopharmacology 72:103–106Google Scholar
  68. Schwyzer R (1977) ACTH: a short introductory review. Ann NY Acad Sci 297:3–14Google Scholar
  69. Seizinger BR, Bovermann K, Maysinger D, Hollt V, Herz A (1983) Differential effects of acute and chronic ethanol treatment on particular opioid peptide systems in discrete regions of rat brain and pituitary. Pharmacol Biochem Behav 18:361–369Google Scholar
  70. Self DW, Stein L (1992) Receptor subtypes in opioid and stimulant reward. Pharmacol Toxicol 70:87–94Google Scholar
  71. Shide DJ, Blass EM (1991) Opioid mediation of odor preferences induced by sugar and fat in 6-day-old rats. Physiol Behav 50:961–966Google Scholar
  72. Shippenberg TS, Herz A, Spanagel R, Bals-Kubik, Stein C (1992) Conditioning of opioid reinforcement: neuroanatomical and neurochemical substrates. In: Kalivas PW, Samson HH (eds) The neurobiology and drug and alcohol addiction. Ann NY Acad Sci 654:347–356Google Scholar
  73. Sinclair JD, Kampov-Polevoy A, Stewart R, Li T-K (1992) Taste preferences in rat lines selected for low and high alcohol consumption. Alcohol 9:155–160Google Scholar
  74. Sinden JD, Marfaing-Jallat P, LeMagnen J (1983) The effect of naloxone on intragastric ethanol self-administration. Pharmacol Biochem Behav 19:1045–1048Google Scholar
  75. Siviy SM, Reid LD (1983) Endorphinergic modulation of acceptability of putative reinforcers. Appetite 4:249–257Google Scholar
  76. Sofuoglu M, Portoghese PS, Takemori AE (1991) Differential antagonism of delta opioid agonists by naltrindole and its benzofuran analog naltriben in mice: evidence for delta opioid receptor subtypes. J Pharmacol Exp Ther 257:676–680Google Scholar
  77. Stein L (1978) Reward transmitters: catecholamines and opioid peptides. In: Lipton MA, DiMascio A, Killam KF (eds) Psychopharmacology: a generation of progress. Raven Press, New York, pp 569–581Google Scholar
  78. Stewart RB, Russell RN, Lumeng L, Li T-K, Murphy JM (1994) Consumption of sweet, salty, sour and bitter solutions by selectively bred alcohol-preferring P and nonpreferring NP lines of rats. Alcohol Clin Exp Res 18:375–381Google Scholar
  79. Thiagarajan AB, Mefford IN, Eskay RL (1989) Single-dose ethanol administration activates the hypothalamic-pituitary-adrenal axis: exploration of the mechanism of action. Neuroendocrinology 50:427–432Google Scholar
  80. Volpicelli JR, Davis MA, Olgin JE (1986) Naltrexone blocks the post-shock increase of ethanol consumption. Life Sci 38:841–847Google Scholar
  81. Volpicelli JR, Alterman AI, Hayashida M, O'Brien CP (1992) Naltrexone in the treatment of alcohol dependence. Arch Gen Psychiatry 49:876–880Google Scholar
  82. Wand GS (1989) Ethanol differentially regulates proadrenocorticotropin/endorphin production and corticosterone secretion in LS and SS lines of mice. Endocrinology 124:518–525Google Scholar
  83. Weiss F, Mitchiner M, Bloom FE, Koob GF (1990) Free-choice responding for ethanol versus water in alcohol preferring (P) and unselected Wistar rats is differentially modified by naloxone, bromocriptine, and methysergide. Psychopharmacology 101:178–186Google Scholar
  84. Wild KD, Marglin SH, Reid LD (1988) Small doses of morphine enhance intake of a solution of only ethanol and water. Bull Psychon Soc 26:129–131Google Scholar
  85. Winer BJ (1971) Statistical principles in experimental design, 2nd edn. McGraw-Hill, New YorkGoogle Scholar
  86. Wise RA, Pasqualino B, Carlezone WA, Trojniar W (1992) In: Kalivas PW, Samson HH (eds) The neurobiology of drug and alcohol addiction. Ann NY Acad Sci 654:192–198Google Scholar
  87. Yung L, Godis E, Holt J (1983) Dietary choices and likelihood of abstinence among alcoholic patients in an outpatient clinic. Drug Alcohol Depend 12:355–362Google Scholar

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • S. Krishnan-Sarin
    • 1
  • S. -L. Jing
    • 1
  • D. L. Kurtz
    • 1
  • M. Zweifel
    • 1
  • P. S. Portoghese
    • 4
  • T. -K. Li
    • 1
    • 3
  • J. C. Froehlich
    • 1
    • 2
  1. 1.Department of MedicineIndiana University School of MedicineIndianapolisUSA
  2. 2.Department of Physiology/BiophysicsIndiana University School of MedicineIndianapolisUSA
  3. 3.Department of Biochemistry/Molecular BiologyIndiana University School of MedicineIndianapolisUSA
  4. 4.Department of Medicinal Chemistry, College of PharmacyUniversity of MinnesotaMinneapolisUSA

Personalised recommendations