Skip to main content
SpringerLink
Log in

A single injection of the kappa opioid antagonist norbinaltorphimine increases ethanol consumption in rats

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Kappa opioid receptor (KOR) agonists interfere with the reinforcing effects of drugs of abuse. KOR agonists decrease heroin, cocaine, and ethanol self-administration, and block heroin and cocaine conditioned place preference (CPP) in rats. However, KOR agonists also produce emesis and dysphoria, making it difficult to determine if their effects on self-administration are due to an action on reward mechanisms or are secondary to the drug's direct aversive effects. Assuming that endogenous KOR ligands modulate circuits involved in drug and alcohol reward, selective KOR antagonists can be used to clarify these issues. If KOR antagonists increase drug self-administration then it is likely that endogenous KOR agonists directly modulate drug intake.

Objectives

To determine the effects of nor-BNI, the highly selective KOR antagonist, on ethanol consumption and CPP.

Methods

Thirty-eight male Lewis rats were given free access to ethanol until stable self-administration was achieved. Animals were then administered a single injection of nor-BNI (10 mg kg−1) while ethanol intake was monitored.

Results

A single injection of nor-BNI induces a long-lasting increase in ethanol consumption, but does not induce a CPP. A high/low split revealed that this effect was primarily due to an increase in drinking in nor-BNI-treated high drinkers, which drank significantly more than saline-treated high drinkers and also drank significantly more when compared to their own pretreatment baseline.

Conclusions

Blocking the KOR system increases ethanol self-administration, suggesting that the decrease in self-administration seen with KOR agonists is due to a direct modulation of reward circuitry.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Belluzzi JD, Lee AG, Oliff HS, Leslie FM (2004) Age-dependent effects of nicotine on locomotor activity and conditioned place preference in rats. Psychopharmacology 174(3):389–395

    Article  PubMed  CAS  Google Scholar 

  • Butelman ER, Negus SS, Ai Y, de Costa BR, Woods JH (1993) Kappa opioid antagonist effects of systemically administered nor-binaltorphimine in a thermal antinociception assay in rhesus monkeys. J Pharmacol Exp Ther 267(3):1269–1276

    PubMed  CAS  Google Scholar 

  • Chen AC, LaForge KS, Ho A, McHugh PF, Kellogg S, Bell K, Schluger RP, Leal SM, Kreek MJ (2002) Potentially functional polymorphism in the promoter region of prodynorphin gene may be associated with protection against cocaine dependence or abuse. Am J Med Genet 114(4):429–435

    Article  PubMed  Google Scholar 

  • Cosgrove KP, Carroll ME (2002) Effects of bremazocine on self-administration of smoked cocaine base and orally delivered ethanol, phencyclidine, saccharin, and food in rhesus monkeys: a behavioral economic analysis. J Pharmacol Exp Ther 301(3):993–1002

    Article  PubMed  CAS  Google Scholar 

  • Craft RM, McNiel DM (2003) Agonist/antagonist properties of nalbuphine, butorphanol and (−)-pentazocine in male vs. female rats. Pharmacol Biochem Behav 75(1):235–245

    Article  PubMed  CAS  Google Scholar 

  • Di Chiara G, Imperato A (1988) Opposite effects of mu and kappa opiate agonists on dopamine release in the nucleus accumbens and in the dorsal caudate of freely moving rats. J Pharmacol Exp Ther 244:1067–1080

    PubMed  Google Scholar 

  • Endoh T, Matsuura H, Tanaka C, Nagase H (1992) Nor-binaltorphimine: a potent and selective kappa-opioid receptor antagonist with long-lasting activity in vivo. Arch Int Pharmacodyn Ther 316:30–42

    PubMed  CAS  Google Scholar 

  • Fadda P, Tronci S, Colombo G, Fratta W (1999) Differences in the opioid system in selected brain regions of alcohol-preferring and alcohol-nonpreferring rats. Alcohol Clin Exp Res 23(8):1296–1305

    PubMed  CAS  Google Scholar 

  • Funada M, Suzuki T, Narita M, Misawa M, Nagase H (1993) Blockade of morphine reward through the activation of kappa-opioid receptors in mice. Neuropharmacology 32(12):1315–1323

    Article  PubMed  CAS  Google Scholar 

  • Gear RW, Miaskowski C, Gordon NC, Paul SM, Heller PH, Levine JD (1999) The kappa opioid nalbuphine produces gender- and dose-dependent analgesia and antianalgesia in patients with postoperative pain. Pain 83(2):339–345

    Article  PubMed  CAS  Google Scholar 

  • Glick SD, Maisonneuve IM, Raucci J, Archer S (1995) Kappa-opioid inhibition of morphine and cocaine self-administration in rats. Brain Res 681:147–152

    Article  PubMed  CAS  Google Scholar 

  • Holter SM, Henniger MS, Lipkowski AW, Spanagel R (2000) Kappa-opioid receptors and relapse-like drinking in long-term ethanol-experienced rats. Psychopharmacology 153(1):93–102

    Article  PubMed  CAS  Google Scholar 

  • Horan P, Taylor J, Yamamura HI, Porreca F (1992) Extremely long-lasting antagonistic actions of nor-binaltorphimine (nor-BNI) in the mouse tail-flick test. J Pharmacol Exp Ther 260(3):1237–1243

    PubMed  CAS  Google Scholar 

  • Kanarek RB, Homoleski BA, Wiatr C (2000) Intake of a palatable sucrose solution modifies the actions of spiradoline, a kappa opioid receptor agonist, on analgesia and feeding behavior in male and female rats. Pharmacol Biochem Behav 65(1):97–104

    Article  PubMed  CAS  Google Scholar 

  • Kreek MJ, Schluger J, Borg L, Gunduz M, Ho A (1999) Dynorphin A1–13 causes elevation of serum levels of prolactin through an opioid receptor mechanism in humans: gender differences and implications for modulation of dopaminergic tone in the treatment of addictions. J Pharmacol Exp Ther 288:260–269

    PubMed  CAS  Google Scholar 

  • Kuzmin AV, Semenova S, Gerrits MA, Zvartau EE, Van Ree JM (1997) Kappa-opioid receptor agonist U50, 488H modulates cocaine and morphine self-administration in drug-naive rats and mice. Eur J Pharmacol 321(3):265–271

    Article  PubMed  CAS  Google Scholar 

  • Kuzmin AV, Gerrits MA, Van Ree JM (1998) Kappa-opioid receptor blockade with nor-binaltorphimine modulates cocaine self-administration in drug-naive rats. Eur J Pharmacol 358(3):197–202

    Article  PubMed  CAS  Google Scholar 

  • Leone P, Pocock D, Wise RA (1991) Morphine–dopamine interaction: ventral tegmental morphine increases nucleus accumbens dopamine release. Pharmacol Biochem Behav 39(2):469–472

    Article  PubMed  CAS  Google Scholar 

  • Lindholm S, Ploj K, Franck J, Nylander I (2000) Repeated ethanol administration induces short- and long-term changes in enkephalin and dynorphin tissue concentrations in rat brain. Alcohol 22(3):165–171

    Article  PubMed  CAS  Google Scholar 

  • Lindholm S, Werme M, Brene S, Franck J (2001) The selective kappa-opioid receptor agonist U50, 488H attenuates voluntary ethanol intake in the rat. Behav Brain Res 120(2):137–146

    Article  PubMed  CAS  Google Scholar 

  • Maisonneuve IM, Archer S, Glick SD (1994) U50, 488, a kappa opioid receptor agonist, attenuates cocaine-induced increases in extracellular dopamine in the nucleus accumbens of rats. Neurosci Lett 181:57–60

    Article  PubMed  CAS  Google Scholar 

  • Margolis EB, Hjelmstad GO, Bonci A, Fields HL (2003) Kappa-opioid agonists directly inhibit midbrain dopaminergic neurons. J Neurosci 23(31):9981–9986

    PubMed  CAS  Google Scholar 

  • Marinelli PW, Kiianmaa K, Gianoulakis C (2000) Opioid propeptide mRNA content and receptor density in the brains of AA and ANA rats. Life Sci 66(20):1915–1927

    Article  PubMed  CAS  Google Scholar 

  • Mash DC, Staley JK (1999) D3 dopamine and kappa opioid receptor alterations in human brain of cocaine-overdose victims. Ann N Y Acad Sci 877:507–522

    Article  PubMed  CAS  Google Scholar 

  • Matsuzawa S, Suzuki T, Misawa M, Nagase H (1999) Different roles of mu-, delta-, and kappa-opioid receptors in ethanol-associated place preference in rats exposed to conditioned fear stress. Eur J Pharmacol 368(1):9–16

    Article  PubMed  CAS  Google Scholar 

  • Mello NK, Negus SS (1998) Effects of kappa opioid agonists on cocaine- and food-maintained responding by rhesus monkeys. J Pharmacol Exp Ther 286(2):812–824

    PubMed  CAS  Google Scholar 

  • Mori T, Nomura M, Nagase H, Narita M, Suzuki T (2002) Effects of a newly synthesized kappa-opioid receptor agonist, TRK-820, on the discriminative stimulus and rewarding effects of cocaine in rats. Psychopharmacology 161(1):17–22

    Article  PubMed  CAS  Google Scholar 

  • Morse AC, Schulteis G, Holloway FA, Koob GF (2000) Conditioned place aversion to the “hangover” phase of acute ethanol administration in the rat. Alcohol 22(1):19–24

    Article  PubMed  CAS  Google Scholar 

  • Negus SS, Zuzga DS, Mello NK (2002) Sex differences in opioid antinociception in rhesus monkeys: antagonism of fentanyl and U50,488 by quadazocine. J Pain 3(3):218–226

    Article  PubMed  Google Scholar 

  • Nestby P, Schoffelmeer AN, Homberg JR, Wardeh G, De Vries TJ, Mulder AH, Vanderschuren LJ (1999) Bremazocine reduces unrestricted free-choice ethanol self-administration in rats without affecting sucrose preference. Psychopharmacology 142(3):309–317

    Article  PubMed  CAS  Google Scholar 

  • Nylander I, Hyytia P, Forsander O, Terenius L (1994) Differences between alcohol-preferring (AA) and alcohol-avoiding (ANA) rats in the prodynorphin and proenkephalin systems. Alcohol Clin Exp Res 18(5):1272–1279

    Article  PubMed  CAS  Google Scholar 

  • O'Brien CP, Volpicelli LA, Volpicelli JR (1996) Naltrexone in the treatment of alcoholism: a clinical review. Alcohol 13:35–39

    Article  PubMed  Google Scholar 

  • O'Malley SS (1996) Opioid antagonists in the treatment of alcohol dependence: clinical efficacy and prevention of relapse. Alcohol Alcohol Suppl 1:77–81

    PubMed  Google Scholar 

  • Parker LA (1991) Taste reactivity responses elicited by reinforcing drugs: a dose-response analysis. Behav Neurosci 105(6):955–964

    Article  PubMed  CAS  Google Scholar 

  • Ploj K, Roman E, Gustavsson L, Nylander I (2000) Basal levels and alcohol-induced changes in nociceptin/orphanin FQ, dynorphin, and enkephalin levels in C57BL/6J mice. Brain Res Bull 53(2):219–226

    Article  PubMed  CAS  Google Scholar 

  • Przewlocka B, Turchan J, Lason W, Przewlocki R (1997) Ethanol withdrawal enhances the prodynorphin system activity in the rat nucleus accumbens. Neurosci Lett 238(1–2):13–16

    Article  PubMed  CAS  Google Scholar 

  • Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res Rev 18(3):247–291

    Article  PubMed  CAS  Google Scholar 

  • Rosin A, Lindholm S, Franck J, Georgieva J (1999) Downregulation of kappa opioid receptor mRNA levels by chronic ethanol and repetitive cocaine in rat ventral tegmentum and nucleus accumbens. Neurosci Lett 275(1):1–4

    Article  PubMed  CAS  Google Scholar 

  • Sandi C, Borrell J, Guaza C (1988) Involvement of kappa type opioids on ethanol drinking. Life Sci 42(10):1067–1075

    Article  PubMed  CAS  Google Scholar 

  • Schenk S, Partridge B, Shippenberg T (1999) U69593, a kappa opioid receptor agonist, decreases cocaine self-administration and decreases the ability of cocaine to elicit drug-seeking. Psychopharmacology 144:339–346

    Article  PubMed  CAS  Google Scholar 

  • Shippenberg TS, Herz A (1986) Differential effects of mu and kappa opioid systems on motivational processes. NIDA Res Monogr 75:563–566

    PubMed  CAS  Google Scholar 

  • Shippenberg TS, Bals-Kubik R, Herz A (1993) Examination of the neurochemical substrates mediating the motivational effects of opioids: role of the mesolimbic dopamine system and D-1 vs. D-2 dopamine receptors. J Pharmacol Exp Ther 265(1):53–59

    PubMed  CAS  Google Scholar 

  • Spanagel R, Herz A, Shippenberg TS (1992) Opposing tonically active endogenous opioid systems modulate the mesolimbic dopaminergic pathway. Proc Natl Acad Sci U S A 89:2046–2050

    Article  PubMed  CAS  Google Scholar 

  • Tershner SA, Mitchell JM, Fields HL (2000) Brainstem pain modulating circuitry is sexually dimorphic with respect to mu and kappa opioid receptor function. Pain 85(1–2):153–159

    Article  PubMed  CAS  Google Scholar 

  • Thompson AC, Zapata A, Justice JB Jr, Vaughan RA, Sharpe LG, Shippenberg TS (2000) Kappa-opioid receptor activation modifies dopamine uptake in the nucleus accumbens and opposes the effects of cocaine. J Neurosci 20(24):9333–9340

    PubMed  CAS  Google Scholar 

  • Unterwald EM, Rubenfeld JM, Kreek MJ (1994) Repeated cocaine administration upregulates kappa and mu, but not delta, opioid receptors. NeuroReport 5(13):1613–1616

    Article  PubMed  CAS  Google Scholar 

  • Walsh SL, Strain EC, Abreu ME, Bigelow GE (2001) Enadoline, a selective kappa opioid agonist: comparison with butorphanol and hydromorphone in humans. Psychopharmacology (Berl) 157(2):151–162

    Article  CAS  Google Scholar 

  • Williams KL, Woods JH (1998) Oral ethanol-reinforced responding in rhesus monkeys: effects of opioid antagonists selective for the mu-, kappa-, or delta-receptor. Alcohol Clin Exp Res 22(8):1634–1639

    PubMed  CAS  Google Scholar 

  • Xi ZX, Fuller SA, Stein EA (1998) Dopamine release in the nucleus accumbens during heroin self-administration is modulated by kappa opioid receptors: an in vivo fast-cyclic voltammetry study. J Pharmacol Exp Ther 284(1):151–161

    PubMed  CAS  Google Scholar 

  • Zimprich A, Kraus J, Woltje M, Mayer P, Rauch E, Hollt V (2000) An allelic variation in the human prodynorphin gene promoter alters stimulus-induced expression. J Neurochem 74(2):472–477

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Wheeler Center for the Neurobiology of Addiction and the Ernest Gallo Clinic and Research Center. The experiments contained herein comply with the current laws of the United States and were conducted in accordance with the Guide for the Care and Use of Laboratory Animals (NIH).

Author information

Authors and Affiliations

  1. Department of Neurology, University of California at San Francisco, P. O. Box 0114, San Francisco, CA, 94143, USA

    Jennifer M. Mitchell & Howard L. Fields

  2. Wheeler Center for the Neurobiology of Addiction, University of California at San Francisco, P. O. Box 0453, San Francisco, CA, 94143, USA

    Jennifer M. Mitchell & Howard L. Fields

  3. Ernest Gallo Clinic and Research Center, University of California at San Francisco, 5858 Horton Street, Suite 200, Emeryville, CA, 94608, USA

    Jennifer M. Mitchell, Marisa T. Liang & Howard L. Fields

Authors
  1. Jennifer M. Mitchell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marisa T. Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Howard L. Fields
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jennifer M. Mitchell.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mitchell, J.M., Liang, M.T. & Fields, H.L. A single injection of the kappa opioid antagonist norbinaltorphimine increases ethanol consumption in rats. Psychopharmacology 182, 384–392 (2005). https://doi.org/10.1007/s00213-005-0067-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-005-0067-7

Keywords

Search

Navigation