Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Occupancy of the kappa opioid receptor by naltrexone predicts reduction in drinking and craving

Molecular Psychiatry volume 26, pages 5053–5060 (2021)Cite this article

Subjects

Abstract

The efficacy of naltrexone to treat alcohol use disorder (AUD) is modest. A better understanding of the neurobiology underlying naltrexone effects could optimize treatments. We evaluated the occupancy of the kappa opioid receptor (KOR) by naltrexone measured with [11C]-LY2795050 positron emission tomography (PET) as a predictor of response to naltrexone. Response to naltrexone was defined as the difference in craving and the difference between the number of drinks consumed during an alcohol drinking paradigm (ADP) before and after 1 week of supervised 100 mg daily oral naltrexone. Forty-four (14 F) nontreatment seeking heavy drinkers meeting criteria for AUD were enrolled. Participants drank 47 ± 16 drinks per week and were balanced in family history of alcoholism (FH, 26 positive). High KOR occupancy (92 ± 1%) was achieved. Occupancy was negatively associated with number of years drinking (YOD) in FH positive, but not FH negative, participants (t3,42 = 4.00, p = 0.0003). Higher KOR occupancy by naltrexone was associated with higher alcohol craving during the ADP (F1,81 = 4.88, p = 0.030). The reduction in drinking after naltrexone was negatively associated with KOR occupancy, with significant effects of FH status (t1,43 = −2.08, p = 0.044). A logistic regression model including KOR occupancy, YOD, and FH variables achieved an 84% prediction accuracy for ≥50% reduction in drinking. These results confirm that naltrexone binds at the KOR site and suggest that KOR occupancy by naltrexone may be related to clinical response. Based on our results, we propose that differential affinities for the mu and KOR could explain why lower doses of naltrexone can have greater clinical efficacy.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Detailed overview of the alcohol drinking paradigm.
Fig. 2: Family History alters associations with KOR.
Fig. 3: KOR occupancy is associated with craving.
Fig. 4: Accurate classification of responders and non-responders to naltrexone.
Fig. 5: Simulated receptor occupancy of naltrexone at the mu (red) and kappa (blue) opioid receptor as a function the log10 of the oral dose (D).

References

  1. WHO. Global health risks: mortality and burden of disease attributable to selected major risks. 2009. https://www.who.int/healthinfo/global_burden_disease/GlobalHealthRisks_report_full.pdf.

  2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th edn. Washington: DC; 2013.

    Google Scholar 

  3. National Institute on Alcohol Abuse and Alcoholism. Special Report to Congress on Alcohol and Health. 2000. https://pubs.niaaa.nih.gov/publications/10report/10thspecialreport.pdf.

  4. Jonas DE, Amick HR, Feltner C, Bobashev G, Thomas K, Wines R, et al. Pharmacotherapy for adults with alcohol use disorders in outpatient settings: a systematic review and meta-analysis. JAMA. 2014;311:1889–900.

    PubMed  Google Scholar 

  5. Harris AHS, Oliva E, Bowe T, Humphreys KN, Kivlahan DR, Trafton JA. Pharmacotherapy of alcohol use disorders by the veterans health administration: patterns of receipt and persistence. Psychiatr Serv. 2012;63:679–85.

    PubMed  Google Scholar 

  6. Marinelli PW, Quirion R, Gianoulakis C. An in vivo profile of β-endorphin release in the arcuate nucleus and nucleus accumbens following exposure to stress or alcohol. Neuroscience. 2004;127:777–84.

    CAS  PubMed  Google Scholar 

  7. Marinelli PW, Lam M, Bai L, Quirion R, Gianoulakis C. A microdialysis profile of dynorphin A1–8 release in the rat nucleus accumbens following alcohol administration. Alcohol Clin Exp Res. 2006;30:982–90.

    CAS  PubMed  Google Scholar 

  8. Rasmussen DD, Bryant CA, Boldt BM, Colasurdo EA, Levin N, Wilkinson CW. Acute alcohol effects on opiomelanocortinergic regulation. Alcohol Clin Exp Res. 1998;22:789–801.

    CAS  PubMed  Google Scholar 

  9. Anton RF, O’Malley SS, Ciraulo DA, Cisler RA, Couper D, Donovan DM, et al. Combined pharmacotherapies and behavioral interventions for alcohol dependence The COMBINE Study: a randomized controlled trial. JAMA. 2006;295:2003–17.

    CAS  PubMed  Google Scholar 

  10. Gueorguieva R, Wu R, Pittman B, Cramer J, Rosenheck RA, O’Malley SS, et al. New insights into the efficacy of naltrexone based on trajectory-based reanalyses of two negative clinical trials. Biol Psychiatry. 2007;61:1290–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Kiefer F, Helwig H, Tarnaske T, Otte C, Jahn H, Wiedemann K. Pharmacological relapse prevention of alcoholism: clinical predictors of outcome. Eur Addict Res. 2005;11:83–91.

    PubMed  Google Scholar 

  12. Rubio G, Ponce G, Hoenicka J, Jiménez-Arriero MA, Rodriguez-Jiménez R, Palomo T. Clinical predictors of response to naltrexone in alcoholic patients: who benefits most from treatment with naltrexone? Alcohol Alcohol. 2005;40:227–33.

    CAS  PubMed  Google Scholar 

  13. Fucito LM, Park A, Gulliver SB, Mattson ME, Gueorguieva RV, O’Malley SS. Cigarette smoking predicts differential benefit from naltrexone for alcohol dependence. Biol Psychiatry. 2012;72:832–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Anton RF, Latham PK, Voronin KE, Randall PK, Book SW, Hoffman M, et al. Nicotine-use/smoking is associated with the efficacy of naltrexone in the treatment of alcohol dependence. Alcohol Clin Exp Res. 2018;42:751–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Schacht JP, Randall PK, Latham PK, Voronin KE, Book SW, Myrick H, et al. Predictors of naltrexone response in a randomized trial: reward-related brain activation, OPRM1 genotype, and smoking status. Neuropsychopharmacology. 2017;42:2640.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Garbutt JC, Greenblatt AM, West SL, Morgan LC, Kampov-Polevoy A, Jordan HS, et al. Clinical and biological moderators of response to naltrexone in alcohol dependence: a systematic review of the evidence. Addiction. 2014;109:1274–84.

    PubMed  Google Scholar 

  17. Pettinati HM, Kampman KM, Lynch KG, Suh JJ, Dackis CA, Oslin DW, et al. Gender differences with high-dose naltrexone in patients with co-occurring cocaine and alcohol dependence. J Subst Abus Treat. 2008;34:378–90.

    Google Scholar 

  18. Setiawan E, Pihl RO, Cox SML, Gianoulakis C, Palmour RM, Benkelfat C, et al. The effect of naltrexone on alcohol’s stimulant properties and self-administration behavior in social drinkers: influence of gender and genotype. Alcohol Clin Exp Res. 2011;35:1134–41.

    CAS  PubMed  Google Scholar 

  19. Krishnan-Sarin S, Krystal JH, Shi J, Pittman B, O’Malley SS. Family history of alcoholism influences naltrexone-induced reduction in alcohol drinking. Biol Psychiatry. 2007;62:694–7.

    CAS  PubMed  Google Scholar 

  20. Monterosso JR, Flannery BA, Pettinati HM, Oslin DW, Rukstalis M, O’Brien CP, et al. Predicting treatment response to naltrexone: the influence of craving and family history. Am J Addict. 2001;10:258–68.

    CAS  PubMed  Google Scholar 

  21. Litten RZ, Ryan ML, Falk DE, Reilly M, Fertig JB, Koob GF. Heterogeneity of alcohol use disorder: understanding mechanisms to advance personalized treatment. Alcohol Clin Exp Res. 2015;39:579–84.

    PubMed  Google Scholar 

  22. Streeton C, Whelan G. Naltrexone, a relapse prevention maintenance treatment of alcohol dependence: a meta-analysis of randomized controlled trials. Alcohol Alcohol. 2001;36:544–52.

    CAS  PubMed  Google Scholar 

  23. Weerts EM, Kim YK, Wand GS, Dannals RF, Lee JS, Frost JJ, et al. Differences in δ- and μ-opioid receptor blockade measured by positron emission tomography in naltrexone-treated recently abstinent alcohol-dependent subjects. Neuropsychopharmacology. 2007;33:653.

    PubMed  Google Scholar 

  24. Vijay A, Cavallo D, Goldberg A, de Laat B, Nabulsi N, Huang Y, et al. PET imaging reveals lower kappa opioid receptor availability in alcoholics but no effect of age. Neuropsychopharmacology. 2018;43:2539.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Karkhanis A, Holleran KM, Jones SR. Dynorphin/kappa opioid receptor signaling in preclinical models of alcohol, drug, and food addiction. Int Rev Neurobiol. 2017;136:53–88.

    CAS  PubMed  Google Scholar 

  26. O’Malley SS, Krishnan-Sarin S, Farren C, Sinha R, Kreek M. Naltrexone decreases craving and alcohol self-administration in alcohol-dependent subjects and activates the hypothalamo–pituitary–adrenocortical axis. Psychopharmacology. 2002;160:19–29.

    PubMed  Google Scholar 

  27. Krishnan-Sarin S, O’Malley SS, Franco N, Cavallo DA, Morean M, Shi J, et al. N-methyl-d-aspartate receptor antagonism has differential effects on alcohol craving and drinking in heavy drinkers. Alcohol Clin Exp Res. 2015;39:300–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Kiefer F, Jahn H, Wiedemann K. A neuroendocrinological hypothesis on gender effects of naltrexone in relapse prevention treatment. Pharmacopsychiatry. 2005;38:184–6.

    CAS  PubMed  Google Scholar 

  29. De Laat B, Goldberg A, Shi J, Tetrault JM, Nabulsi N, Zheng M-Q et al. The kappa opioid receptor is associated with naltrexone-induced reduction of drinking and craving. Biol Psychiatry. 2019;86:864–71.

    CAS  PubMed  Google Scholar 

  30. Sobell LC, Sobell MB. Timeline Follow-Back. In: Litten RZ, Allen JP (eds). Measuring Alcohol Consumption: Psychosocial and Biochemical Methods. Totowa, NJ: Humana Press; 1992. p. 41–72.

    Google Scholar 

  31. National Advisory Council on Alcohol Abuse and Alcoholism. Recommended Council Guidelines on Alcohol Administration in Human Experimentation. 2005. https://www.niaaa.nih.gov/research/guidelines-and-resources/administering-alcohol-human-studies.

  32. Vijay A, Wang S, Worhunsky P, Zheng M-Q, Nabulsi N, Ropchan J, et al. PET imaging reveals sex differences in kappa opioid receptor availability in humans, in vivo. Am J Nucl Med Mol imaging. 2016;6:205–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Ichise M, Toyama H, Innis RB, Carson RE. Strategies to improve neuroreceptor parameter estimation by linear regression analysis. J Cereb Blood Flow Metab. 2002;22:1271–81.

    PubMed  Google Scholar 

  34. Cunningham VJ, Rabiner EA, Slifstein M, Laruelle M, Gunn RN. Measuring drug occupancy in the absence of a reference region: the Lassen plot re-visited. J Cereb Blood Flow Metab. 2010;30:46–50.

    PubMed  Google Scholar 

  35. Bohn MJ, Krahn DD, Staehler BA. Development and initial validation of a measure of drinking urges in abstinent alcoholics. Alcohol Clin Exp Res. 1995;19:600–6.

    CAS  PubMed  Google Scholar 

  36. Rojewski AM, Morean ME, Toll BA, McKee SA, Krishnan-Sarin S, Green BG, et al. The Yale Craving Scale: development and psychometric properties. Drug Alcohol Depend. 2015;154:158–66.

    PubMed  PubMed Central  Google Scholar 

  37. McLeod RL, Parra LE, Mutter JC, Erickson CH, Carey GJ, Tulshian DB, et al. Nociceptin inhibits cough in the guinea-pig by activation of ORL(1) receptors. Br J Pharm. 2001;132:1175–1178.

    CAS  Google Scholar 

  38. Van’t Veer A, Carlezon WA. Role of kappa-opioid receptors in stress and anxiety-related behavior. Psychopharmacology. 2013;229:435–52.

    PubMed  PubMed Central  Google Scholar 

  39. Ranganathan M, Schnakenberg A, Skosnik PD, Cohen BM, Pittman B, Sewell RA, et al. Dose-related behavioral, subjective, endocrine, and psychophysiological effects of the κ opioid agonist salvinorin A in humans. Biol Psychiatry. 2012;72:871–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Berger AL, Williams AM, McGinnis MM, Walker BM. Affective cue-induced escalation of alcohol self-administration and increased 22-kHz ultrasonic vocalizations during alcohol withdrawal: role of kappa-opioid receptors. Neuropsychopharmacology. 2013;38:647–54.

    CAS  PubMed  Google Scholar 

  41. Tate SR, Wu J, McQuaid JR, Cummins K, Shriver C, Krenek M, et al. Comorbidity of substance dependence and depression: Role of life stress and self-efficacy in sustaining abstinence. Psychol Addict Behav. 2008;22:47.

    PubMed  Google Scholar 

  42. Fox HC, Bergquist KL, Hong K-I, Sinha R. Stress-induced and alcohol cue-induced craving in recently abstinent alcohol-dependent individuals. Alcohol Clin Exp Res. 2007;31:395–403.

    PubMed  Google Scholar 

  43. Logrip ML, Janak PH, Ron D. Blockade of ethanol reward by the kappa opioid receptor agonist U50,488H. Alcohol. 2009;43:359–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Mitchell JM, Liang MT, Fields HL. A single injection of the kappa opioid antagonist norbinaltorphimine increases ethanol consumption in rats. Psychopharmacology. 2005;182:384–92.

    CAS  PubMed  Google Scholar 

  45. Powell KJ, Abul-Husn NS, Jhamandas A, Olmstead MC, Beninger RJ, Jhamandas K. Paradoxical effects of the opioid antagonist naltrexone on morphine analgesia, tolerance, and reward in rats. J Pharmacol Exp therapeutics. 2002;300:588–96.

    CAS  Google Scholar 

  46. Bowen CA, Negus SS, Zong R, Neumeyer JL, Bidlack JM, Mello NK. Effects of mixed-action kappa/mu opioids on cocaine self-administration and cocaine discrimination by rhesus monkeys. Neuropsychopharmacology. 2003;28:1125–39.

    CAS  PubMed  Google Scholar 

  47. Kuzmin AV, Semenova S, Gerrits MA, Zvartau EE, Van Ree JM. Kappa-opioid receptor agonist U50,488H modulates cocaine and morphine self-administration in drug-naive rats and mice. Eur J Pharmacol. 1997;321:265–71.

    CAS  PubMed  Google Scholar 

  48. O’Malley SS, Krishnan-Sarin S, McKee SA, Leeman RF, Cooney NL, Meandzija B, et al. Dose-dependent reduction of hazardous alcohol use in a placebo-controlled trial of naltrexone for smoking cessation. Int J Neuropsychopharmacol. 2009;12:589–97.

    PubMed  Google Scholar 

  49. O’Malley SS, Krishnan-Sarin S, Farren C, O’Connor PG. Naltrexone-induced nausea in patients treated for alcohol dependence: clinical predictors and evidence for opioid-mediated effects. J Clin Psychopharmacol. 2000;20:69–76.

    PubMed  Google Scholar 

  50. Jaffe AJ, Rounsaville B, Chang G, Schottenfeld RS, Meyer RE, O’Malley SS. Naltrexone, relapse prevention, and supportive therapy with alcoholics: an analysis of patient treatment matching. J Consult Clin Psychol. 1996;64:1044–53.

    CAS  PubMed  Google Scholar 

  51. Chamorro AJ, Marcos M, Miron-Canelo JA, Pastor I, Gonzalez-Sarmiento R, Laso FJ. Association of micro-opioid receptor (OPRM1) gene polymorphism with response to naltrexone in alcohol dependence: a systematic review and meta-analysis. Addict Biol. 2012;17:505–12.

    CAS  PubMed  Google Scholar 

  52. Rohsenow DJ, Miranda R Jr, McGeary JE, Monti PM. Family history and antisocial traits moderate naltrexone’s effects on heavy drinking in alcoholics. Exp Clin Psychopharmacol. 2007;15:272–81.

    CAS  PubMed  Google Scholar 

  53. Capone C, Kahler CW, Swift RM, O’Malley SS. Does family history of alcoholism moderate naltrexone’s effects on alcohol use? J Stud Alcohol Drugs. 2011;72:135–40.

    PubMed  Google Scholar 

Download references

Acknowledgements

This work would not have been possible without the work of the Yale PET center chemistry team, imaging technologists and nurses. Special thanks to Ralitza Gueorguieva for her advice on the statistical analysis. This work was supported by research grants AA021818 (EDM and SK-S), UL1RR024139, MH091537 (YH), and the Yale Center for Translational Neuroscience of Alcoholism (CTNA; P50AA12870).

Author information

Author notes

  1. These authors contributed equally: Evan D. Morris, Suchitra Krishnan-Sarin

Authors and Affiliations

  1. Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA

    Bart de Laat, Nabeel Nabulsi, Yiyun Huang & Evan D. Morris

  2. Department of Psychiatry, Yale University, New Haven, CT, USA

    Stephanie S. O’Malley, Evan D. Morris & Suchitra Krishnan-Sarin

  3. Department of Medicine, Indiana University, Indianapolis, IN, USA

    Janice C. Froehlich

  4. Department of Biomedical Engineering, Yale University, New Haven, CT, USA

    Evan D. Morris

  5. Invicro LLC, Boston, MA, USA

    Evan D. Morris

Authors
  1. Bart de Laat
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nabeel Nabulsi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yiyun Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stephanie S. O’Malley
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Janice C. Froehlich
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Evan D. Morris
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Suchitra Krishnan-Sarin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bart de Laat.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

de Laat, B., Nabulsi, N., Huang, Y. et al. Occupancy of the kappa opioid receptor by naltrexone predicts reduction in drinking and craving. Mol Psychiatry 26, 5053–5060 (2021). https://doi.org/10.1038/s41380-020-0811-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-020-0811-8

This article is cited by

Search

Advanced search

Quick links