Pharmacological evidence for a motivational role of κ-opioid systems in ethanol dependence
Open accessAbstract
The purpose of this study was to test the hypothesis that activation of the dynorphin/kappa (kappa)-opioid system has a role in the increased consumption of ethanol in dependent animals. The effects of three opioid receptor antagonists with different effects on opioid receptors, naltrexone, nalmefene, and nor-binaltorphimine (nor-BNI), were compared in their ability to decrease ethanol self-administration in nondependent and ethanol-dependent male Wistar rats. Nalmefene and naltrexone are both opioid receptor ligands with comparable molecular weights and pharmacokinetic profiles, but differing specificity for the three opioid receptor subtypes at low doses, while nor-BNI is a selective kappa-opioid receptor antagonist. Dependence was induced in half the animals by subjecting them to a 4-week intermittent vapor exposure period in which animals were exposed to ethanol vapor for 14 h per day. Subsequent to dependence induction, nalmefene, naltrexone, and nor-BNI were tested for their ability to modulate self-administration of ethanol in vapor-exposed and control rats. The results indicated that both nalmefene and naltrexone induced a significant dose-dependent decrease in the number of lever presses for ethanol in both groups of animals. However, in ethanol-dependent animals, nalmefene was significantly more effective in suppressing ethanol intake than naltrexone. Nor-BNI selectively attenuated ethanol-dependent self-administration while leaving nondependent ethanol self-administration intact. Because naltrexone is primarily selective for the mu-opioid receptor, and nalmefene is primarily selective for the mu- and kappa-opioid receptor subtypes, the fact that nalmefene demonstrates more suppression in dependent animals suggests that opioid systems distinct from the mu-regulated portion may be involved in the increased drinking seen during withdrawal in dependent animals. The results with nor-BNI confirm that kappa-opioid receptor antagonism selectively decreases dependence-induced ethanol self-administration, which supports the hypothesis that dynorphin/kappa-opioid systems are dysregulated in dependence and contribute to the increased drinking seen during acute withdrawal in dependent rats.
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κ opioid receptor antagonists injected into the nucleus accumbens shell block the development of compulsive drug seeking.
“Equally compelling, κ opioid receptor antagonists, when injected into the nucleus accumbens shell, can block the development of compulsive drug seeking (tables 1, 2, circuit 8).”
From Neurobiology of addiction: a neurocircuitry analysis (2016) · cites this paper as [76]
The Drugs section says the κ-opioid receptor antagonist nor-BNI was injected into the lateral ventricles, not the nucleus accumbens shell. The Nor-Binaltorphimine results report reduced ethanol self-administration in dependent rats during withdrawal, not prevention of the development of compulsive drug seeking. The claim captures an effect of κ-opioid antagonism on drug-related responding but changes both the injection site and the outcome. (LLM, conf=0.90)
Experimental — accuracy not yet measuredSystemic and intracerebral k-opioid receptor antagonist administration blocks high compulsive-like drug intake associated with extended access to and dependence on alcohol.
“Both systemic and intracerebral k-opioid receptor antagonist administration blocked high compulsivelike drug intake that was associated with extended access to and dependence on alcohol (Hölter et al., 2000;Walker and Koob, 2008).”
From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Walker and Koob, 2008
The Drugs and Results sections report that systemic nalmefene reduced ethanol self-administration and intracerebral nor-BNI selectively reduced it in ethanol-dependent rats. But nalmefene is not a selective κ-opioid antagonist, and the study reports reduced—not completely blocked—intake after ethanol-vapor-induced dependence. It does not establish the claimed effect under extended-access drinking conditions. (LLM, conf=0.85)
Experimental — accuracy not yet measuredDuring withdrawal, this up-regulation and subsequent activation of KOR may contribute to negative affect and thus promote relapse.
“During withdrawal, this up-regulation and subsequent activation of KOR may contribute to negative affect and thus promote relapse (Przewlocka et al 1997; Simonin et al 1998; Walker and Koob 2008).”
From The behavioral, anatomical and pharmacological parallels between social attachment, love and addiction (2012) · cites this paper as Walker and Koob 2008
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References 78 · Cited by 392
- Authors
- Walker, B. M., & Koob, G. F.
- Affiliations
- Scripps Research Institute (US)
- Venue
- Neuropsychopharmacology
- Published
- 2007-05-02
- Volume
- 33
- Issue
- 3
- Pages
- 643-652
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC2739278
- OpenAlex
- W1963557453
- Cited by
- 392
- References
- 78
- Citations by year
- 2026: 11 · 2025: 12 · 2024: 13 · 2023: 13 · 2022: 11 · 2021: 12 · 2020: 21 · 2019: 21 · 2018: 29 · 2017: 24 · 2016: 32 · 2015: 31 · 2014: 27 · 2013: 27 · 2012: 26
- FWCI
- 8.10
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (AA012602, F32AA014723, AA 014723, R01AA012602)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Keywords
- ethanol dependence, kappa opioid receptor, dynorphin, naltrexone, nalmefene, nor-binaltorphimine, ethanol self-administration, opioid antagonists, ethanol vapor exposure, mu-opioid receptor, alcoholism
- MeSH terms
- Administration, Inhalation, Ethanol, Alcoholism, Animals, Central Nervous System Depressants, Conditioning, Operant, Data Interpretation, Statistical, Dynorphins, Injections, Intraventricular, Male, Motivation, Naltrexone, Narcotic Antagonists, Self Administration, Substance Withdrawal Syndrome, Rats, Wistar, Receptors, Opioid, mu, Receptors, Opioid, delta, Receptors, Opioid, kappa, Rats
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