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κ-opioid receptors are implicated in the increased potency of intra-accumbens nalmefene in ethanol-dependent rats

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Nealey, Kathryn A., Smith, Alexander W., Davis, Seth M., Smith, Daniel G., Walker, Brendan M.·2011·Neuropharmacology

DOI 10.1016/j.neuropharm.2011.02.012PMC PMC3955175

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Abstract

Previously, it was shown that ethanol-dependent animals display increased sensitivity to the general opioid receptor antagonist nalmefene compared to naltrexone. It was hypothesized that the dissociable effects of the two antagonists were attributable to a κ-opioid receptor mechanism. Nucleus accumbens dynorphin is upregulated following chronic ethanol exposure and such neuroadaptations could contribute to nalmefene's increased potency in ethanol-dependent animals. To test this hypothesis, male Wistar rats were trained to self-administer ethanol using an operant conditioning procedure. Animals were then implanted with bilateral intra-accumbens shell guide cannulae and assigned to either a chronic intermittent ethanol vapor-exposure condition (to induce dependence) or an air-exposed control group. Following a one-month exposure period, nalmefene, nor-binaltorphimine (nor-BNI; selective for κ-opioid receptors) or a combination of the selective opioid receptor antagonists CTOP and naltrindole (selective for the μ- and δ-opioid receptors, respectively) were site-specifically infused into the nucleus accumbens shell prior to ethanol self-administration sessions during acute withdrawal. Nalmefene and CTOP/naltrindole dose-dependently reduced ethanol self-administration in nondependent and dependent animals, whereas nor-BNI selectively attenuated ethanol self-administration in ethanol-dependent animals without affecting the self-administration of nondependent animals. Further analysis indentified that intra-accumbens shell nalmefene was more potent in ethanol-dependent animals and that the increased potency was attributable to a κ-opioid receptor mechanism. These data support the concept that dysregulation of DYN/κ-opioid receptor systems contributes to the excessive self-administration observed in dependent animals and suggest that pharmacotherapeutics for ethanol dependence that target κ-opioid receptors, in addition to μ- and δ-opioid receptors, are preferable to those that target μ- and δ-opioid receptor mechanisms alone.

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Authors: Nealey, K. A., Smith, A. W., Davis, S. M., Smith, D. G., & Walker, B. M.
Affiliations: Washington State University (US)
Lundbeck (United States) (US)
Corresponding author: Walker, Brendan M.
ORCID: Davis, Seth M.
Smith, Daniel G.
Walker, Brendan M.
Venue: Neuropharmacology
Publisher: Elsevier BV
Published: 2011-07
Volume: 61
Issue: 1-2
Pages: 35-42
ISSN: 0028-3908 (ISSN-L)
DOI: 10.1016/j.neuropharm.2011.02.012
PMC: PMC3955175
OpenAlex: W2054879676
Cited by: 133
References: 66
Citations by year: 2026: 3 · 2025: 6 · 2024: 4 · 2023: 7 · 2022: 7 · 2021: 7 · 2020: 2 · 2019: 5 · 2018: 13 · 2017: 11 · 2016: 15 · 2015: 11 · 2014: 9 · 2013: 15 · 2012: 14
FWCI: 5.39
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Neuropharmacology (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institute on Alcohol Abuse and Alcoholism (R01AA020394)
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: kappa opioid receptor, nalmefene, ethanol dependence, nucleus accumbens shell, dynorphin, nor-binaltorphimine, CTOP, naltrindole, ethanol self-administration, ethanol withdrawal, opioid antagonists
MeSH terms: Ethanol, Alcoholism, Animals, Male, Naltrexone, Nucleus Accumbens, Self Administration, Rats, Wistar, Receptors, Opioid, kappa, Rats, Infusions, Intraventricular

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κ-opioid receptors are implicated in the increased potency of intra-accumbens nalmefene in ethanol-dependent rats

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