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κ-opioid receptors are implicated in the increased potency of intra-accumbens nalmefene in ethanol-dependent rats
Open accessAbstract
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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“These effects may be mediated by the extended amygdala, including the CeA and shell of the NAc (Nealey et al., 2011).”
From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Nealey et al., 2011
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Metadata
- 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.
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2011-07
- Volume
- 61
- Issue
- 1-2
- Pages
- 35-42
- ISSN
- 0028-3908 (ISSN-L)
- 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
- 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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