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

NEUROPHARMACOLOGY

卷:61

Article

Nealey, Kathryn A.¹  Smith, Alexander W.¹  Davis, Seth M.¹  Smith, Daniel G.³  Walker, Brendan M.^1,2 

[1] Washington State Univ, Dept Psychol, Lab Alcoholism & Addict Neurosci, Pullman, WA 99164 USA

[2] Washington State Univ, Grad Program Neurosci, Pullman, WA 99164 USA

[3] Lundbeck Res USA Inc, Dept Neurosci, Paramus, NJ USA

关键词: Alcohol;    delta-opioid receptor;    Dependence;    Dynorphin;    Ethanol;    kappa-opioid receptor;    mu-opioid receptor;    Nalmefene;    Nucleus accumbens shell;    Self-administration;    Withdrawal;   

DOI  :  10.1016/j.neuropharm.2011.02.012

来源: Elsevier

【 摘 要 】

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 kappa-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 kappa-opioid receptors) or a combination of the selective opioid receptor antagonists CTOP and naltrindole (selective for the mu- and delta-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 kappa-opioid receptor mechanism. These data support the concept that dysregulation of DYN/kappa-opioid receptor systems contributes to the excessive self-administration observed in dependent animals and suggest that pharmacotherapeutics for ethanol dependence that target kappa-opioid receptors, in addition to mu- and delta-opioid receptors, are preferable to those that target mu- and delta-opioid receptor mechanisms alone. (C) 2011 Elsevier Ltd. All rights reserved.

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