kappa-opioid receptors are implicated in the increased potency of intra-accumbens nalmefene in ethanol-dependent rats
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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ABSTRACT: To determine whether nalmefene combined with psychosocial support is cost-effective compared with psychosocial support alone for reducing alcohol consumption in alcohol-dependent patients with high/very high drinking risk levels (DRLs) as defined by the WHO, and to evaluate the public health benefit of reducing harmful alcohol-attributable diseases, injuries and deaths.BMJ Open 09/2014; 4(9):e005376. DOI:10.1136/bmjopen-2014-005376 · 2.06 Impact Factor
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ABSTRACT: Reduction of alcohol consumption is not yet a widely accepted treatment objective for alcohol-dependent patients, as abstinence is often considered to be the only possible objective in this situation. However, various studies have demonstrated the value of proposing these two options to such patients. Firstly, reduction of alcohol consumption very significantly reduces the risk of alcohol-related damage, and also modifies the patient's and the doctor's perception of the disease, resulting in improved access to care and better patient adherence with the proposed treatment objective and consequently better clinical results. Recent studies have shown that some medicinal products can help patients reduce their alcohol consumption. One such product, nalmefene, has been granted European marketing authorization and is now being released onto the market in various countries. The ESENSE 1 and 2 studies in alcohol-dependent patients showed that, in combination with BRENDA, a psychosocial intervention focusing on reinforcement of motivation and treatment adherence, nalmefene significantly reduced the number of heavy drinking days and mean daily total alcohol consumption versus placebo. This reduction was more marked in the marketing authorization target population, ie, patients with a high or very high drinking risk level according to World Health Organization criteria. Another original feature of this molecule is that it can be used as needed if the patient perceives a risk of drinking, which is a more flexible approach and more likely to ensure the patient's active involvement in the treatment of his/her disease. This molecule opens up interesting and original therapeutic prospects in the treatment of alcohol dependence.08/2014; 5:87-94. DOI:10.2147/SAR.S45666
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ABSTRACT: Introduction: Alcohol dependence is one of the most important psychiatric disorders leading to enormous harm in individuals and indeed within society. Yet, although alcohol dependence is a disease of significant importance, the availability of efficacious pharmacological treatment is still limited. Areas covered: The current review focuses on neurobiological pathways that are the rationale for recent preclinical and clinical studies testing novel compounds that could be used as treatments for alcohol dependence. These neurobiological mechanisms include the: glutamatergic, dopaminergic and GABA mediated pathways as well as neuroendocrine systems. There is also an interest in the approaches for influencing chromatin structure. Expert opinion: There are several compounds in Phase I and Phase II clinical studies that have produced potentially useful results for the treating alcoholism. Further evaluation is still necessary, and the implementation of Phase III studies will help to elucidate the usefulness of these compounds. It is important that personalized approaches (e.g., pharmacogenomics) are investigated in these later studies, as the efficacy of different compounds may vary substantially between subgroups of patients.Expert Opinion on Investigational Drugs 08/2014; 24(1):1-14. DOI:10.1517/13543784.2014.954037 · 5.43 Impact Factor