Pharmacological Evidence for a Motivational Role of κ-Opioid Systems in Ethanol Dependence

Abstract

The purpose of this study was to test the hypothesis that activation of the dynorphin/kappa (k)-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 k-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 m-opioid receptor, and nalmefene is primarily selective for the m-and k-opioid receptor subtypes, the fact that nalmefene demonstrates more suppression in dependent animals suggests that opioid systems distinct from the m-regulated portion may be involved in the increased drinking seen during withdrawal in dependent animals. The results with nor-BNI confirm that k-opioid receptor antagonism selectively decreases dependence-induced ethanol self-administration, which supports the hypothesis that dynorphin/k-opioid systems are dysregulated in dependence and contribute to the increased drinking seen during acute withdrawal in dependent rats. INTRODUCTIONThe acute effects of ethanol have been shown to be both reinforcing and rewarding in animal models such as operant self-administration (Anderson and Thompson, 1974;Smith and Davis, 1974) and the conditioned place preference paradigm (Bozarth, 1990;Walker and Ettenberg, 2007). Ethanol produces its effects on the central nervous system via a variety of pharmacological mechanisms. These include alterations in the function of the cholinergic, dopaminergic, g-aminobutyric acid, glutamatergic, opioidergic, and serotonergic neurotransmitter systems (for review see Eckardt et al, 1998). In the case of the endogenous opioid system and its receptor subtypes (m, d, kFselective for the three main classes of endogenous opioids: b-endorphin, enkephalins, and dynorphins, respectively), acute ethanol has been shown to stimulate the release of b-endorphin...

Potent Inhibition of Alcohol Self-Administration in Alcohol-Preferring Rats by aκ-Opioid Receptor Antagonist

“…Presumably, the profile of opioid receptor binding coupled with the drug-like properties of compound 5 contributes to the optimal functional activity as an alcohol selfadministration inhibition agent in vivo. This is in agreement with recent studies that show that an opioid with strong k-opioid receptor antagonism, albeit possessing some opioid agonism (i.e., nalmefene) (Bart et al, 2005), was more effective at inhibition of alcohol self-administration than an opioid with broad opioid receptor antagonism (i.e., naltrexone) (Walker and Koob, 2008). Consequently, compound 5 and related agents may represent exciting leads for the next generation of opioid compounds useful in the treatment of alcohol abuse.…”

“…Nor-BNI is effective at decreasing alcohol self-administration in small animals (Walker and Koob, 2008;Walker et al, 2011). Despite its promise, nor-BNI possesses very long-lasting effects (Horan et al, 1992) and is possibly unstable to oxidation (Osa et al, 2007).…”

Early-Life Social Isolation Stress Increases Kappa Opioid Receptor Responsiveness and Downregulates the Dopamine System

“…For example, blockade of KORs with nor-binaltorphimine (nor-BNI) attenuates the augmented ethanol intake observed in adult-dependent animals (Berger et al, 2013). KOR blockade also reduces motivation for heroin and ethanol intake in adult-dependent animals, as measured by progressive ratio performance (Walker and Koob, 2008;Schlosburg et al, 2013). These studies suggest that decreasing KOR activity may represent a promising treatment for AUDs.…”

“…Kappa opioid receptors (KORs) are located presynaptically on DA terminals and suppress DA release in the NAc (Werling et al, 1988;Svingos et al, 2001;Ebner et al, 2010). Previous data suggest that exposure to chronic stress, such as repeated withdrawal from chronic intermittent ethanol (CIE) exposure, leads to prolonged activation of KORs (Walker and Koob, 2008), possibly contributing to reduced DA function, which is positively correlated with negative affect (see Koob et al, 2014 for a review). Elevations in intra-cranial self-stimulation (ICSS) thresholds are associated with anhedonia, and a recent study showed that prolonged activation of KORs resulted in significantly elevated ICSS thresholds (Chartoff et al, 2016).…”

Neurochemical and Neurostructural Plasticity in Alcoholism

“…57,58 Recent findings that κ receptor antagonists suppress alcohol consumption preferentially in dependent rats lends support to this hypothesis. 54 Familial alcohol dependence has also been shown to be associated with specific alleles of the κ opioid receptor, 58 suggesting that pharmacogenomic approaches to the treatment of alcoholism with ligands targeting κ opioid receptors in specific individuals warrants further exploration.…”