The Opioid Peptides Enkephalin and β-Endorphin in Alcohol Dependence

Institute of Molecular Psychiatry, Life & Brain Center, University of Bonn, Bonn, Germany.
Biological psychiatry (Impact Factor: 10.26). 07/2008; 64(11):989-97. DOI: 10.1016/j.biopsych.2008.05.008
Source: PubMed


Experimental evidence indicates that the endogenous opioid system influences stress responses as well as reinforces effects of addictive drugs. Because stress is an important factor contributing to drug dependence and relapse, we have now studied ethanol preference in enkephalin- and beta-endorphin-deficient mice under baseline conditions and after stress exposure.
In the present study we used a two-bottle choice paradigm to study ethanol consumption and stress-induced ethanol preference. To examine alcohol withdrawal symptoms the forced drinking procedure was employed. We performed an association analysis in two case-control samples of alcohol addicts to determine whether these opioid peptides also contribute to ethanol dependence in humans.
Ethanol consumption was significantly reduced in the absence of beta-endorphins, particularly in female knockout animals. Stress exposure results in an increased ethanol consumption in wild-type mice but did not influence ethanol-drinking in beta-endorphin knockouts. Enkephalin-deficient mice showed no difference from wild-type mice in baseline ethanol preference but also showed no stress-induced elevation of ethanol consumption. Interestingly, we found a two-marker haplotype in the POMC gene that was associated with alcohol dependence in females in both cohorts.
Together these results indicate a contribution of beta-endorphin to ethanol consumption and dependence.


Available from: Ildiko Racz
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    • "In support, endogenous enkephalins are necessary for NAL-CPA (Skoubis et al. 2005) but not opioid-induced CPP (Marquez et al. 2006) whereas mu opioid receptors are necessary for both phenotypes (Matthes et al. 1996; Skoubis et al. 2001). Interestingly, NAL-CPA-prone J mice also drink more ethanol than C57BL/6N mice from the Charles River vendor (Bryant et al. 2008) and this behavior is in part mediated by endogenous opioids (Racz et al. 2008). Future studies will examine the potential for B6 strain differences in basal and druginduced endogenous opioid levels as a potential neurochemical mechanism for variation in motivational behaviors. "
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    ABSTRACT: Drug liking versus drug disliking is a subjective motivational measure in humans that assesses the addiction liability of drugs. Variation in this trait is hypothesized to influence vulnerability versus resilience toward substance abuse disorders and likely contains a genetic component. In rodents and humans, conditioned place preference (CPP) / aversion (CPA) is a Pavlovian conditioning paradigm whereby a learned preference for the drug-paired environment is used to infer drug liking whereas a learned avoidance or aversion is used to infer drug disliking. C57BL/6 inbred mouse substrains are nearly genetically identical, yet demonstrate robust differences in addiction-relevant behaviors, including locomotor sensitization to cocaine and consumption of ethanol. Here, we tested the hypothesis that B6 substrains would demonstrate differences in the rewarding properties of the mu opioid receptor agonist oxycodone (5 mg/kg, i.p.) and the aversive properties of the opioid receptor antagonist naloxone (4 mg/kg, i.p.). Both substrains showed similar degrees of oxycodone-induced CPP; however, there was a three-fold enhancement of naloxone-induced CPA in agonist-naïve C57BL/6J relative to C57Bl/6NJ mice. Exploratory factor analysis of CPP and CPA identified unique factors that explain variance in behavioral expression of reward versus aversion. “Conditioned Opioid-Like Behavior” was a reward-based factor whereby drug-free locomotor variables resembling opioid treatment co-varied with the degree of CPP. “Avoidance and Freezing” was an aversion-based factor, whereby the increase in the number of freezing bouts co-varied with the degree of aversion. These results provide new insight into the behavioral architecture of the motivational properties of opioids. Future studies will use quantitative trait locus mapping in B6 substrains to identify novel genetic factors that contribute to the marked strain difference in NAL-CPA.
    Frontiers in Behavioral Neuroscience 12/2014; accepted. DOI:10.3389/fnbeh.2014.00450 · 3.27 Impact Factor
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    • "E2 may modulate the behavioral effects of cocaine by regulating MOR and KOR signaling in mesocorticolimbic brain structures in female rats [135]. In addition, sex-dependent differences have been found in the intake of ethanol in the absence of β-endorphins in mice [136], and in the regulation of gonadal hormone, DOR binding, and MOR density in the hippocampus by prenatal exposure to morphine in rats [137,138]. "
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    ABSTRACT: Opioids are widely used as the pain reliever and also notorious for being addictive drugs. Sex differences in the opioid analgesia and addiction have been reported and investigated in human subjects and animal models. Yet, the molecular mechanism underlying the differences between males and females is still unclear. Here, we reviewed the literature describing the sex differences in analgesic responses and addiction liabilities to clinically relevant opioids. The reported interactions among opioids, estrogens, opioid receptors, and estrogen receptors are also evaluated. We postulate that the sex differences partly originated from the crosstalk among the estrogen and opioid receptors when stimulated by the exogenous opioids, possibly through common secondary messengers and the downstream gene transcriptional regulators.
    Molecular Pain 09/2013; 9(1):45. DOI:10.1186/1744-8069-9-45 · 3.65 Impact Factor
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    • "In a family-based association study, among other SNPs, association of intron 1 SNPs (rs934778 and rs1009388) was found in a smaller subgroup of subjects with both alcohol and opioid dependence within European American (EA) families (Xuei et al., 2007). Also, an association of alcoholism with 3 POMC gene SNPs, among them rs934778, was reported for European population (Racz et al., 2008). A number of studies investigated association of kappa opioid receptor gene (OPRK1) SNPs with alcoholism and other addictions (rev in (Levran et al., 2012)). "
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    ABSTRACT: Due to their involvement in dependence pathways, opioid system genes represent strong candidates for association studies investigating alcoholism. In this study, single nucleotide polymorphisms within the genes for mu (OPRM1) and kappa (OPRK1) opioid receptors and precursors of their ligands - proopiomelanocortin (POMC), coding for beta-endorphin and prodynorphin (PDYN) coding for dynorphins, were analyzed in a case-control study that included 354 male alcohol-dependent and 357 male control subjects from Croatian population. Analysis of allele and genotype frequencies of the selected polymorphisms of the genes OPRM1/POMC and OPRK1/PDYN revealed no differences between the tested groups. The same was true when alcohol-dependent persons were subdivided according to the Cloninger's criteria into type-1 and type-2 groups, known to differ in the extent of genetic control. Thus, the data obtained suggest no association of the selected polymorphisms of the genes OPRM1/POMC and OPRK1/PDYN with alcoholism in Croatian population.
    Neuropeptides 08/2013; 47(5). DOI:10.1016/j.npep.2013.08.002 · 2.64 Impact Factor
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