Ethanol consumption and reward are decreased in µ-opiate receptor knockout mice

Hall, F. Scott; Sora, Ichiro; Uhl, George R.

doi:10.1007/s002130000622

Cited by 199 publications

(157 citation statements)

References 62 publications

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“…Both rodent and human studies have shown that chronic cocaine and alcohol use lead to altered mu-opioid receptor expression measured as change in levels of mRNA, by quantitative autoradiography, or by PET (Unterwald et al, 1992(Unterwald et al, , 1993(Unterwald et al, , 1994Zubieta et al, 1996;Yuferov et al, 1999;Bencherif et al, 2004). In mu-opioid receptor knockout mice, opiate self-administration is blocked and both cocaine and alcohol self-administration are attenuated (Roberts et al, 2000;Hall et al, 2001). In addition, several animal models have shown that mu-opioid receptor antagonists will eliminate or curtail alcohol and psychostimulant self-administration and conditioned place preference (Altshuler et al, 1980;Myers et al, 1986;Trujillo et al, 1991;Middaugh and Bandy, 2000).…”

Section: Mu-and Kappa-opioid System and Addictionmentioning

confidence: 99%

Nalmefene Induced Elevation in Serum Prolactin in Normal Human Volunteers: Partial Kappa Opioid Agonist Activity?

Bart

Schluger

Borg

et al. 2005

Neuropsychopharmacol

126

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In humans, mu-and kappa-opioid receptor agonists lower tuberoinfundibular dopamine, which tonically inhibits prolactin release. Serum prolactin is, therefore, a useful biomarker for tuberoinfundibular dopamine. The current study evaluated the unexpected finding that the relative mu-and kappa-opioid receptor selective antagonist nalmefene increases serum prolactin, indicating possible kappa-opioid receptor agonist activity. In all, 33 healthy human volunteers (14 female) with no history of psychiatric or substance use disorders received placebo, nalmefene 3 mg, and nalmefene 10 mg in a double-blind manner. Drugs were administered between 0900 and 1000 on separate days via 2-min intravenous infusion. Serial blood specimens were analyzed for serum levels of prolactin. Additional in vitro studies of nalmefene binding to cloned human kappa-opioid receptors transfected into Chinese hamster ovary cells were performed. Compared to placebo, both doses of nalmefene caused significant elevations in serum prolactin (po0.002 for nalmefene 3 mg and po0.0005 for nalmefene 10 mg). There was no difference in prolactin response between the 3 and 10 mg doses. Binding assays confirmed nalmefene's affinity at kappa-opioid receptors and antagonism of mu-opioid receptors. [ 35 S]GTPgS binding studies demonstrated that nalmefene is a full antagonist at mu-opioid receptors and has partial agonist properties at kappa-opioid receptors. Elevations in serum prolactin following nalmefene are consistent with this partial agonist effect at kappa-opioid receptors. As kappaopioid receptor activation can lower dopamine in brain regions important to the persistence of alcohol and cocaine dependence, the partial kappa agonist effect of nalmefene may enhance its therapeutic efficacy in selected addictive diseases.

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Section: Mu-and Kappa-opioid System and Addictionmentioning

confidence: 99%

Nalmefene Induced Elevation in Serum Prolactin in Normal Human Volunteers: Partial Kappa Opioid Agonist Activity?

Bart

Schluger

Borg

et al. 2005

Neuropsychopharmacol

126

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“…Endogenous opioids acting at the -opioid receptor (MOR) serve a pivotal function in reward processing and addictive behaviors (Matthes et al, 1996;Hall et al, 2001;Olive et al, 2001;Ghozland et al, 2002;Mathon et al, 2003Mathon et al, , 2005Roth-Deri et al, 2003;Solinas et al, 2004;Jarjour et al, 2009;Mitchell et al, 2012). This is especially the case for MORs regulating the ventral tegmental area (VTA) (Bozarth and Wise, 1984;Wise, 1989;Laviolette et al, 2004), which typically suppress GABAergic inputs to VTA dopamine neurons (Johnson and North, 1992;Manzoni and Williams, 1999;Bergevin et al, 2002;Jalabert et al, 2011;Matsui and Williams, 2011).…”

Section: Introductionmentioning

confidence: 99%

Morphine Withdrawal Enhances Constitutive μ-Opioid Receptor Activity in the Ventral Tegmental Area

et al. 2012

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-Opioid receptors (MORs) in the ventral tegmental area (VTA) are pivotally involved in addictive behavior. While MORs are typically activated by opioids, they can also become constitutively active in the absence of any agonist. In the current study, we present evidence that MOR constitutive activity is highly relevant in the mouse VTA, as it regulates GABAergic input to dopamine neurons. Specifically, suppression of MOR constitutive activity with the inverse agonist KC-2-009 enhanced GABAergic neurotransmission onto VTA dopamine neurons. This inverse agonistic effect was fully blocked by the specific MOR neutral antagonist CTOP, which had no effect on GABAergic transmission itself. We next show that withdrawal from chronic morphine further increases the magnitude of inverse agonistic effects at the MOR, suggesting enhanced MOR constitutive activity. We demonstrate that this increase can be an adaptive response to the detrimental elevation in cAMP levels known to occur during morphine withdrawal. These findings offer important insights in the physiological occurrence and function of MOR constitutive activity, and have important implications for therapeutic strategies aimed at normalizing MOR signaling during addiction and opioid overdose.

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“…Quantitative trait locus studies have identified the chromosomal region containing the MOR (OPRM1) gene as important to the development and perpetuation of alcohol consumption (Grisel, 2000). Also, knockout mice lacking OPRM1 do not self-administer alcohol (Hall et al, 2001;Roberts et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Increased Attributable Risk Related to a Functional μ-Opioid Receptor Gene Polymorphism in Association with Alcohol Dependence in Central Sweden

Bart

Kreek

Ott

et al. 2004

Neuropsychopharmacol

199

130

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The m-opioid receptor (MOR), through its effects on reward and stress-responsivity, modulates alcohol intake in both animal and human laboratory studies. We have previously demonstrated that the frequently occurring A118G single-nucleotide polymorphism (SNP) in exon 1 of the MORgene (OPRM1), which encodes an amino-acid substitution, is functional and receptors encoded by the variant 118G allele bind the endogenous opioid peptide b-endorphin with three-fold greater affinity than prototype receptors. Other groups subsequently reported that this variant alters stress-responsivity in normal volunteers and also increases the therapeutic response to naltrexone (a m-preferring opioid antagonist) in the treatment of alcohol dependence. We compared frequencies of genotypes containing an 118G allele in 389 alcohol-dependent individuals and 170 population-based controls without drug or alcohol abuse or dependence. The A118G SNP was present in the Hardy-Weinberg equilibrium with an overall frequency of the 118G allele of 10.9%. There was a significant overall association between genotypes with an 118G allele and alcohol dependence (p ¼ 0.0074). The attributable risk for alcohol dependence in subjects with an 118G allele was 11.1%. There was no difference in A118G genotype between type 1 and type 2 alcoholics. In central Sweden, the functional variant 118G allele in exon 1 of OPRM1 is associated with an increased attributable risk for alcohol dependence.

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Ethanol consumption and reward are decreased in µ-opiate receptor knockout mice

Abstract: These data fit with the reported therapeutic efficacy of MOR antagonists in the treatment of human alcoholism. Allelic variants that confer differing levels of MOR expression could provide different degrees of risk for alcoholism.

Cited by 199 publications

References 62 publications

Nalmefene Induced Elevation in Serum Prolactin in Normal Human Volunteers: Partial Kappa Opioid Agonist Activity?

Nalmefene Induced Elevation in Serum Prolactin in Normal Human Volunteers: Partial Kappa Opioid Agonist Activity?

Morphine Withdrawal Enhances Constitutive μ-Opioid Receptor Activity in the Ventral Tegmental Area

Increased Attributable Risk Related to a Functional μ-Opioid Receptor Gene Polymorphism in Association with Alcohol Dependence in Central Sweden

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