Buprenorphine Reduces Alcohol Drinking Through Activation of the Nociceptin/Orphanin FQ-NOP Receptor System

Ciccocioppo, Roberto; Economidou, Daina; Rimondini, R; Sommer, Wolfgang; Massi, Maurizio; Heilig, Markus

doi:10.1016/j.biopsych.2006.01.006

Cited by 89 publications

(78 citation statements)

References 87 publications

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“…In low doses buprenorphine increases alcohol consumption, but at high doses consumption decreases. However, the intracerebroventricular administration of the peptide NOP antagonist UFP-101 reverses the high dose buprenorphine-induced inhibition and results in the continued increase in alcohol consumption (Ciccocioppo et al, 2007). These results are consistent with a mu receptor-mediated increase in alcohol consumption at low buprenorphine doses, which is blocked and reversed by NOP receptor activation at higher doses of buprenorphine.…”

Section: B Bifunctional Compoundssupporting

confidence: 56%

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

et al. 2016

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The NOP receptor (nociceptin/orphanin FQ opioid peptide receptor) is the most recently discovered member of the opioid receptor family and, together with its endogenous ligand, N/OFQ, make up the fourth members of the opioid receptor and opioid peptide family. Because of its more recent discovery, an understanding of the cellular and behavioral actions induced by NOP receptor activation are less well developed than for the other members of the opioid receptor family. All of these factors are important because NOP receptor activation has a clear modulatory role on mu opioid receptor-mediated actions and thereby affects opioid analgesia, tolerance development, and reward. In addition to opioid modulatory actions, NOP receptor activation has important effects on motor function and other physiologic processes. This review discusses how NOP pharmacology intersects, contrasts, and interacts with the mu opioid receptor in terms of tertiary structure and mechanism of receptor activation; location of receptors in the central nervous system; mechanisms of desensitization and downregulation; cellular actions; intracellular signal transduction pathways; and behavioral actions with respect to analgesia, tolerance, dependence, and reward. This is followed by a discussion of the agonists and antagonists that have most contributed to our current knowledge. Because NOP receptors are highly expressed in brain and spinal cord and NOP receptor activation sometimes synergizes with mu receptor-mediated actions and sometimes opposes them, an understanding of NOP receptor pharmacology in the context of these interactions with the opioid receptors will be crucial to the development of novel therapeutics that engage the NOP receptor

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Section: B Bifunctional Compoundssupporting

confidence: 56%

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

et al. 2016

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“…†, significant difference from day 1 (P Ͻ 0.05). ]nociceptin-NH 2 (UFP-101), suggesting that the buprenorphine-induced reduction in alcohol consumption is caused by activation of NOP receptors (Ciccocioppo et al, 2007). An NOP-mediated reduction in CPP and self-administration of a variety of abused drugs by N/OFQ is already well documented (Murphy et al, 1999;Kotliń ska et al, 2002;Ciccocioppo et al, 2003;Zhao et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…A similar phenomenon has been reported when measuring the ability of buprenorphine to modify ethanol consumption in rats. Buprenorphine increases alcohol consumption at low doses but attenuates consumption at higher doses (Ciccocioppo et al, 2007). In both cases, the high dose reduction in antinociception and alcohol consumption is attributed to activation of nociceptin/orphanin FQ peptide (NOP) receptors (formerly known as ORL1), thereby diminishing the -mediated antinociceptive activity and -mediated increase in alcohol consumption.…”

Section: Introductionmentioning

confidence: 99%

The First Universal Opioid Ligand, (2S)-2-[(5R,6R,7R,14S)-N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylpentan-2-ol (BU08028): Characterization of the In Vitro Profile and In Vivo Behavioral Effects in Mouse Models of Acute Pain and Cocaine-Induced Reward

Khroyan¹,

Polgar²,

Cami‐Kobeci³

et al. 2010

J Pharmacol Exp Ther

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Certain behavioral features of buprenorphine, including a bellshaped curve for antinociception and attenuation of alcohol consumption, are thought to be mediated by activation of nociceptin/orphanin FQ peptide (NOP) receptors, despite moderate affinity and low efficacy at NOP receptors. We hypothesized that ligands with buprenorphine's physical properties, but possessing increased NOP receptor affinity and efficacy, would improve the profile as a drug abuse medication and reduce addiction liability. Using this strategy, we designed several compounds with universally high affinity, i.e., less than 10 nM at , ␦, , and NOP receptors. Among these, (2S)-2-[(5R,6R,7R,14S)-N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylpentan-2-ol (BU08028) has high affinity at all opioid receptors and increased NOP receptor efficacy in vitro in the [35 S]GTP␥S binding assay, however, while still being a partial agonist. In vivo, BU08028 was evaluated in an acute thermal antinociception assay, for its ability to induce conditioned place preference (CPP), and for its effect on cocaine-induced CPP. BU08028 is a very potent long-lasting analgesic. It produces an increase in locomotor activity and a significant CPP. As a pretreatment to cocaine, BU08028 does not alter cocaine CPP but causes a further increase in cocaine-induced locomotor activity. The analgesic, rewarding, and stimulant effects are probably caused by receptor stimulation. It is likely that with BU08028, a partial agonist at both NOP and receptors, -mediated activity overpowers NOPmediated effects. Thus, it is possible that a different buprenorphine analog that is a universal high-affinity opioid ligand but with "full agonist" activity at NOP may counteract traditional opioidmediated effects such as antinociception and reward.

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“…However, buprenorphine, a MOPr partial agonist and KOPr antagonist has been shown to have low efficacy at NOPr (Huang et al, 2001;Spagnolo et al, 2008). Its NOPr agonist activity has been reported to be responsible for the attenuation of its antinociceptive activity at high doses (Lutfy et al, 2003), and for the attenuation of alcohol consumption (Ciccocioppo et al, 2007). Buprenorphine's NOPr agonist activity is also implicated in the reduction of cocaine use in dually addicted cocaine-alcohol addicts (Montoya et al, 2004).…”

mentioning

confidence: 99%

Comparison of the Antinociceptive and Antirewarding Profiles of Novel Bifunctional Nociceptin Receptor/μ-Opioid Receptor Ligands: Implications for Therapeutic Applications

Toll

Khroyan²,

Polgar³

et al. 2009

J Pharmacol Exp Ther

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The nociceptin receptor (NOPr), a member of the opioid receptor family, is a target for the treatment of pain and drug abuse. Nociceptin/orphanin FQ (N/OFQ), the endogenous peptide for NOPr, not only modulates opioid antinociception, but also blocks the rewarding effects of several abused drugs, such as morphine, cocaine, and amphetamine. We hypothesized that NOPr agonists, with bifunctional activity at the -opioid receptor (MOPr), may function as nonaddicting analgesics or as drug abuse medications. Bifunctional small-molecule NOPr agonists possessing different selectivities and efficacies at MOPr were evaluated in an acute thermal antinociception assay, and for their ability to induce conditioned place preference (CPP) and their effect on morphineinduced CPP.

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Buprenorphine Reduces Alcohol Drinking Through Activation of the Nociceptin/Orphanin FQ-NOP Receptor System

Cited by 89 publications

References 87 publications

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

The First Universal Opioid Ligand, (2S)-2-[(5R,6R,7R,14S)-N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylpentan-2-ol (BU08028): Characterization of the In Vitro Profile and In Vivo Behavioral Effects in Mouse Models of Acute Pain and Cocaine-Induced Reward

Comparison of the Antinociceptive and Antirewarding Profiles of Novel Bifunctional Nociceptin Receptor/μ-Opioid Receptor Ligands: Implications for Therapeutic Applications

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