A Selective Nociceptin Receptor Antagonist to Treat Depression: Evidence from Preclinical and Clinical Studies

Post, Anke; Smart, Trevor S.; Krikke-Workel, Judith; Dawson, Gerard R.; Harmer, Catherine J.; Browning, Michael; Jackson, Kimberley; Kakar, Rishi; Mohs, Richard C.; Statnick, Michael A.; Wafford, Keith A.; McCarthy, Andrew; Barth, Vanessa N.; Witkin, Jeffrey M.

doi:10.1038/npp.2015.348

Cited by 88 publications

(124 citation statements)

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“…Thus, these findings further support a large body of evidence indicating that the blockade of NOP receptors promotes antidepressant-like effects. In fact, the actions of distinct NOP antagonists (i.e., [Nphe 1 ]N/OFQ(1-13)-NH 2 , UFP-101, SB-612111, J-113397, LY2940094) has been well established in behavioral despair tests (Gavioli and Calo' 2013;Post et al 2015). Moreover, it is worth highlighting the studies of Vitale et al (2009) andMedeiros et al (2015) which have demonstrated that the blockade of NOP receptors reversed depressive-like behaviors induced by chronic exposure to an unpredictable sequence of mild stressful stimuli in rats and by the transient inflammatory process elicited by a single administration of lipopolysaccharide in mice.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, these preclinical findings were corroborated by studies performed with the novel NOP receptor antagonist LY2940094 (Toledo et al 2014). This compound induces antidepressant-like effects in rodent models, and more importantly displayed antidepressant efficacy in patients with major depressive disorder (Post et al 2015).…”

Section: Introductionmentioning

confidence: 93%

“…The antidepressant-like effects produced by the NOP receptor blockade has been well established, at least by analyzing the rodents basal behavior in despair tests (Redrobe et al 2002;Gavioli et al 2003;Gavioli et al 2004;Rizzi et al 2007;Goeldner et al 2010;Post et al 2015). However, these tests, despite their wide use to predict the effects of antidepressants, have no direct relationship to depressive symptoms in humans (Holmes 2003;Petit-Demouliere et al 2005).…”

Section: Introductionmentioning

confidence: 94%

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Antidepressant activity of nociceptin/orphanin FQ receptor antagonists in the mouse learned helplessness

et al. 2016

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 94%

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Antidepressant activity of nociceptin/orphanin FQ receptor antagonists in the mouse learned helplessness

et al. 2016

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“…The available information in this specific field was recently reviewed (Gavioli and Calo', 2013). Very recently a double-blind, placebocontrolled trial performed with the novel NOP selective antagonist LY2940094 in patients with major depressive disorder provided the first clinical evidence that the blockade of NOP receptor signaling represents a promising strategy for the treatment of depression (Post et al, 2015).…”

Section: S]mentioning

confidence: 99%

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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“…Pharmacological blockade of NOP receptors by selective antagonists specifically attenuated the motivation for alcohol in Wt but not in NOP ( − / − ) rats. A novel NOP antagonist with a safe pharmacological profile is currently under investigation for depression in humans (Post et al, 2016). Substance use disorders may possibly represent an additional clinical indication for this compound.…”

Section: Nop Antagonists Attenuate Ethanol Drinking In Wtmentioning

confidence: 99%

Genetic Deletion of the Nociceptin/Orphanin FQ Receptor in the Rat Confers Resilience to the Development of Drug Addiction

Kallupi

Scuppa

Guglielmo

et al. 2016

Neuropsychopharmacol

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The nociceptin (NOP) receptor is a G-protein-coupled receptor whose natural ligand is the NOP/orphanin FQ (N/OFQ) peptide. Evidence from pharmacological studies suggests that the N/OFQ system is implicated in the regulation of several addiction-related phenomena, such as drug intake, withdrawal, and relapse. Here, to further explore the role of NOP system in addiction, we used NOP (− / − ) rats to study the motivation for cocaine, heroin, and alcohol self-administration in the absence of N/OFQ function. Conditioned place preference (CPP) and saccharin (0.2% w/v) self-administration were also investigated. Results showed that NOP ( − / − ) rats selfadminister less cocaine (0.25, 0.125, or 0.5 mg/infusion) both under a fixed ratio 1 and a progressive ratio schedule of reinforcement compared with wild-type (Wt) controls. Consistently, cocaine (10 mg/kg, i.p.) was able to induce CPP in Wt but not in NOP ( − / − ). When NOP ( − / − ) rats were tested for heroin (20 μg/infusion) and ethanol (10% v/v) self-administration, they showed significantly lower drug intake compared with Wt. Conversely, saccharin self-administration was not affected by NOP deletion, excluding the possibility of nonspecific learning deficits or generalized disruption of reward mechanisms in NOP ( − / − ) rats. These findings were confirmed with pharmacological experiments using two selective NOP antagonists, SB-612111 and LY2817412. Both drugs attenuated alcohol selfadministration in Wt rats but not in NOP ( − / − ) rats. In conclusion, our results demonstrate that genetic deletion of NOP receptors confers resilience to drug abuse and support a role for NOP receptor antagonism as a potential treatment option for drug addiction.

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A Selective Nociceptin Receptor Antagonist to Treat Depression: Evidence from Preclinical and Clinical Studies

Cited by 88 publications

References 50 publications

Antidepressant activity of nociceptin/orphanin FQ receptor antagonists in the mouse learned helplessness

Antidepressant activity of nociceptin/orphanin FQ receptor antagonists in the mouse learned helplessness

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

Genetic Deletion of the Nociceptin/Orphanin FQ Receptor in the Rat Confers Resilience to the Development of Drug Addiction

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