[3h]-nociceptin ligand-binding and nociceptin opioid receptor mrna expression in the human brain

Berthele, Achim; Platzer, Stefan; Dworzak, D.; Schadrack, Jan; Mahal, Beatrice; Büttner, Andreas; Assmus, Hans; Wurster, K; Zieglgänsberger, W.; Conrad, Bastian; Tölle, TR

doi:10.1016/s0306-4522(03)00484-6

Cited by 63 publications

(44 citation statements)

References 45 publications

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“…Brain autoradiography studies in rodents have revealed a very high concentration of NOP receptors in the frontal cortex, and there are particularly high levels of NOP receptors in the cingulate cortex (Neal et al 1999; Sim and Childers 1997; Sim et al 1996). Consistent with these rodent findings, human positron emission tomography (PET) and post-mortem autoradiography studies have also reported high distribution of NOP receptors in the cingulate cortex and striatum (Berthele et al 2003; Lohith et al 2014; Lohith et al 2012). Moreover, NOP receptors are localized on dopaminergic nuclei in the VTA, and administration of a NOP receptor agonist inhibited dopamine neurotransmission in the VTA and NAc (Koizumi et al 2004a; Koizumi et al 2004b; Murphy et al 1996; Murphy and Maidment 1999; Murphy et al 2004).…”

Section: Discussionsupporting

confidence: 54%

Social defeat disrupts reward learning and potentiates striatal nociceptin/orphanin FQ mRNA in rats

et al. 2017

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Rationale Mood disorders can be triggered by stress and are characterized by deficits in reward processing, including disrupted reward learning (the ability to modulate behavior according to past rewards). Reward learning is regulated by the anterior cingulate cortex (ACC) and striatal circuits, both of which are implicated in the pathophysiology of mood disorders. Objectives Here we assessed in rats the effects of a potent stressor (social defeat) on reward learning and gene expression in the ACC, ventral tegmental area (VTA), and striatum. Methods Adult male Wistar rats were trained on an operant probabilistic reward task (PRT) and then exposed to three days of social defeat before assessment of reward learning. After testing, ACC, VTA, and striatum were dissected and expression of genes previously implicated in stress was assessed. Results Social defeat blunted reward learning (manifested as reduced response bias toward a more frequently rewarded stimulus), and was associated with increased nociceptin/orphanin FQ (N/OFQ) peptide mRNA levels in the striatum and decreased Fos mRNA levels in the VTA. Moreover, N/OFQ peptide and nociceptin receptor mRNA levels in ACC, VTA and striatum were inversely related to reward learning. Conclusions The behavioral findings parallel previous data in humans, suggesting that stress similarly disrupts reward learning in both species. Increased striatal N/OFQ mRNA in stressed rats characterized by impaired reward learning is consistent with accumulating evidence that antagonism of nociceptin receptors, which bind N/OFQ, has antidepressant-like effects. These results raise the possibility that nociceptin systems represent a molecular substrate through which stress produces reward learning deficits in mood disorders.

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Section: Discussionsupporting

confidence: 54%

Social defeat disrupts reward learning and potentiates striatal nociceptin/orphanin FQ mRNA in rats

et al. 2017

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“…We have recently discovered both labeled and unlabeled NOP receptor tracers with subnanomolar binding affinities with no intrinsic activity (i.e., antagonists), high selectivity, CNS penetration, and low nonspecific binding (Pedregal et al, 2012). 5 was safe, with favorable kinetics and reproducibility (Lohith et al, 2012(Lohith et al, , 2014, and exhibited distribution volume (V T ) consistent with known NOP density distribution (Berthele et al, 2003).…”

Section: Introductionmentioning

confidence: 78%

Occupancy of Nociceptin/Orphanin FQ Peptide Receptors by the Antagonist LY2940094 in Rats and Healthy Human Subjects

Raddad

Chappell

Meyer

et al. 2016

Drug Metabolism and Disposition

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Therapeutic benefits from nociceptin opioid peptide receptor (NOP) antagonism were proposed for obesity, eating disorders, and depression. LY2940094 ([2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methyl-pyrazol-1-yl]-3-pyridyl]methanol) is a novel, orally bioavailable, potent, and selective NOP antagonist. We studied NOP receptor occupancy (RO) after single oral LY2940094 doses in rat hypothalamus and human brain by use of liquid chromatography with tandem mass spectrometry (LC-MS/MS) (LSN2810397) and positron emission tomography (PET) ([(11)C]NOP-1A) tracers, respectively. A bolus plus constant infusion tracer protocol with PET was employed in humans at 2.5 and 26.5 hours after administration of the LY2940094 dose. The RO was calculated from the change in regional distributional volume (VT) corrected for nondisplaceable volume using Lasson plots. The RO followed a simple Emax relationship to plasma LY2940094 concentration, reaching near complete occupancy in both species. For rat hypothalamus, the plasma concentration at half-maximum RO (EC50) was 5.8 ng/ml. In humans, LY2940094 was well tolerated and safe over the 4-40 mg dose range, and it peaked in plasma at 2 to 6 hours after a 1- to 2-hour lag, with approximate dose-proportional exposure. After 4-40 mg doses, NOP RO was similar across the prefrontal cortex, occipital cortex, putamen, and thalamus, with EC50 of 2.94 to 3.46 ng/ml, less than 2-fold lower than in rats. Over 4-40 mg doses, LY2940094 mean plasma levels at peak and 24 hours were 7.93-102 and 1.17-14.1 ng/ml, corresponding to the cross-region average NOP RO of 73%-97% and 28%-82%, respectively. The rat EC50 translates well to humans. LY2940094 readily penetrates the human brain, and a once-daily oral dose of 40 mg achieves sustainably high (>80%) NOP RO levels suitable for testing clinical efficacy.

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“…This suggests that up-regulation of DOR or KOR in cells expressing the NOP receptor would be one means of reducing N/OFQmediated calcium channel modulation. Although autoradiographic and/or in situ hybridization studies suggest that KOR and NOP receptors are regionally colocalized in the descending analgesic reward pathways (Mansour et al, 1995;Berthele et al, 2003) and that DOR and NOP receptors are regionally colocalized in the cortex, nucleus accumbens, amygdala, and dorsal horn (Neal et al, 1999;Berthele et al, 2003), these methods do not confirm colocalization at a cellular level. However, functional evidence also supports cellular colocalization of KOR/NOP receptor in PAG and RVM, suggesting that KOR/NOP receptor heterodimerization may mediate nociceptive processing (Vaughan et al, 2001(Vaughan et al, , 2003.…”

Section: Heterodimerizationmentioning

confidence: 93%

Cellular Mechanisms of Nociceptin/Orphanin FQ (N/OFQ) Peptide (NOP) Receptor Regulation and Heterologous Regulation by N/OFQ

et al. 2013

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The nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor is the fourth and most recently discovered member of the opioid receptor superfamily that also includes m, d, and k opioid receptor subtypes (MOR, DOR, and KOR, respectively). The widespread anatomic distribution of the NOP receptor enables the modulation of several physiologic processes by its endogenous agonist, N/OFQ. Accordingly, the NOP receptor has gained a lot of attention as a potential target for the development of ligands with therapeutic use in several pathophysiological states. NOP receptor activation frequently results in effects opposing classic opioid receptor action; therefore, regulation of the NOP receptor and conditions affecting its modulatory tone are important to understand. Mounting evidence reveals a heterologous interaction of the NOP receptor with other G protein-coupled receptors, including MOR, DOR, and KOR, which may subsequently influence their function. Our focus in this review is to summarize and discuss the findings that delineate the cellular mechanisms of NOP receptor signaling and regulation and the regulation of other receptors by N/OFQ and the NOP receptor.

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[3h]-nociceptin ligand-binding and nociceptin opioid receptor mrna expression in the human brain

Cited by 63 publications

References 45 publications

Social defeat disrupts reward learning and potentiates striatal nociceptin/orphanin FQ mRNA in rats

Social defeat disrupts reward learning and potentiates striatal nociceptin/orphanin FQ mRNA in rats

Occupancy of Nociceptin/Orphanin FQ Peptide Receptors by the Antagonist LY2940094 in Rats and Healthy Human Subjects

Cellular Mechanisms of Nociceptin/Orphanin FQ (N/OFQ) Peptide (NOP) Receptor Regulation and Heterologous Regulation by N/OFQ

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