Dataset Information

Modification of anxiety-like behaviors by nociceptin/orphanin FQ (N/OFQ) and time-dependent changes in N/OFQ-NOP gene expression following ethanol withdrawal.

ABSTRACT: Anxiety is a key consequence of ethanol withdrawal and important risk factor for relapse. The neuropeptide nociceptin/orphanin FQ (N/OFQ) or agonists at this peptide's receptor (NOP) exert anxiolytic-like and antistress actions. N/OFQ dysfunction has been linked to both a high-anxiety behavioral phenotype and excessive ethanol intake. Recent studies suggest a possible link between genetic polymorphisms of the NOP transcript and alcoholism. Thus, in the present study, the effects of intracerebroventricularly administered N/OFQ were tested for modification of anxiety-like behaviors, using the shock-probe defensive burying and elevated plus-maze tests, in ethanol-dependent versus non-dependent rats, 1 and 3 weeks following termination of ethanol exposure. Additionally, prepro-N/OFQ (ppN/OFQ) and NOP receptor gene expression was measured in the central nucleus of the amygdala, in the bed nucleus of the stria terminalis and in the lateral hypothalamus at the same timepoints in separate subjects. One week post-ethanol, N/OFQ dose-dependently attenuated elevated anxiety-like behavior in ethanol-dependent rats and produced anxiolytic-like effects in non-dependent controls in both behavioral tests. However, 3 weeks post-ethanol, N/OFQ altered behavior consistent with anxiogenic-like actions in ethanol-dependent rats but continued to exert anxiolytic-like actions in non-dependent controls. These findings were paralleled by ethanol history-dependent changes of ppN/OFQ and NOP gene expression that showed a distinctive time course in the examined brain structures. The results demonstrate that ethanol dependence and withdrawal are associated with neuroadaptive changes in the N/OFQ-NOP system, suggesting a role of this neuropeptidergic pathway as a therapeutic target for the treatment of alcohol abuse.

SUBMITTER: Aujla H

PROVIDER: S-EPMC3477306 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Modification of anxiety-like behaviors by nociceptin/orphanin FQ (N/OFQ) and time-dependent changes in N/OFQ-NOP gene expression following ethanol withdrawal.

Aujla Harinder H Cannarsa Rosalia R Romualdi Patrizia P Ciccocioppo Roberto R Martin-Fardon Rémi R Weiss Friedbert F

Addiction biology 20120715 3

Anxiety is a key consequence of ethanol withdrawal and important risk factor for relapse. The neuropeptide nociceptin/orphanin FQ (N/OFQ) or agonists at this peptide's receptor (NOP) exert anxiolytic-like and antistress actions. N/OFQ dysfunction has been linked to both a high-anxiety behavioral phenotype and excessive ethanol intake. Recent studies suggest a possible link between genetic polymorphisms of the NOP transcript and alcoholism. Thus, in the present study, the effects of intracerebrov ...[more]

PMID: 22804785

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Project description:Sepsis is a dysregulated host response to infection that can cause widespread effects on other organs including cardiovascular depression, hypotension and organ failure. The receptor for Nociceptin/Orphanin FQ (N/OFQ), NOP is expressed on immune cells and these cells can release the peptide. Exogenous N/OFQ can dilate blood vessels and this peptide is increased in animal and human sepsis. We hypothesise that NOP receptors are present on vascular endothelial cells and therefore provide the target for released N/OFQ to cause vasodilation and hence hypotension. Using human umbilical vein endothelial cells (HUVEC) and human vascular smooth muscle cells (HVSMC) freshly prepared from umbilical cords and up to passage 4, we assessed NOP mRNA expression by Polymerase Chain Reaction (PCR), NOP surface receptor expression using a fluorescent NOP selective probe (N/OFQATTO594) and NOP receptor function with N/OFQ stimulated ERK1/2 phosphorylation. As an in vitro sepsis mimic we variably incubated cells with 100ng/ml Lipopolysaccharide and Peptidoglycan G (LPS/PepG). HUVECs express NOP mRNA and this was reduced by ~80% (n = 49) after 24-48 hours treatment with LPS/PepG. Untreated cells do not express surface NOP receptors but when treated with LPS/PepG the reduced mRNA was translated into protein visualised by N/OFQATTO594 binding (n = 49). These NOP receptors in treated cells produced an N/OFQ (1μM) driven increase in ERK1/2 phosphorylation (n = 20). One (of 50) HUVEC lines expressed NOP mRNA and receptor protein in the absence of LPS/PepG treatment. In contrast, HVSMC expressed NOP mRNA and surface receptor protein (n = 10) independently of LPS/PepG treatment. These receptors were also coupled to ERK1/2 where N/OFQ (1μM) increased phosphorylation. Collectively these data show that an in vitro sepsis mimic (LPS/PepG) upregulates functional NOP expression in the vascular endothelium. Activation of these endothelial receptors as suggested from in vivo whole animal work may contribute to the hypotensive response seen in sepsis. Moreover, blockade of these receptors might be a useful adjunct in the treatment of sepsis.

Project description:UnlabelledNociceptin/orphanin FQ peptide (NOP) receptor is a new class of opioid receptor that may play a pathophysiologic role in anxiety and drug abuse and is a potential therapeutic target in these disorders. We previously developed a high-affinity PET ligand, (11)C-NOP-1A, which yielded promising results in monkey brain. Here, we assessed the ability of (11)C-NOP-1A to quantify NOP receptors in human brain and estimated its radiation safety profile.MethodsAfter intravenous injection of (11)C-NOP-1A, 7 healthy subjects underwent brain PET for 2 h and serial sampling of radial arterial blood to measure parent radioligand concentrations. Distribution volume (V(T); a measure of receptor density) was determined by compartmental (1- and 2-tissue) and noncompartmental (Logan analysis and Ichise's bilinear analysis [MA1]) methods. A separate group of 9 healthy subjects underwent whole-body PET to estimate whole-body radiation exposure (effective dose).ResultsAfter (11)C-NOP-1A injection, the peak concentration of radioactivity in brain was high (∼5-7 standardized uptake values), occurred early (∼10 min), and then washed out quickly. The unconstrained 2-tissue-compartment model gave excellent V(T) identifiability (∼1.1% SE) and fitted the data better than a 1-tissue-compartment model. Regional V(T) values (mL·cm(-3)) ranged from 10.1 in temporal cortex to 5.6 in cerebellum. V(T) was well identified in the initial 70 min of imaging and remained stable for the remaining 50 min, suggesting that brain radioactivity was most likely parent radioligand, as supported by the fact that all plasma radiometabolites of (11)C-NOP-1A were less lipophilic than the parent radioligand. Voxel-based MA1 V(T) values correlated well with results from the 2-tissue-compartment model, showing that parametric methods can be used to compare populations. Whole-body scans showed radioactivity in brain and in peripheral organs expressing NOP receptors, such as heart, pancreas, and spleen. (11)C-NOP-1A was significantly metabolized and excreted via the hepatobiliary route. Gallbladder had the highest radiation exposure (21 μSv/MBq), and the effective dose was 4.3 μSv/MBq.Conclusion(11)C-NOP-1A is a promising radioligand that reliably quantifies NOP receptors in human brain. The effective dose in humans is low and similar to that of other (11)C-labeled radioligands, allowing multiple scans in 1 subject.

Dataset Information

Modification of anxiety-like behaviors by nociceptin/orphanin FQ (N/OFQ) and time-dependent changes in N/OFQ-NOP gene expression following ethanol withdrawal.

Publications

Modification of anxiety-like behaviors by nociceptin/orphanin FQ (N/OFQ) and time-dependent changes in N/OFQ-NOP gene expression following ethanol withdrawal.

Similar Datasets

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