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Central nociceptin/orphanin FQ system elevates food consumption by both increasing energy intake and reducing aversive responsiveness
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
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2010 (English)In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 299, no 2, R655-R663 p.Article in journal (Refereed) Published
Abstract [en]

Nociceptin/orphanin FQ (N/OFQ), the nociceptin opioid peptide (NOP) receptor ligand, increases feeding when injected centrally. Initial data suggest that N/OFQ blocks the development of a conditioned taste aversion (CTA). The current project further characterized the involvement of N/OFQ in the regulation of hunger vs. aversive responses in rats by employing behavioral, immunohistochemical, and real-time PCR methodology. We determined that the same low dose of the NOP antagonist [Nphe(1)]N/OFQ(1-13)NH(2) delivered via the lateral ventricle diminishes both N/OFQ- and deprivation-induced feeding. This anorexigenic effect did not stem from aversive consequences, as the antagonist did not cause the development of a CTA. When [Nphe(1)]N/OFQ(1-13)NH(2) was administered with LiCl, it moderately delayed extinction of the LiCl-induced CTA. Injection of LiCl + antagonist compared with LiCl alone generated an increase in c-Fos immunoreactivity in the central nucleus of the amygdala. The antagonist alone elevated Fos immunoreactivity in the paraventricular nucleus of the hypothalamus, nucleus of the solitary tract, and central nucleus of the amygdala. Hypothalamic NOP mRNA levels were decreased during energy intake restriction induced by aversion, as well as in non-CTA rats food-restricted to match CTA-reduced consumption. Brain stem NOP was upregulated only in aversion. Prepro-N/OFQ mRNA showed a trend toward upregulation in restricted rats (P = 0.068). We conclude that the N/OFQ system promotes feeding by affecting the need to replenish lacking calories and by reducing aversive responsiveness. It may belong to mechanisms that shift a balance between the drive to ingest energy and avoidance of potentially tainted food.

Place, publisher, year, edition, pages
2010. Vol. 299, no 2, R655-R663 p.
Keyword [en]
food intake, conditioning, hypothalamus, brain stem, amygdala, lithium chloride, NOP receptor, ORL1
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-135060DOI: 10.1152/ajpregu.00556.2009ISI: 000280569800028PubMedID: 20427724OAI: oai:DiVA.org:uu-135060DiVA: diva2:374333
Available from: 2010-12-03 Created: 2010-12-03 Last updated: 2014-06-30Bibliographically approved
In thesis
1. Non-caloric regulation of food intake
Open this publication in new window or tab >>Non-caloric regulation of food intake
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Food intake is shaped by environmental, endocrine, metabolic, and reward-related signals. A change in appetite is an outcome of integration of the relevant external and internal stimuli. While the main purpose of eating is to reverse a negative energy balance, mechanisms protecting homeostasis change appetite for other reasons. This thesis examines the role of select brain mechanisms in regulating consumption driven by aspects other than energy.

In paper I, an increased percentage of c-Fos positive OT neurons was observed after mice ingested sucrose, while no change was found after Intralipid intake. Given a choice between isocaloric sugar and Intralipid solutions, mice injected with an OT receptor antagonist increase their preference for sucrose, while total calorie intake remains unchanged, suggesting that OT prevents overconsumption of sugar.

Paper II addresses whether MCH, which has anxiolytic properties and mediates reward-motivated feeding, has the ability to alleviate conditioned taste aversion in rats. We found that while mRNA expression of MCH and its receptor are changed in aversive animals, central injections of MCH do not prevent the acquisition of aversion, nor do they affect the rate of extinction of the taste aversion.

Paper III describes evidence that the N/OFQ system facilitates food intake by alleviating aversive responsiveness. Blocking the NOP receptor delays extinction of aversion and reduces food intake in hungry rats.

Paper IV reports that leucine ingestion increases mRNA expression levels of genes known to mediate reward, as well as orexigenic gene expression in the nucleus accumbens (Nacc), a key component of the reward circuit. Adding leucine to drinking water increases activity of the reward system, which possibly contributes to the pleasure of consumption.

A separate approach using Drosophila melanogaster is introduced in paper V which provides evidence that knocking down the gene for the transcription factor Ets96B during development results in a simultaneous disruption in sleep patterns and appetite, thus highlighting the interplay between these physiological parameters.

We conclude that OT, MCH, N/OFQ and Ets96B belong to mechanisms regulating food intake for reasons other than energy balance. Composition of food and negative associations with diets affect neural networks controlling appetite.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 54 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1007
National Category
Research subject
urn:nbn:se:uu:diva-223809 (URN)978-91-554-8966-3 (ISBN)
Public defence
2014-06-13, B:21, BMC, Husargatan 3, Uppsala, 09:15 (English)
Available from: 2014-05-23 Created: 2014-04-25 Last updated: 2014-06-30

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