A novel nociceptin receptor antagonist LY2940094 inhibits excessive feeding behavior in rodents: A possible mechanism for the treatment of binge eating disorder

Michael A. Statnick, Yanyun Chen, Michael Ansonoff, Jeffrey M. Witkin, Linda Rorick-Kehn, Todd M. Suter, Min Song, Charlie Hu, Celia Lafuente, Alma Jiménez, Ana Benito, Nuria Diaz, Maria Angeles Martínez-Grau, Miguel A. Toledo, John E. Pintar

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

Abstract

Nociceptin/orphanin FQ (N/OFQ), a 17 amino acid peptide, is the endogenous ligand of the ORL1/nociceptin-opioid-peptide (NOP) receptor. N/OFQ appears to regulate a variety of physiologic functions including stimulating feeding behavior. Recently, a new class of thienospiro-piperidine-based NOP antagonists was described. One of these molecules, LY2940094 has been identified as a potent and selective NOP antagonist that exhibited activity in the central nervous system. Herein, we examined the effects of LY2940094 on feeding in a variety of behavioralmodels. Fasting-induced feeding was inhibited by LY2940094 in mice, an effect that was absent in NOP receptor knockoutmice. Moreover, NOP receptor knockout mice exhibited a baseline phenotype of reduced fasting-induced feeding, relative to wild-type littermate controls. In lean rats, LY2940094 inhibited the overconsumption of a palatable high-energy diet, reducing caloric intake to control chow levels. In dietary-induced obese rats, LY2940094 inhibited feeding and body weight regain induced by a 30% daily caloric restriction. Last, in dietary-induced obese mice, LY2940094 decreased 24-hour intake of a high-energy diet made freely available. These are the first data demonstrating that a systemically administered NOP receptor antagonist can reduce feeding behavior and body weight in rodents. Moreover, the hypophagic effect of LY2940094 is NOP receptor dependent and not due to off-target or aversive effects. Thus, LY2940094 may be useful in treating disorders of appetitive behavior such as binge eating disorder, food choice, and overeating, which lead to obesity and its associated medical complications and morbidity.

Original languageEnglish (US)
Pages (from-to)493-502
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume356
Issue number2
DOIs
StatePublished - Feb 1 2016

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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