title: The biology of Nociceptin/Orphanin FQ (N/OFQ) related to obesity, stress, anxiety, mood, and drug dependence.
abstract: Nociceptin/Orphanin FQ (N/OFQ) is a 17 amino acid peptide that was deorphanized in 1995. The generation of specific agonists, antagonists and receptor deficient mice and rats has enabled progress in elucidating the biological functions of N/OFQ. Additionally, radio-imaging technologies have been advanced for investigation of this system in animals and humans. Together with traditional neurobehavioral techniques, these tools have been utilized to identify the biological significance of the N/OFQ system and its interacting partners. The present review focuses on the role of N/OFQ in the regulation of feeding, body weight homeostasis, stress, the stress-related psychiatric disorders of depression and anxiety, and in drug and alcohol dependence. Critical evaluation of the current scientific preclinical literature suggests that small molecule modulators of nociceptin opioid peptide receptors (NOP) might be useful in the treatment of diseases related to these biological functions. In particular, the literature data suggest that antagonism of NOP receptors will produce anti-obesity and antidepressant activities in humans. However, there are also contradictory data discussed. The current literature on the role of N/OFQ in anxiety and addiction, on the other hand points primarily to a role of agonist modulation being potentially therapeutic. Some drug-like molecules that function either as agonists or antagonists of NOP receptors have been optimized for human clinical study to test some of these hypotheses. The discovery of PET ligands for NOP receptors, combined with the pharmacological tools and burgeoning preclinical data set discussed here bodes well for a rapid advancement of clinical understanding and potential therapeutic benefit.
authors.affiliation: Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN, USA. Electronic address: jwitkin@lilly.com.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Witkin
authors.affiliation: Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Statnick
authors.affiliation: Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Rorick-Kehn
authors.affiliation: University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Pintar
authors.affiliation: University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Ansonoff
authors.affiliation: Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Yanyun
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: R Craig
authors.initials: RC
authors.lastname: Tucker
authors.affiliation: School of Pharmacy, University of Camerino, Camerino, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Ciccocioppo
mesh_terms: D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000503:physiopathology; D015195:Drug Design; D006801:Humans; D051379:Mice; D019964:Mood Disorders / Q000188:drug therapy / Q000503:physiopathology; D009292:Narcotic Antagonists; D009765:Obesity / Q000188:drug therapy / Q000503:physiopathology; D018847:Opioid Peptides / Q000378:metabolism*; D051381:Rats; D011957:Receptors, Opioid / Q000819:agonists / Q000378:metabolism*; D013315:Stress, Psychological / Q000188:drug therapy / Q000503:physiopathology; D019966:Substance-Related Disorders / Q000188:drug therapy / Q000503:physiopathology; D000094942:Nociceptin Receptor; D000097629:Nociceptin
chemical_list: D009292:Narcotic Antagonists; D018847:Opioid Peptides; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; D000097629:Nociceptin
keywords: (1S,3aS)-8- (2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one, a NOP receptor agonist; (±)trans-1-[1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one, a NOP receptor antagonist; 2-{3-[1-((1R)-acenaphthen-1-yl)piperidin-4-yl]-2,3-dihydro-2-oxo-benzimidazol-1-yl}-N-methylacetamide, a NOP receptor agonist; 5-HT; 5-hydroxytryptamine or serotonin; 8-[bis(2-methylphenyl)-methyl]-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol; ACTH; Alcohol-preferring rats; Anxiety; BED; BNST; CGRP; CPP; CRF; CTA; Calcitonin gene related peptide; CeA; DA; Depression; Drug dependence; EPSC; FST; G-protein activated, inwardly rectifying K(+) channel; G-protein-coupled receptor; GIRK; GPCR; HPA; J-113397; JTC-801; KO; MDD; Marchigian Sardinian Alcohol-Preferring; N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl)benzamide hydrochloride, a NOP receptor antagonist; N/OFQ; NAcc; NE; NOP; NPY; Nociceptin opioid peptide or Nociceptin opioid peptide receptor; Nociceptin/Orphanin FQ; Nociceptin/Orphanin FQ (F: phenylalanine, Q: glutamine, the amino acids that begin and end the peptide sequence); ORL; Obesity; P rats; POMC; Pro-opiomelanocortin; Ro 64-6198; SB-612111; SCH 221510; SCH 655842; Stress; TST; UFP-101; VTA; W212393; [(–)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol, a NOP receptor antagonist; [Nphe(1),Arg(14),Lys(15)]N/OFQ-NH(2), a NOP receptor antagonist; adrenocorticotropic hormone; bed nucleus of stria terminalis; binge eating disorder; central nucleus of the amygdala; conditioned place preference; conditioned taste aversion; corticotrophin-releasing factor; dopamine; endo-8-[bis(2-chlorophenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octane-3-carboxamide, a NOP receptor agonist; excitatory post-synaptic current; forced-swim test; hypothalamic–pituitary axis; knockout; mPFC; major depressive disorder; medial prefrontal cortex; msP; neuropeptide Y; norepinephrine; nucleus accumbens; opioid-receptor-like; tail-suspension test; ventral tegmental area