Skip to main content
SpringerLink
Log in
Book cover

The Nociceptin/Orphanin FQ Peptide Receptor pp 233–257Cite as

NOP Ligands for the Treatment of Anxiety and Mood Disorders

  • Chapter
  • First Online:

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 254))

Abstract

Many studies point toward the nociceptin/orphanin FQ (N/OFQ) and the N/OFQ peptide receptor (NOP) as targets for the development of innovative drugs for treating anxiety- and mood-related disorders. Evidence supports the view that the activation of NOP receptors with agonists elicits anxiolytic-like effects, while its blockade with NOP antagonists promotes antidepressant-like actions in rodents. Genetic studies showed that NOP receptor knockout mice display an antidepressant-like phenotype, and NOP antagonists are inactive in these animals. In contrast, the genetic blockade of NOP receptor signaling generally displays an increase of anxiety states in the elevated plus-maze test. In this chapter we summarized the most relevant findings of NOP receptor ligands in the modulation of anxiety and mood disorders, and the putative mechanisms of action are discussed.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Abbreviations

ACTH:

Adrenocorticotropic hormone

BDNF:

Brain-derived neurotrophic factor

BNST:

Bed nucleus of the stria terminalis

CRF:

Corticotropin-releasing factor

DRL:

Differential reinforcement of low rate schedule

DRN:

Dorsal raphe nucleus

FGF-2:

Fibroblast growth factor

HPA:

Hypothalamus-pituitary-adrenal axis

Icv:

Intracerebroventricular

IL-6:

Interleukin-6

J-113397:

1-[(3R,4R)-1-(cyclooctylmethyl)-3-(hydroxymethyl)-4-piperidinyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one

JTC-801:

N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl)benzamide hydrochloride

LPS:

Bacterial lipopolysaccharide

LY2940094:

[2-[4-[(2-chloro-4,4-difluoro-spiro[5Hthieno[2,3-c]pyran-7,4′-piperidine]-1′-yl)methyl]-3-methylpyrazol-1-yl]-3-pyridyl]methanol

N/OFQ:

Nociceptin/orphanin FQ

NOP(−/−):

Mice knockout for the NOP receptor

ppN/OFQ:

N/OFQ precursor

ppN/OFQ(−/−):

Mice knockout for the N/OFQ precursor

PTSD:

Post-traumatic stress disorder

PVN:

Paraventricular nucleus of hypothalamus

Ro 64-6198:

(1S,3aS)-8-(2,3,3a,4,5,6-Hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one

Ro 65-6570:

(RS)-8-(1,2-Dihydro-1-acenaphthylenyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one

SB-612111:

(5S,7S)-7-[[4-(2,6-dichlorophenyl)-1-piperidinyl]methyl]-6,7,8,9-tetrahydro-1-methyl-5H-benzocyclohepten-5-ol

SNP:

Single-nucleotide polymorphism

SSRI:

Selective serotonin reuptake inhibitor

TNF-α:

Tumor necrosis factor-α

UFP-101:

[Nphe1, Arg14, Lys15] N/OFQ-NH2

References

  • Aguilera G, Pham Q, Rabadan-Diehl C (1994) Regulation of pituitary vasopressin receptors during chronic stress: relationship to corticotroph responsiveness. J Neuroendocrinol 6(3):299–304

    PubMed  CAS  Google Scholar 

  • American Psychiatric Association (APA) (2013) Diagnostic and statistical manual of mental disorders, 5th edn. American Psychiatric Press, Washington

    Google Scholar 

  • Andero R, Brothers SP, Jovanovic T, Chen YT, Salah-Uddin H, Cameron M, Bannister TD, Almli L, Stevens JS, Bradley B, Binder EB, Wahlestedt C, Ressler KJ (2013) Amygdala-dependent fear is regulated by Oprl1 in mice and humans with PTSD. Sci Transl Med 5(188):188ra73

    PubMed  PubMed Central  Google Scholar 

  • Asth L, Correia N, Lobão-Soares B, De Lima TC, Guerrini R, Calo’ G, Soares-Rachetti VP, Gavioli EC (2015) Nociceptin/orphanin FQ induces simultaneously anxiolytic and amnesic effects in the mouse elevated T-maze task. Naunyn Schmiedeberg's Arch Pharmacol 388(1):33–41

    CAS  Google Scholar 

  • Asth L, Ruzza C, Malfacini D, Medeiros I, Guerrini R, Zaveri NT, Gavioli EC, Calo’ G (2016) Beta-arrestin 2 rather than G protein efficacy determines the anxiolytic-versus antidepressant-like effects of nociceptin/orphanin FQ receptor ligands. Neuropharmacology 105:434–442

    PubMed  PubMed Central  CAS  Google Scholar 

  • Aujla H, Cannarsa R, Romualdi P, Ciccocioppo R, Martin-Fardon R, Weiss F (2013) Modification of anxiety-like behaviours by nociceptin/orphanin FQ (N/OFQ) and time-dependent changes in N/OFQ-NOP gene expression following ethanol withdrawal. Addict Biol 18(3):467–479

    PubMed  CAS  Google Scholar 

  • Aziz AM, Brothers S, Sartor G, Holm L, Heilig M, Wahlestedt C, Thorsell A (2016) The nociceptin/orphanin FQ receptor agonist SR-8993 as a candidate therapeutic for alcohol use disorders: validation in rat models. Psychopharmacology 233(19–20):3553–3563

    PubMed  PubMed Central  CAS  Google Scholar 

  • Baxter AJ, Scott KM, Vos T, Whiteford HA (2013) Global prevalence of anxiety disorders: a systematic review and meta-regression. Psychol Med 43:897–910

    PubMed  CAS  Google Scholar 

  • Berton O, Nestler EJ (2006) New approaches to antidepressant drug discovery: beyond monoamines. Nat Rev Neurosci 7(2):137–151

    PubMed  CAS  Google Scholar 

  • Blakley GG, Pohorecky LA, Benjamin D (2004) Behavioural and endocrine changes following antisense oligonucleotide-induced reduction in the rat NOP receptor. Psychopharmacology 171:421–428

    PubMed  CAS  Google Scholar 

  • Boom A, Mollereau C, Meunier JC, Vassart G, Parmentier M, Vanderhaeghen JJ, Schiffmann SN (1999) Distribution of the nociceptin and nocistatin precursor transcript in the mouse central nervous system. Neuroscience 91:991–1007

    PubMed  CAS  Google Scholar 

  • Bornhövd K, Quante M, Glauche V, Bromm B, Weiller C, Büchel C (2002) Painful stimuli evoke different stimulus-response functions in the amygdala, prefrontal, insula and somatosensorycortex: a single-trial fMRI study. Brain 125:1326–1336

    PubMed  Google Scholar 

  • Chang SD, Brieaddy LE, Harvey JD, Lewin AH, Mascarella SW, Seltzman HH, Reddy PA, Decker AM, McElhinny CJ Jr, Zhong D, Peterson EE, Navarro HA, Bruchas MR, Carroll FI (2015) Novel synthesis and pharmacological characterization of NOP receptor agonist 8-[(1S,3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (Ro 64-6198). ACS Chem Neurosci 6(12):1956–1964

    PubMed  PubMed Central  CAS  Google Scholar 

  • Ciccocioppo R, de Guglielmo G, Hansson AC, Ubaldi M, Kallupi M, Cruz MT, Oleata CS, Heilig M, Roberto M (2014) Restraint stress alters nociceptin/orphanin FQ and CRF systems in the rat central amygdala: significance for anxiety-like behaviours. J Neurosci 34(2):363–372

    PubMed  PubMed Central  CAS  Google Scholar 

  • Connor M, Vaughan CW, Chieng B, Christie MJ (1996) Nociceptin receptor coupling to a potassium conductance in rat locus coeruleus neurones in vitro. Br J Pharmacol 119(8):1614–1618

    PubMed  PubMed Central  CAS  Google Scholar 

  • Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9(1):46–56

    PubMed  PubMed Central  CAS  Google Scholar 

  • Dautzenberg FM, Wichmann J, Higelin J, Py-Lang G, Kratzeisen C, Malherbe P, Kilpatrick GJ, Jenck F (2001) Pharmacological characterization of the novel nonpeptide orphanin FQ/nociceptin receptor agonist Ro 64-6198: rapid and reversible desensitization of the ORL1 receptor in vitro and lack of tolerance in vivo. J Pharmacol Exp Ther 298:812–819

    PubMed  CAS  Google Scholar 

  • Dawe KL, Wakerley JB, Fulford AJ (2010) Nociceptin/orphanin FQ and the regulation of neuronal excitability in the rat bed nucleus of the stria terminalis: interaction with glucocorticoids. Stress 13(6):516–527

    PubMed  CAS  Google Scholar 

  • Devine DP, Watson SJ, Akil H (2001) Nociceptin/orphanin FQ regulates neuroendocrine function of the limbic–hypothalamic–pituitary–adrenal axis. Neuroscience 102(3):541–553

    PubMed  CAS  Google Scholar 

  • Duzzioni M, Duarte FS, Leme LR, Gavioli EC, De Lima TC (2011) Anxiolytic-like effect of central administration of NOP receptor antagonist UFP-101 in rats submitted to the elevated T-maze. Behav Brain Res 222(1):206–211

    PubMed  CAS  Google Scholar 

  • Fernandez F, Misilmeri MA, Felger JC, Devine DP (2004) Nociceptin/orphanin FQ increases anxiety-related behavior and circulating levels of corticosterone during neophobic tests of anxiety. Neuropsychopharmacology 29(1):59–71

    PubMed  CAS  Google Scholar 

  • Ferrari AJ, Somerville AJ, Baxter AJ, Norman R, Patten SB, Vos T, Whiteford HA (2013) Global variation in the prevalence and incidence of major depressive disorder: a systematic review of the epidemiological literature. Psychol Med 43(3):471–481

    PubMed  CAS  Google Scholar 

  • Filaferro M, Ruggieri V, Novi C, Calò G, Cifani C, Micioni Di Bonaventura MV, Sandrini M, Vitale G (2014) Functional antagonism between nociceptin/orphanin FQ and corticotropin-releasing factor in rat anxiety-related behaviours: involvement of the serotonergic system. Neuropeptides 48(4):189–197

    PubMed  CAS  Google Scholar 

  • Gavioli EC, Calo’ G (2006) Antidepressant- and anxiolytic-like effects of nociceptin/orphanin FQ receptor ligands. Naunyn Schmiedeberg’s Arch Pharmacol 372(5):319–330

    CAS  Google Scholar 

  • Gavioli EC, Calo’ G (2013) Nociceptin/orphanin FQ receptor antagonists as innovative antidepressant drugs. Pharmacol Ther 140(1):10–25

    PubMed  CAS  Google Scholar 

  • Gavioli EC, Rae GA, Calo G, Guerrini R, De Lima TC (2002) Central injections of nocistatin or its C-terminal hexapeptide exert anxiogenic-like effect on behaviour of mice in the plus-maze test. Br J Pharmacol 136:764–772

    PubMed  PubMed Central  CAS  Google Scholar 

  • Gavioli EC, Marzola G, Guerrini R, Bertorelli R, Zucchini S, De Lima TC, Rae GA, Salvadori S, Regoli D, Calo G (2003) Blockade of nociceptin/orphanin FQ-NOP receptor signalling produces antidepressant-like effects: pharmacological and genetic evidences from the mouse forced swimming test. Eur J Neurosci 17:1987–1990

    PubMed  CAS  Google Scholar 

  • Gavioli EC, Vaughan CW, Marzola G, Guerrini R, Mitchell VA, Zucchini S, De Lima TC, Rae GA, Salvadori S, Regoli D, Calo G (2004) Antidepressant-like effects of the nociceptin/orphanin FQ receptor antagonist UFP-101: new evidence from rats and mice. Naunyn Schmiedeberg’s Arch Pharmacol 369:547–553

    CAS  Google Scholar 

  • Gavioli EC, Rizzi A, Marzola G, Zucchini S, Regoli D, Calo’ G (2007) Altered anxiety-related behaviour in nociceptin/orphanin FQ receptor gene knockout mice. Peptides 28(6):1229–1239

    PubMed  CAS  Google Scholar 

  • Genovese RF, Dobre S (2017) Mitigation of adverse behavioural impact from predator exposure by the nociceptin/orphanin FQ peptide antagonist J-113397 in rats. Behav Pharmacol 28(7):521–530

    PubMed  CAS  Google Scholar 

  • Goeldner C, Reiss D, Kieffer BL, Ouagazzal AM (2010) Endogenous nociceptin/orphanin-FQ in the dorsal hippocampus facilitates despair-related behaviour. Hippocampus 20(8):911–916

    PubMed  PubMed Central  CAS  Google Scholar 

  • Goeldner C, Spooren W, Wichmann J, Prinssen EP (2012) Further characterization of the prototypical nociceptin/orphanin FQ peptide receptor agonist Ro 64-6198 in rodent models of conflict anxiety and despair. Psychopharmacology 222(2):203–214

    PubMed  CAS  Google Scholar 

  • Golan M, Schreiber G, Avissar S (2010) Antidepressants increase β-arrestin 2 ubiquitinylation and degradation by the proteasomal pathway in C6 rat glioma cells. J Pharmacol Exp Ther 332(3):970–976

    PubMed  CAS  Google Scholar 

  • Green MK, Barbieri EV, Brown BD, Chen KW, Devine DP (2007) Roles of the bed nucleus of stria terminalis and of the amygdala in N/OFQ-mediated anxiety and HPA axis activation. Neuropeptides 41(6):399–410

    PubMed  CAS  Google Scholar 

  • Griebel G, Perrault G, Sanger DJ (1999) Orphanin FQ, a novel neuropeptide with anti-stress-like activity. Brain Res 836:221–224

    PubMed  CAS  Google Scholar 

  • Gu H, Hu D, Hong XR, Mao J, Cui Y, Hui N, Sha JY (2003) Changes and significance of orphanin and serotonin in patients with postpartum depression. Zhonghua Fu Chan Ke Za Zhi 38:727–728

    PubMed  Google Scholar 

  • Hirao A, Imai A, Sugie Y, Tamura T, Shimokawa H, Toide K (2008a) Pharmacological properties of a novel nociceptin/orphanin FQ receptor agonist, 2-(3,5-dimethylpiperazin-1-yl)-1-[1-(1-methylcyclooctyl)piperidin-4-yl]-1H-benzimidazole, with anxiolytic potential. Eur J Pharmacol 579(1–3):189–195

    PubMed  CAS  Google Scholar 

  • Hirao A, Imai A, Sugie Y, Yamada Y, Hayashi S, Toide K (2008b) Pharmacological characterization of the newly synthesized nociceptin/orphanin FQ-receptor agonist 1-[1-(1-methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole as an anxiolytic agent. J Pharmacol Sci 106(3):361–368

    PubMed  CAS  Google Scholar 

  • Ho GD, Anthes J, Bercovici A, Caldwell JP, Cheng KC, Cui X, Fawzi A, Fernandez X, Greenlee WJ, Hey J, Korfmacher W, Lu SX, McLeod RL, Ng F, Torhan AS, Tan Z, Tulshian D, Varty GB, Xu X, Zhang H (2009) The discovery of tropane derivatives as nociceptin receptor ligands for the management of cough and anxiety. Bioorg Med Chem Lett 19(9):2519–2523

    PubMed  CAS  Google Scholar 

  • Holanda VA, Medeiros IU, Asth L, Guerrini R, Calo’ G, Gavioli EC (2016) Antidepressant activity of nociceptin/orphanin FQ receptor antagonists in the mouse learned helplessness. Psychopharmacology 233(13):2525–2532

    PubMed  CAS  Google Scholar 

  • Holanda VAD, Santos WB, Asth L, Guerrini R, Calo’ G, Ruzza C, Gavioli EC (2018) NOP agonists prevent the antidepressant-like effects of nortriptyline and fluoxetine but not R-ketamine. Psychopharmacology (Berl) 235(11):3093–3102

    CAS  Google Scholar 

  • Jenck F, Moreau JL, Martin JR, Kilpatrick GJ, Reinscheid RK, Monsma FJ Jr, Nothacker HP, Civelli O (1997) Orphanin FQ acts as an anxiolytic to attenuate behavioural responses to stress. Proc Natl Acad Sci U S A 94:14854–14858

    PubMed  PubMed Central  CAS  Google Scholar 

  • Jenck F, Wichmann J, Dautzenberg FM, Moreau JL, Ouagazzal AM, Martin JR, Lundstrom K, Cesura AM, Poli SM, Roever S, Kolczewski S, Adam G, Kilpatrick G (2000) A synthetic agonist at the orphanin FQ/nociceptin receptor ORL1: anxiolytic profile in the rat. Proc Natl Acad Sci U S A 97:4938–4943

    PubMed  PubMed Central  CAS  Google Scholar 

  • Kamei J, Matsunawa Y, Miyata S, Tanaka S, Saitoh A (2004) Effects of nociceptin on the exploratory behaviour of mice in the hole-board test. Eur J Pharmacol 489:77–87

    PubMed  CAS  Google Scholar 

  • Kawahara Y, Hesselink MB, van Scharrenburg G, Westerink BH (2004) Tonic inhibition by orphanin FQ/nociceptin of noradrenaline neurotransmission in the amygdala. Eur J Pharmacol 485(1–3):197–200

    PubMed  CAS  Google Scholar 

  • Kirshenbaum AP, Brown SJ, Hughes DM, Doughty AH (2008) Differential-reinforcement-of-low-rate-schedule performance and nicotine administration: a systematic investigation of dose, dose-regimen, and schedule requirement. Behav Pharmacol 19(7):683–697

    PubMed  PubMed Central  CAS  Google Scholar 

  • Koster A, Montkowski A, Schulz S, Stube EM, Knaudt K, Jenck F, Moreau JL, Nothacker HP, Civelli O, Reinscheid RK (1999) Targeted disruption of the orphanin FQ/nociceptin gene increases stress susceptibility and impairs stress adaptation in mice. Proc Natl Acad Sci U S A 96:10444–10449

    PubMed  PubMed Central  CAS  Google Scholar 

  • Le Maitre E, Vilpoux C, Costentin J, Leroux-Nicollet I (2005) Opioid receptor-like 1 (NOP) receptors in the rat dorsal raphe nucleus: evidence for localization on serotoninergic neurons and functional adaptation after 5,7-dihydroxytryptamine lesion. J Neurosci Res 81(4):488–496

    PubMed  Google Scholar 

  • Le Pen G, Wichmann J, Moreau JL, Jenck F (2002) The orphanin receptor agonist RO 64-6198 does not induce place conditioning in rats. Neuroreport 13(4):451–454

    PubMed  Google Scholar 

  • Leggett JD, Harbuz MS, Jessop DS, Fulford AJ (2006) The nociceptin receptor antagonist [Nphe1, Arg14, Lys15]nociceptin/orphanin FQ-NH2 blocks the stimulatory effects of nociceptin/orphanin FQ on the HPA axis in rats. Neuroscience 141(4):2051–2057

    PubMed  CAS  Google Scholar 

  • Leonard BE (2005) The HPA and immune axes in stress: the involvement of the serotonergic system. Eur Psychiatry 20(Suppl 3):S302–S306

    PubMed  Google Scholar 

  • Lu SX, Higgins GA, Hodgson RA, Hyde LA, Del Vecchio RA, Guthrie DH, Kazdoba T, McCool MF, Morgan CA, Bercovici A, Ho GD, Tulshian D, Parker EM, Hunter JC, Varty GB (2011) The anxiolytic-like profile of the nociceptin receptor agonist, endo-8-[bis(2-chlorophenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octane-3-carboxamide (SCH 655842): comparison of efficacy and side effects across rodent species. Eur J Pharmacol 661(1–3):63–71

    PubMed  CAS  Google Scholar 

  • Marcinkiewcz CA, Mazzone CM, D’Agostino G, Halladay LR, Hardaway JA, DiBerto JF, Navarro M, Burnham N, Cristiano C, Dorrier CE, Tipton GJ, Ramakrishnan C, Kozicz T, Deisseroth K, Thiele TE, McElligott ZA, Holmes A, Heisler LK, Kash TL (2016) Serotonin engages an anxiety and fear-promoting circuit in the extended amygdala. Nature 537(7618):97–101

    PubMed  PubMed Central  CAS  Google Scholar 

  • Marek GJ, Day M, Hudzik TJ (2016) The utility of impulsive bias and altered decision making as predictors of drug efficacy and target selection: rethinking behavioural screening for antidepressant drugs. J Pharmacol Exp Ther 356:534–548

    PubMed  CAS  Google Scholar 

  • Marti M, Mela F, Veronesi C, Guerrini R, Salvadori S, Federici M, Mercuri NB, Rizzi A, Franchi G, Beani L, Bianchi C, Morari M (2004) Blockade of nociceptin/orphanin FQ receptor signaling in rat substantia nigra pars reticulata stimulates nigrostriatal dopaminergic transmission and motor behavior. J Neurosci 24(30):6659–6666

    PubMed  CAS  Google Scholar 

  • McEwen BS (2005) Glucocorticoids, depression, and mood disorders: structural remodeling in the brain. Metabolism 54(Suppl. 1):20–23

    PubMed  CAS  Google Scholar 

  • Medeiros IU, Ruzza C, Asth L, Guerrini R, Romão PR, Gavioli EC, Calo G (2015) Blockade of nociceptin/orphanin FQ receptor signaling reverses LPS-induced depressive-like behaviour in mice. Peptides 72:95–103

    PubMed  CAS  Google Scholar 

  • Mollereau C, Mouledous L (2000) Tissue distribution of the opioid receptor-like (ORL1) receptor. Peptides 21:907–917

    PubMed  CAS  Google Scholar 

  • Mustazza C, Bastanzio G (2011) Development of nociceptin receptor (NOP) agonists and antagonists. Med Res Rev 31(4):605–648

    PubMed  CAS  Google Scholar 

  • Nazzaro C, Barbieri M, Varani K, Beani L, Valentino RJ, Siniscalchi A (2010) Swim stress enhances nociceptin/orphanin FQ-induced inhibition of rat dorsal raphe nucleus activity in vivo and in vitro: role of corticotropin releasing factor. Neuropharmacology 58(2):457–464

    PubMed  CAS  Google Scholar 

  • Neal CR Jr, Mansour A, Reinscheid R, Nothacker HP, Civelli O, Akil H, Watson SJ Jr (1999a) Opioid receptor-like (ORL1) receptor distribution in the rat central nervous system: comparison of ORL1 receptor mRNA expression with (125)I-[(14)Tyr]-orphanin FQ binding. J Comp Neurol 412:563–605

    PubMed  CAS  Google Scholar 

  • Neal CR Jr, Mansour A, Reinscheid R, Nothacker HP, Civelli O, Watson SJ Jr (1999b) Localization of orphanin FQ (nociceptin) peptide and messenger RNA in the central nervous system of the rat. J Comp Neurol 406:503–547

    PubMed  CAS  Google Scholar 

  • Nicholson JR, Akil H, Watson SJ (2002) Orphanin FQ-induced hyperphagia is mediated by corticosterone and central glucocorticoid receptors. Neuroscience 115(2):637–643

    PubMed  CAS  Google Scholar 

  • Nicolas LB, Kolb Y, Prinssen EP (2006) A combined marble burying-locomotor activity test in mice: a practical screening test with sensitivity to different classes of anxiolytics and antidepressants. Eur J Pharmacol 547(1–3):106–115

    PubMed  CAS  Google Scholar 

  • Nicolas LB, Klein S, Prinssen EP (2007) Defensive-like behaviours induced by ultrasound: further pharmacological characterization in Lister-hooded rats. Psychopharmacology 194(2):243–252

    PubMed  CAS  Google Scholar 

  • Okawa H, Kudo M, Kudo T, Guerrini R, Lambert DG, Kushikata T, Yoshida H, Matsuki A (2001) Effects of nociceptinNH2 and [Nphe1]nociceptin(1-13)NH2 on rat brain noradrenaline release in vivo and in vitro. Neurosci Lett 303:173–176

    PubMed  CAS  Google Scholar 

  • Ouagazzal AM, Moreau JL, Pauly-Evers M, Jenck F (2003) Impact of environmental housing conditions on the emotional responses of mice deficient for nociceptin/orphanin FQ peptide precursor gene. Behav Brain Res 144:111–117

    PubMed  CAS  Google Scholar 

  • Post A, Smart TS, Krikke-Workel J, Dawson GR, Harmer CJ, Browning M, Jackson K, Kakar R, Mohs R, Statnick M, Wafford K, McCarthy A, Barth V, Witkin JM (2016) A selective nociceptin receptor antagonist to treat depression: evidence from preclinical and clinical studies. Neuropsychopharmacology 41(7):1803–1812

    PubMed  CAS  Google Scholar 

  • Pryce CR, Azzinnari D, Spinelli S, Seifritz E, Tegethoff M, Meinlschmidt G (2011) Helplessness: a systematic translational review of theory and evidence for its relevance to understanding and treating depression. Pharmacol Ther 132(3):242–267

    PubMed  CAS  Google Scholar 

  • Redrobe JP, Calo G, Regoli D, Quirion R (2002) Nociceptin receptor antagonists display antidepressant-like properties in the mouse forced swimming test. Naunyn Schmiedeberg’s Arch Pharmacol 365:164–167

    CAS  Google Scholar 

  • Reul JM, Stec I, Söder M, Holsboer F (1993) Chronic treatment of rats with the antidepressant amitriptyline attenuates the activity of the hypothalamic–pituitary–adrenocortical system. Endocrinology 133(1):312–320

    PubMed  CAS  Google Scholar 

  • Rizzi A, Gavioli EC, Marzola G, Spagnolo B, Zucchini S, Ciccocioppo R, Trapella C, Regoli D, Calò G (2007) Pharmacological characterization of the nociceptin/orphanin FQ receptor antagonist SB-612111 [(-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol]: in vivo studies. J Pharmacol Exp Ther 321(3):968–974

    PubMed  CAS  Google Scholar 

  • Rizzi A, Molinari S, Marti M, Marzola G, Calo’ G (2011) Nociceptin/orphanin FQ receptor knockout rats: in vitro and in vivo studies. Neuropharmacology 60(4):572–579

    PubMed  CAS  Google Scholar 

  • Rodi D, Zucchini S, Simonato M, Cifani C, Massi M, Polidori C (2008) Functional antagonism between nociceptin/orphanin FQ (N/OFQ) and corticotropin-releasing factor (CRF) in the rat brain: evidence for involvement of the bed nucleus of the stria terminalis. Psychopharmacology 196(4):523–531

    PubMed  CAS  Google Scholar 

  • Ross TM, Battista K, Bignan GC, Brenneman DE, Connolly PJ, Liu J, Middleton SA, Orsini M, Reitz AB, Rosenthal DI, Scott MK, Vaidya AH (2015) A selective small molecule NOP (ORL-1 receptor) partial agonist for the treatment of anxiety. Bioorg Med Chem Lett 25(3):602–606

    PubMed  CAS  Google Scholar 

  • Sakoori K, Murphy NP (2009) Enhanced nicotine sensitivity in nociceptin/orphanin FQ receptor knockout mice. Neuropharmacology 56(5):896–904

    PubMed  CAS  Google Scholar 

  • Sandin J, Georgieva J, Schött PA, Ogren SO, Terenius L (1997) Nociceptin/orphanin FQ microinjected into hippocampus impairs spatial learning in rats. Eur J Neurosci 9(1):194–197

    PubMed  CAS  Google Scholar 

  • Schlicker E, Morari M (2000) Nociceptin/orphanin FQ and neurotransmitter release in the central nervous system. Peptides 21:1023–1029

    PubMed  CAS  Google Scholar 

  • Steimer T (2002) The biology of fear- and anxiety-related behaviours. Dialogues Clin Neurosci 4(3):231–249

    PubMed  PubMed Central  Google Scholar 

  • Tafet GE, Bernardini R (2003) Psychoneuroendocrinological links between chronic stress and depression. Prog Neuro-Psychopharmacol Biol Psychiatry 27(6):893–903

    Google Scholar 

  • Tao R, Ma Z, Thakkar MM, McCarley RW, Auerbach SB (2007) Nociceptin/orphanin FQ decreases serotonin efflux in the rat brain but in contrast to a kappa-opioid has no antagonistic effect on mu-opioid-induced increases in serotonin efflux. Neuroscience 147(1):106–116

    PubMed  CAS  Google Scholar 

  • Toledo MA, Pedregal C, Lafuente C, Diaz N, Martinez-Grau MA, Jiménez A, Benito A, Torrado A, Mateos C, Joshi EM, Kahl SD, Rash KS, Mudra DR, Barth VN, Shaw DB, McKinzie D, Witkin JM, Statnick MA (2014) Discovery of a novel series of orally active nociceptin/orphanin FQ (NOP) receptor antagonists based on a dihydrospiro(piperidine-4,7′-thieno[2,3-c]pyran) scaffold. J Med Chem 57(8):3418–3429

    PubMed  CAS  Google Scholar 

  • Toll L, Bruchas MR, Calo’ G, Cox BM, Zaveri NT (2016) Nociceptin/orphanin FQ receptor structure, signaling, ligands, functions, and interactions with opioid systems. Pharmacol Rev 68(2):419–457

    PubMed  PubMed Central  Google Scholar 

  • Uchiyama H, Toda A, Hiranita T, Watanabe S, Eyanagi R (2008a) Role of amygdaloid nuclei in the anxiolytic-like effect of nociceptin/orphanin FQ in rats. Neurosci Lett 431(1):66–70

    PubMed  CAS  Google Scholar 

  • Uchiyama H, Yamaguchi T, Toda A, Hiranita T, Watanabe S, Eyanagi R (2008b) Involvement of the GABA/benzodiazepine receptor in the axiolytic-like effect of nociceptin/orphanin FQ. Eur J Pharmacol 590(1–3):185–189

    PubMed  CAS  Google Scholar 

  • Van de Velde S, Bracke P, Levecque K (2010) Gender differences in depression in 23 European countries. Cross-national variation in the gender gap in depression. Soc Sci Med 71(2):305–313

    PubMed  Google Scholar 

  • Varty GB, Hyde LA, Hodgson RA, Lu SX, McCool MF, Kazdoba TM, Del Vecchio RA, Guthrie DH, Pond AJ, Grzelak ME, Xu X, Korfmacher WA, Tulshian D, Parker EM, Higgins GA (2005) Characterization of the nociceptin receptor (ORL-1) agonist, Ro64-6198, in tests of anxiety across multiple species. Psychopharmacology 15:1–12

    Google Scholar 

  • Varty GB, Lu SX, Morgan CA, Cohen-Williams ME, Hodgson RA, Smith-Torhan A, Zhang H, Fawzi AB, Graziano MP, Ho GD, Matasi J, Tulshian D, Coffin VL, Carey GJ (2008) The anxiolytic-like effects of the novel, orally active nociceptin opioid receptor agonist 8-[bis(2-methylphenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol (SCH 221510). J Pharmacol Exp Ther 326(2):672–682

    PubMed  CAS  Google Scholar 

  • Vaughan CW, Christie MJ (1996) Increase by the ORL1 receptor (opioid receptor-like1) ligand, nociceptin, of inwardly rectifying K conductance in dorsal raphe nucleus neurones. Br J Pharmacol 117:1609–1611

    PubMed  PubMed Central  CAS  Google Scholar 

  • Vitale G, Arletti R, Ruggieri V, Cifani C, Massi M (2006) Anxiolytic-like effects of nociceptin/orphanin FQ in the elevated plus maze and in the conditioned defensive burying test in rats. Peptides 27(9):2193–2200

    PubMed  CAS  Google Scholar 

  • Vitale G, Ruggieri V, Filaferro M, Frigeri C, Alboni S, Tascedda F, Brunello N, Guerrini R, Cifani C, Massi M (2009) Chronic treatment with the selective NOP receptor antagonist [Nphe 1, Arg 14, Lys 15]N/OFQ-NH 2 (UFP-101) reverses the behavioural and biochemical effects of unpredictable chronic mild stress in rats. Psychopharmacology 207(2):173–189

    PubMed  CAS  Google Scholar 

  • Vitale G, Filaferro M, Micioni Di Bonaventura MV, Ruggieri V, Cifani C, Guerrini R, Simonato M, Zucchini S (2017) Effects of [Nphe1, Arg14, Lys15] N/OFQ-NH2 (UFP-101), a potent NOP receptor antagonist, on molecular, cellular and behavioural alterations associated with chronic mild stress. J Psychopharmacol 31(6):691–703

    PubMed  CAS  Google Scholar 

  • Wang LN, Liu LF, Zhang JX, Zhao GF (2009) Plasma levels of nociceptin/orphanin FQ in patients with bipolar disorders and health adults. Zhonghua Yi Xue Za Zhi 89(13):916–918

    PubMed  CAS  Google Scholar 

  • Werner FM, Coveñas R (2010) Classical neurotransmitters and neuropeptides involved in major depression: a review. Int J Neurosci 120(7):455–470

    PubMed  CAS  Google Scholar 

  • Wichmann J, Adam G, Röver S, Cesura AM, Dautzenberg FM, Jenck F (1999) 8-Acenaphthen-1-yl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one derivatives as orphanin FQ receptor agonists. Bioorg Med Chem Lett 9(16):2343–2348

    PubMed  CAS  Google Scholar 

  • Wichmann J, Adam G, Rover S, Hennig M, Scalone M, Cesura AM, Dautzenberg FM, Jenck F (2000) Synthesis of (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 potent and selective orphanin FQ (OFQ) receptor agonist with anxiolytic-like properties. Eur J Med Chem 35:839–851

    PubMed  CAS  Google Scholar 

  • Willner P (1997) Validity, reliability and utility of the chronic mild stress model of depression: a 10-year review and evaluation. Psychopharmacology 134(4):319–329

    PubMed  CAS  Google Scholar 

  • Witkin JM, Rorick-Kehn LM, Benvenga MJ, Adams BL, Gleason SD, Knitowski KM, Li X, Chaney S, Falcone JF, Smith JW, Foss J, Lloyd K, Catlow JT, McKinzie DL, Svensson KA, Barth VN, Toledo MA, Diaz N, Lafuente C, Jiménez A, Benito A, Pedregal C, Martínez-Grau MA, Post A, Ansonoff MA, Pintar JE, Statnick MA (2016) Preclinical findings predicting efficacy and side-effect profile of LY2940094, an antagonist of nociceptin receptors. Pharmacol Res Perspect 4(6):e00275

    PubMed  PubMed Central  Google Scholar 

  • Yang SW, Ho G, Tulshian D, Greenlee WJ, Tan Z, Zhang H, Smith-Torhan A, Fawzi A, Anthes J, Lu S, Varty G, Fernandez X, McLeod RL, Hey J (2009) Identification of 3-substituted N-benzhydryl-nortropane analogs as nociceptin receptor ligands for the management of cough and anxiety. Bioorg Med Chem Lett 19(9):2482–2486

    PubMed  CAS  Google Scholar 

  • Zhang Y, Simpson-Durand CD, Standifer KM (2015) Nociceptin/orphanin FQ peptide receptor antagonist JTC-801 reverses pain and anxiety symptoms in a rat model of post-traumatic stress disorder. Br J Pharmacol 172(2):571–582

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Behavioral Pharmacology Laboratory, Department of Biophysics and Pharmacology, Federal University of Rio Grande do Norte, Natal, Brazil

    Elaine C. Gavioli & Victor A. D. Holanda

  2. Department of Medical Sciences, Section of Pharmacology, and National Institute of Neuroscience, University of Ferrara, Ferrara, Italy

    Chiara Ruzza

Authors
  1. Elaine C. Gavioli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Victor A. D. Holanda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chiara Ruzza
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Elaine C. Gavioli .

Editor information

Editors and Affiliations

  1. Department of Physiology and Pharmacology, Wake Forest University, School of Medicine, Winston-Salem, NC, USA

    Mei-Chuan Ko

  2. Department of Medical Sciences, Section of Pharmacology, University of Ferrara, Ferrara, Italy

    Girolamo Caló

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Gavioli, E.C., Holanda, V.A.D., Ruzza, C. (2018). NOP Ligands for the Treatment of Anxiety and Mood Disorders. In: Ko, MC., Caló, G. (eds) The Nociceptin/Orphanin FQ Peptide Receptor. Handbook of Experimental Pharmacology, vol 254. Springer, Cham. https://doi.org/10.1007/164_2018_188

Download citation

Publish with us

Policies and ethics

Search

Navigation