Regulation of the Genes Encoding the ppN/OFQ and NOP Receptor

  • Francesca Felicia Caputi
  • Patrizia RomualdiEmail author
  • Sanzio Candeletti
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 254)


Over the years, the ability of N/OFQ-NOP receptor system in modulating several physiological functions, including the release of neurotransmitters, anxiety-like behavior responses, modulation of the reward circuitry, inflammatory signaling, nociception, and motor function, has been examined in several brain regions and at spinal level. This chapter collects information related to the genes encoding the ppN/OFQ and NOP receptor, their regulation, and relative transcriptional control mechanisms. Furthermore, genetic manipulations, polymorphisms, and epigenetic alterations associated with different pathological conditions are discussed. The evidence here collected indicates that the study of ppN/OFQ and NOP receptor gene expression may offer novel opportunities in the field of personalized therapies and highlights this system as a good “druggable target” for different pathological conditions.


DNA methylation Epigenetics Gene expression Histone marks N/OFQ NOP−/− NOP-eGFP NOP receptor Polymorphisms ppN/OFQ 


  1. Allen RG, Peng B, Pellegrino MJ, Miller ED, Grandy DK, Lundblad JR, Washburn CL, Pintar JE (2001) Altered processing of pro-orphanin FQ/nociceptin and pro-opiomelanocortin-derived peptides in the brains of mice expressing defective prohormone convertase 2. J Neurosci 21:5864–5870PubMedGoogle Scholar
  2. Andero R (2015) Nociceptin and the nociceptin receptor in learning and memory. Prog Neuro-Psychopharmacol Biol Psychiatry 62:45–50Google Scholar
  3. 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 5:188ra73PubMedPubMedCentralGoogle Scholar
  4. Andoh T, Itoh M, Kuraishi Y (1997) Nociceptin gene expression in rat dorsal root ganglia induced by peripheral inflammation. Neuroreport 8:2793–2796PubMedGoogle Scholar
  5. Aparicio LC, Candeletti S, Binaschi A, Mazzuferi M, Mantovani S, Di Benedetto M, Landuzzi D, Lopetuso G, Romualdi P, Simonato M (2004) Kainate seizures increase nociceptin/orphanin FQ release in the rat hippocampus and thalamus: a microdialysis study. J Neurochem 91:30–37PubMedGoogle Scholar
  6. Arcuri L, Viaro R, Bido S, Longo F, Calcagno M, Fernagut PO, Zaveri NT, Calò G, Bezard E, Morari M (2016) Genetic and pharmacological evidence that endogenous nociceptin/orphanin FQ contributes to dopamine cell loss in Parkinson’s disease. Neurobiol Dis 89:55–64PubMedPubMedCentralGoogle Scholar
  7. Arjomand J, Evans CJ (2001) Differential splicing of transcripts encoding the orphanin FQ/nociceptin precursor. J Neurochem 77:720–729PubMedGoogle Scholar
  8. Arjomand J, Cole S, Evans CJ (2002) Novel orphanin FQ/nociceptin transcripts are expressed in human immune cells. J Neuroimmunol 130:100–108PubMedGoogle Scholar
  9. Aujla H, Cannarsa R, Romualdi P, Ciccocioppo R, Martin-Fardon R, Weiss F (2013) Modification of anxiety-like behaviors by nociceptin/orphanin FQ (N/OFQ) and time-dependent changes in N/OFQ-NOP gene expression following ethanol withdrawal. Addict Biol 18:467–479PubMedGoogle Scholar
  10. Bastías-Candia S, Di Benedetto M, D’Addario C, Candeletti S, Romualdi P (2015) Combined exposure to agriculture pesticides, paraquat and maneb, induces alterations in the N/OFQ-NOPr and PDYN/KOPr systems in rats: relevance to sporadic Parkinson’s disease. Environ Toxicol 30:656–663PubMedGoogle Scholar
  11. Bodnar RJ (2014) Endogenous opiates and behavior: 2013. Peptides 62:67–136PubMedGoogle Scholar
  12. Bregola G, Candeletti S, Romualdi P, Simonato M (1999) Limbic seizures increase pronociceptin mRNA levels in the thalamic reticular nucleus. Neuroreport 10:541–546PubMedGoogle Scholar
  13. Bregola G, Zucchini S, Frigati L, Candeletti S, Romualdi P, Reinscheid R, Simonato M (2002a) Involvement of the neuropeptide orphanin FQ/nociceptin in kainate and kindling seizures and epileptogenesis. Epilepsia 43(Suppl 5):18–19PubMedGoogle Scholar
  14. Bregola G, Zucchini S, Rodi D, Binaschi A, D’Addario C, Landuzzi D, Reinscheid R, Candeletti S, Romualdi P, Simonato M (2002b) Involvement of the neuropeptide nociceptin/orphanin FQ in kainate seizures. J Neurosci 22:10030–10038PubMedGoogle Scholar
  15. Briscini L, Corradini L, Ongini E, Bertorelli R (2002) Up-regulation of ORL-1 receptors in spinal tissue of allodynic rats after sciatic nerve injury. Eur J Pharmacol 447:59–65PubMedGoogle Scholar
  16. Bunzow JR, Saez C, Mortrud M, Bouvier C, Williams JT, Low M, Grandy DK (1994) Molecular cloning and tissue distribution of a putative member of the rat opioid receptor gene family that is not a mu, delta or kappa opioid receptor type. FEBS Lett 347:284–288PubMedGoogle Scholar
  17. Butour JL, Moisand C, Mazarguil H, Mollereau C, Meunier JC (1997) Recognition and activation of the opioid receptor-like ORL 1 receptor by nociceptin, nociceptin analogs and opioids. Eur J Pharmacol 321:97–103PubMedGoogle Scholar
  18. Buzas B, Rosenberger J, Cox BM (1998) Activity and cyclic AMP-dependent regulation of nociceptin/orphanin FQ gene expression in primary neuronal and astrocyte cultures. J Neurochem 71:556–563PubMedGoogle Scholar
  19. Buzas B, Symes AJ, Cox BM (1999) Regulation of nociceptin/orphanin FQ gene expression by neuropoietic cytokines and neurotrophic factors in neurons and astrocytes. J Neurochem 72:1882–1889PubMedGoogle Scholar
  20. Buzas B, Rosenberger J, Kim KW, Cox BM (2002) Inflammatory mediators increase the expression of nociceptin/orphanin FQ in rat astrocytes in culture. Glia 39:237–246PubMedGoogle Scholar
  21. Calò G, Rizzi A, Cifani C, Micioni Di Bonaventura MV, Regoli D, Massi M, Salvadori S, Lambert DG, Guerrini R (2011) UFP-112 a potent and long-lasting agonist selective for the Nociceptin/Orphanin FQ receptor. CNS Neurosci Ther 17:178–198PubMedGoogle Scholar
  22. Cannarsa R, Landuzzi D, Cavina C, Candeletti S, Romualdi P (2008) Kainic acid down-regulates NOP receptor density and gene expression in human neuroblastoma SH-SY5Y cells. J Mol Neurosci 35:171–177PubMedGoogle Scholar
  23. Cannarsa R, Carretta D, Lattanzio F, Candeletti S, Romualdi P (2012) Δ(9)-Tetrahydrocannabinol decreases NOP receptor density and mRNA levels in human SH-SY5Y cells. J Mol Neurosci 46:285–292PubMedGoogle Scholar
  24. Caputi FF, Lattanzio F, Carretta D, Mercatelli D, Candeletti S, Romualdi P (2013) Morphine and fentanyl differently affect MOP and NOP gene expression in human neuroblastoma SH-SY5Y cells. J Mol Neurosci 51:532–538PubMedGoogle Scholar
  25. Caputi FF, Carretta D, Tzschentke TM, Candeletti S, Romualdi P (2014a) Opioid receptor gene expression in human neuroblastoma SH-SY5Y cells following tapentadol exposure. J Mol Neurosci 53:669–676PubMedGoogle Scholar
  26. Caputi FF, Di Benedetto M, Carretta D, Bastias del Carmen Candia S, D’Addario C, Cavina C, Candeletti S, Romualdi P (2014b) Dynorphin/KOP and nociceptin/NOP gene expression and epigenetic changes by cocaine in rat striatum and nucleus accumbens. Prog Neuro-Psychopharmacol Biol Psychiatry 49:36–46Google Scholar
  27. Caputi FF, Carretta D, Lattanzio F, Palmisano M, Candeletti S, Romualdi P (2015) Proteasome subunit and opioid receptor gene expression down-regulation induced by paraquat and maneb in human neuroblastoma SH-SY5Y cells. Environ Toxicol Pharmacol 40:895–900PubMedGoogle Scholar
  28. Caputi FF, Palmisano M, Carboni L, Candeletti S, Romualdi P (2016) Opioid gene expression changes and post-translational histone modifications at promoter regions in the rat nucleus accumbens after acute and repeated 3,4-methylenedioxy-methamphetamine (MDMA) exposure. Pharmacol Res 114:209–218PubMedGoogle Scholar
  29. Caputi FF, Acquas E, Kasture S, Ruiu S, Candeletti S, Romualdi P (2018) The standardized Withania somnifera Dunal root extract alters basal and morphine-induced opioid receptor gene expression changes in neuroblastoma cells. BMC Complement Altern Med 18(1):9. CrossRefPubMedPubMedCentralGoogle Scholar
  30. Chen Y, Fan Y, Liu J, Mestek A, Tian M, Kozak CA, Yu L (1994) Molecular cloning, tissue distribution and chromosomal localization of a novel member of the opioid receptor gene family. FEBS Lett 347:279–283PubMedGoogle Scholar
  31. Ciccocioppo R, Angeletti S, Panocka I, Massi M (2000) Nociceptin/orphanin FQ and drugs of abuse. Peptides 21:1071–1080PubMedGoogle Scholar
  32. Ciccocioppo R, Biondini M, Antonelli L, Wichmann J, Jenck F, Massi M (2002) Reversal of stress- and CRF-induced anorexia in rats by the synthetic nociceptin/orphanin FQ receptor agonist, Ro 64-6198. Psychopharmacology 161:113–119PubMedGoogle Scholar
  33. Ciccocioppo R, Economidou D, Fedeli A, Angeletti S, Weiss F, Heilig M, Massi M (2004a) Attenuation of ethanol self-administration and of conditioned reinstatement of alcohol seeking behaviour by the antiopioid peptide nociceptin/orphanin FQ in alcohol-preferring rats. Psychopharmacology 172:170–178PubMedGoogle Scholar
  34. Ciccocioppo R, Cippitelli A, Economidou D, Fedeli A, Massi M (2004b) Nociceptin/orphanin FQ acts as a functional antagonist of corticotropin-releasing factor to inhibit its anorectic effect. Physiol Behav 82:63–68PubMedGoogle Scholar
  35. Clarke S, Chen Z, Hsu MS, Pintar J, Hill R, Kitchen I (2001) Quantitative autoradiographic mapping of the ORL1, mu-, delta- and kappa-receptors in the brains of knockout mice lacking the ORL1 receptor gene. Brain Res 906:13–24PubMedGoogle Scholar
  36. Collins LM, Dal Bo G, Calcagno M, Monzón-Sandoval J, Sullivan AM, Gutierrez H, Morari M, O’Keeffe G (2016) Nociceptin/orphanin FQ inhibits the survival and axon growth of midbrain dopaminergic neurons through a p38-MAPK dependent mechanism. Mol Neurobiol 53:7284–7297PubMedGoogle Scholar
  37. Cox BM, Christie MJ, Devi L, Toll L, Traynor JR (2015) Challenges for opioid receptor nomenclature: IUPHAR review 9. Br J Pharmacol 172:317–323PubMedGoogle Scholar
  38. Currò D, Yoo JH, Anderson M, Song I, Del Valle J, Owyang C (2001) Molecular cloning of the orphanin FQ receptor gene and differential tissue expression of splice variants in rat. Gene 266:139–145PubMedGoogle Scholar
  39. D’Addario C, Caputi FF, Rimondini R, Gandolfi O, Del Borrello E, Candeletti S, Romualdi P (2013a) Different alcohol exposures induce selective alterations on the expression of dynorphin and nociceptin systems related genes in rat brain. Addict Biol 18:425–433PubMedGoogle Scholar
  40. D’Addario C, Caputi FF, Ekström TJ, Di Benedetto M, Maccarrone M, Romualdi P, Candeletti S (2013b) Ethanol induces epigenetic modulation of prodynorphin and pronociceptin gene expression in the rat amygdala complex. J Mol Neurosci 49:312–319PubMedGoogle Scholar
  41. Darland T, Heinricher MM, Grandy DK (1998) Orphanin FQ/nociceptin: a role in pain and analgesia, but so much more. Trends Neurosci 21:215–221PubMedGoogle Scholar
  42. Di Benedetto M, Cavina C, D’Addario C, Leoni G, Candeletti S, Cox BM, Romualdi P (2009) Alterations of N/OFQ and NOP receptor gene expression in the substantia nigra and caudate putamen of MPP+ and 6-OHDA lesioned rats. Neuropharmacology 56:761–767PubMedGoogle Scholar
  43. Di Benedetto M, Bastías Candia Sdel C, D’Addario C, Porticella EE, Cavina C, Candeletti S, Romualdi P (2011) Regulation of opioid gene expression in the rat brainstem by 3,4-methylenedioxymethamphetamine (MDMA): role of serotonin and involvement of CREB and ERK cascade. Naunyn Schmiedebergs Arch Pharmacol 383:169–178PubMedGoogle Scholar
  44. Economidou D, Policani F, Angellotti T, Massi M, Terada T, Ciccocioppo R (2006) Effect of novel NOP receptor ligands on food intake in rats. Peptides 27:775–783PubMedGoogle Scholar
  45. Feng Y, Chao DM, Li WM, Cao YX, Wang YQ, Wu GC (2004) Inhibition of nociceptin/orphanin FQ on penicillin-induced seizures in rats. Brain Res 1020:214–219PubMedGoogle Scholar
  46. Florin S, Suaudeau C, Meunier J-C, Costentin J (1996) Nociceptin stimulates locomotion and exploratory behavior in mice. Eur J Pharmacol 317:9–13PubMedGoogle Scholar
  47. Florin S, Suaudeau C, Meunier JC, Costentin J (1997) Orphan neuropeptide NocII, a putative pronociceptin maturation product, stimulates locomotion in mice. Neuroreport 8:705–707PubMedGoogle Scholar
  48. Fonteneau M, Filliol D, Anglard P, Befort K, Romieu P, Zwiller J (2017) Inhibition of DNA methyltransferases regulates cocaine self-administration by rats: a genome-wide DNA methylation study. Genes Brain Behav 16:313–327PubMedGoogle Scholar
  49. Fu X, Wang YQ, Wang J, Yu J, Wu GC (2007) Changes in expression of nociceptin/orphanin FQ and its receptor in spinal dorsal horn during electroacupuncture treatment for peripheral inflammatory pain in rats. Peptides 28:1220–1228PubMedGoogle Scholar
  50. Fukuda K, Kato S, Mori K, Nishi M, Takeshima H, Iwabe N, Miyata T, Houtani T, Sugimoto T (1994) cDNA cloning and regional distribution of a novel member of the opioid receptor family. FEBS Lett 343(1):42–46PubMedGoogle Scholar
  51. Gavioli EC, Calò G (2013) Nociceptin/orphanin FQ receptor antagonists as innovative antidepressant drugs. Pharmacol Ther 140:10–25PubMedGoogle Scholar
  52. Gavioli EC, Marzola G, Guerrini R, Bertorelli R, Zucchini S, De Lima TC, Rae GA, Salvadori S, Regoli D, Calò 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 17:1987–1990PubMedGoogle Scholar
  53. Gavioli EC, Rizzi A, Marzola G, Zucchini S, Regoli D, Calò G (2007) Altered anxiety-related behavior in nociceptin/orphanin FQ receptor gene knockout mice. Peptides 28:1229–1239PubMedGoogle Scholar
  54. Gehlert DR, Gackenheimer SL, Shaw JL (2006) Distribution of nociceptin and Ro64-6198 activated [35S]- GTPgammaS binding in the rat brain. Neuropeptides 40:95–105PubMedGoogle Scholar
  55. Gouty S, Brown JM, Rosenberger J, Cox BM (2010) MPTP treatment increases expression of pre-pro-nociceptin/orphanin FQ mRNA in a subset of substantia nigra reticulata neurons. Neuroscience 169:269–278PubMedPubMedCentralGoogle Scholar
  56. Hardawaya JA, Jensena J, Kima M, Mazzone CM, Sugama JA, Dibertoa JF, Lowery-Gionta EG, Hwaa LS, Pleil KE, Bulik CM, Kasha TL (2016) Nociceptin receptor antagonist SB 612111 decreases high fat diet binge eating. Behav Brain Res 307:25–34Google Scholar
  57. Homberg JR, Mul JD, de Wit E, Cuppen E (2009) Complete knockout of the nociceptin/orphanin FQ receptor in the rat does not induce compensatory changes in mu, delta and kappa opioid receptors. Neuroscience 163:308–315PubMedGoogle Scholar
  58. Huang J, Young B, Pletcher MT, Heilig M, Wahlestedt C (2008) Association between the nociceptin receptor gene (OPRL1) single nucleotide polymorphisms and alcohol dependence. Addict Biol 13:88–94PubMedGoogle Scholar
  59. Ito E, Xie G, Maruyama K, Palmer PP (2000) A core-promoter region functions bi-directionally for human opioid-receptor-like gene ORL1 and its 5′-adjacent gene GAIP. J Mol Biol 304:259–270PubMedGoogle Scholar
  60. Itoh M, Takasaki I, Andoh T, Nojima H, Tominaga M, Kuraishi Y (2001) Induction by carrageenan inflammation of prepronociceptin mRNA in VR1-immunoreactive neurons in rat dorsal root ganglia. Neurosci Res 40:227–233PubMedGoogle Scholar
  61. Kallupi M, Scuppa G, de Guglielmo G, Calò G, Weiss F, Statnick MA, Rorick-Kehn LM, Ciccocioppo R (2017) Genetic deletion of the nociceptin/orphanin FQ receptor in the rat confers resilience to the development of drug addiction. Neuropsychopharmacology 42:695–706PubMedGoogle Scholar
  62. Kasai S, Nishizawa D, Hasegawa J, Sato N, Tanioka F, Sugimura H, Ikeda K (2016) Nociceptin/orphanin FQ receptor gene variation is associated with smoking status in Japanese. Pharmacogenomics 17:1441–1451PubMedGoogle Scholar
  63. Kawashima N, Fugate J, Kusnecov AW (2002) Immunological challenge modulates brain orphanin FQ/nociceptin and nociceptive behavior. Brain Res 949:71–78PubMedGoogle Scholar
  64. Kiguchi N, Ding H, Ko MC (2016) Central N/OFQ-NOP receptor system in pain modulation. Adv Pharmacol 75:217–243PubMedGoogle Scholar
  65. Kim HD, Call T, Magazu S, Ferguson D (2017) Drug addiction and histone code alterations. Adv Exp Med Biol 978:127–143PubMedGoogle Scholar
  66. Kiraly K, Caputi FF, Hanuska A, Kató E, Balogh M, Köles L, Palmisano M, Riba P, Hosztafi S, Romualdi P, Candeletti S, Ferdinandy P, Fürst S, Al-Khrasani MA (2015) New potent analgesic agent with reduced liability to produce morphine tolerance. Brain Res Bull 117:32–38PubMedGoogle Scholar
  67. Kuzmin A, Sandin J, Terenius L, Ogren SO (2003) Acquisition, expression, and reinstatement of ethanol-induced conditioned place preference in mice: effects of opioid receptor-like 1 receptor agonists and naloxone. J Pharmacol Exp Ther 304:310–318PubMedGoogle Scholar
  68. Kuzmin A, Bazov I, Sheedy D, Garrick T, Harper C, Bakalkin G (2009) Expression of pronociceptin and its receptor is downregulated in the brain of human alcoholics. Brain Res 1305(Suppl):S80–S85PubMedPubMedCentralGoogle Scholar
  69. Lachowicz JE, Shen Y, Monsma FJ Jr, Sibley DR (1995) Molecular cloning of a novel G protein-coupled receptor related to the opiate receptor family. J Neurochem 64:34–40PubMedGoogle Scholar
  70. Lutfy K, Khaliq I, Carroll FI, Maidment NT (2002) Orphanin FQ/nociceptin blocks cocaine-induced behavioral sensitization in rats. Psychopharmacology 164:168–176PubMedPubMedCentralGoogle Scholar
  71. Ma F, Xie H, Dong ZQ, Wang YQ, Wu GC (2005) Expression of ORL1 mRNA in some brain nuclei in neuropathic pain rats. Brain Res 1043:214–217PubMedGoogle Scholar
  72. Manabe T, Noda Y, Mamiya T, Katagiri H, Houtani T, Nishi M, Noda T, Takahashi T, Sugimoto T, Nabeshima T, Takeshima H (1998) Facilitation of long-term potentiation and memory in mice lacking nociceptin receptors. Nature 394:577–581PubMedGoogle Scholar
  73. Marquez P, Nguyen AT, Hamid A, Lutfy K (2008) The endogenous OFQ/N/ORL-1 receptor system regulates the rewarding effects of acute cocaine. Neuropharmacology 54:564–568PubMedGoogle Scholar
  74. 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 signalling in rat substantia nigra pars reticulata stimulates nigrostriatal dopaminergic transmission and motor behavior. J Neurosci 24:6659–6666PubMedGoogle Scholar
  75. Marti M, Mela F, Fantin M, Zucchini S, Brown JM, Witta J, Di Benedetto M, Buzas B, Reinscheid RK, Salvadori S, Guerrini R, Romualdi P, Candeletti S, Simonato M, Cox BM, Morari M (2005) Blockade of nociceptin/orphanin FQ transmission attenuates symptoms and neurodegeneration associated with Parkinson’s disease. J Neurosci 25:9591–9601PubMedGoogle Scholar
  76. Marti M, Sarubbo S, Latini F, Cavallo M, Eleopra R, Biguzzi S, Lettieri C, Conti C, Simonato M, Zucchini S, Quatrale R, Sensi M, Candeletti S, Romualdi P, Morari M (2010) Brain interstitial nociceptin/orphanin FQ levels are elevated in Parkinson's disease. Mov Disord 25:1723–1732PubMedGoogle Scholar
  77. Mathis JP, Ryan-Moro J, Chang A, Hom JS, Scheinberg DA, Pasternak GW (1997) Biochemical evidence for orphanin FQ/nociceptin receptor heterogeneity in mouse brain. Biochem Biophys Res Commun 230:462–465PubMedGoogle Scholar
  78. Maze I, Wenderski W, Noh KM, Bagot RC, Tzavaras N, Purushothaman I, Elsässer SJ, Guo Y, Ionete C, Hurd YL et al (2015) Critical role of histone turnover in neuronal transcription and plasticity. Neuron 87:77–94PubMedPubMedCentralGoogle Scholar
  79. McGowan PO, Sasaki A, D’Alessio AC, Dymov S, Labonté B, Szyf M, Turecki G, Meaney MJ (2009) Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci 12:342–348PubMedPubMedCentralGoogle Scholar
  80. McGowan PO, Suderman M, Sasaki A, Huang TC, Hallett M, Meaney MJ, Szyf M (2011) Broad epigenetic signature of maternal care in the brain of adult rats. PLoS One 6(2):e14739PubMedPubMedCentralGoogle Scholar
  81. Meunier JC (2003) Utilizing functional genomics to identify new pain treatments: the example of nociceptin. Am J Pharmacogenomics 3:117–130PubMedGoogle Scholar
  82. Meunier JC, Mollereau C, Toll L, Suaudeau C, Moisand C, Alvinerie P, Butour JL, Guillemot JC, Ferrara P, Monsarrat B et al (1995) Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor. Nature 377:532–535PubMedGoogle Scholar
  83. Mews P, Calipari ES (2017) Cross-talk between the epigenome and neural circuits in drug addiction. Prog Brain Res 235:19–63PubMedPubMedCentralGoogle Scholar
  84. Micheli L, Lucarini E, Corti F, Ciccocioppo R, Calò G, Rizzi A, Ghelardini C, Di Cesare Mannelli L (2018) Involvement of the N/OFQ-NOP system in rat morphine antinociceptive tolerance: are astrocytes the crossroad? Eur J Pharmacol 823:79–86PubMedPubMedCentralGoogle Scholar
  85. Miller TR, Fulford AJ (2007) Regulation of nociceptin/orphanin FQ secretion by immune cells and functional modulation of interleukin-2. Peptides 28:2243–2252PubMedGoogle Scholar
  86. Mollereau C, Mouledous L (2000) Tissue distribution of the opioid receptor-like (ORL1) receptor. Peptides 21:907–917PubMedGoogle Scholar
  87. Mollereau C, Parmentier M, Mailleux P, Butour JL, Moisand C, Chalon P, Caput D, Vassart G, Meunier JC (1994) ORL1, a novel member of the opioid receptor family. Cloning, functional expression and localization. FEBS Lett 341:33–38PubMedGoogle Scholar
  88. Mollereau C, Simons MJ, Soularue P, Liners F, Vassart G, Meunier JC, Parmentier M (1996) Structure, tissue distribution, and chromosomal localization of the prepronociceptin gene. Proc Natl Acad Sci U S A 93:8666–8670PubMedPubMedCentralGoogle Scholar
  89. Moonat S, Sakharkar AJ, Zhang H, Tang L, Pandey SC (2013) Aberrant histone deacetylase2- mediated histone modifications and synaptic plasticity in the amygdala predisposes to anxiety and alcoholism. Biol Psychiatry 73:763–773PubMedPubMedCentralGoogle Scholar
  90. Neal CR Jr, Mansour A, Reinscheid R, Nothacker HP, Civelli O, Watson SJ Jr (1999) Localization of orphanin FQ (nociceptin) peptide and messenger RNA in the central nervous system of the rat. J Comp Neurol 406:503–547PubMedGoogle Scholar
  91. Nishi M, Takeshima H, Mori M, Nakagawara K, Takeuchi T (1994) Structure and chromosomal mapping of genes for the mouse kappa-opioid receptor and an opioid receptor homologue (MOR-C). Biochem Biophys Res Commun 205:1353–1357PubMedGoogle Scholar
  92. Nishi M, Houtani T, Noda Y, Mamiya T, Sato K, Doi T, Kuno J, Takeshima H, Nukada T, Nabeshima T, Yamashita T, Noda T, Sugimoto T (1997) Unrestrained nociceptive response and disregulation of hearing ability in mice lacking the nociceptin/orphaninFQ receptor. EMBO J 16:1858–1864PubMedPubMedCentralGoogle Scholar
  93. Nothacker HP, Reinscheid RK, Mansour A, Henningsen RA, Ardati A, Monsma FJ Jr, Watson SJ, Civelli O (1996) Primary structure and tissue distribution of the orphanin FQ precursor. Proc Natl Acad Sci U S A 93:8677–8682PubMedPubMedCentralGoogle Scholar
  94. Okuda-Ashitaka E, Minami T, Tachibana S, Yoshihara Y, Nishiuchi Y, Kimura T, Ito S (1998) Nocistatin, a peptide that blocks nociceptin action in pain transmission. Nature 392:286–289PubMedGoogle Scholar
  95. Osinski MA, Pampusch MS, Murtaugh MP, Brown DR (1999) Cloning, expression and functional role of a nociceptin/orphanin FQ receptor in the porcine gastrointestinal tract. Eur J Pharmacol 365:281–289PubMedGoogle Scholar
  96. Ozawa A, Brunori G, Mercatelli D, Wu J, Cippitelli A, Zou B, Xie XS, Williams M, Zaveri NT, Low S, Scherrer G, Kieffer BL, Toll L (2015) Knock-in mice with NOP-eGFP receptors identify receptor cellular and regional localization. J Neurosci 35:11682–11693PubMedPubMedCentralGoogle Scholar
  97. Ozawa A, Brunori G, Cippitelli A, Toll N, Schoch J, Kieffer BL, Toll L (2018) Analysis of the distribution of spinal NOP receptors in a chronic pain model using NOP-eGFP knock-in mice. Br J Pharmacol 175:2662–2675PubMedPubMedCentralGoogle Scholar
  98. Palmisano M, Pandey SC (2017) Epigenetic mechanisms of alcoholism and stress-related disorders. Alcohol 60:7–18PubMedPubMedCentralGoogle Scholar
  99. Palmisano M, Mercatelli D, Caputi FF, Carretta D, Romualdi P, Candeletti S (2017) N/OFQ system in brain areas of nerve-injured mice: its role in different aspects of neuropathic pain. Genes Brain Behav 16:537–545PubMedGoogle Scholar
  100. Pan YX, Xu J, Pasternak GW (1996) Structure and characterization of the gene encoding a mouse kappa3- related opioid receptor. Gene 171:255–260PubMedGoogle Scholar
  101. Pan YX, Xu J, Wan BL, Zuckerman A, Pasternak GW (1998) Identification and differential regional expression of KOR-3/ORL-1 gene splice variants in mouse brain. FEBS Lett 435:65–68PubMedGoogle Scholar
  102. Pascual M, Do Couto BR, Alfonso-Loeches S, Aguilar MA, Rodriguez-Arias M, Guerri C (2012) Changes in histone acetylation in the prefrontal cortex of ethanol-exposed adolescent rats are associated with ethanol-induced place conditioning. Neuropharmacology 62:2309–2319PubMedGoogle Scholar
  103. Peana AT, Sánchez-Catalán MJ, Hipólito L, Rosas M, Porru S, Bennardini F, Romualdi P, Caputi FF, Candeletti S, Polache A, Granero L, Acquas E (2017) Mystic acetaldehyde: the never-ending story on alcoholism. Front Behav Neurosci 11:81PubMedPubMedCentralGoogle Scholar
  104. Peluso J, LaForge KS, Matthes HW, Kreek MJ, Kieffer BL, Gaveriaux-Ruff C (1998) Distribution of nociceptin/orphanin FQ receptor transcript in human central nervous system and immune cells. J Neuroimmunol 81:184–192PubMedGoogle Scholar
  105. Pomonis JD, Billington CJ, Levine AS (1996) Orphanin FQ, agonist of orphan opioid receptor ORL1, stimulates feeding in rats. Neuroreport 8(1):369–371PubMedGoogle Scholar
  106. Popiolek-Barczyk K, Rojewska E, Jurga AM, Makuch W, Zador F, Borsodi A, Piotrowska A, Przewlocka B, Mika J (2014) Minocycline enhances the effectiveness of nociceptin/orphanin FQ during neuropathic pain. Biomed Res Int 2014:762930PubMedPubMedCentralGoogle Scholar
  107. Pucci M, Micioni Di Bonaventura MV, Giusepponi ME, Romano A, Filaferro M, Maccarrone M, Ciccocioppo R, Cifani C, D’Addario C (2016) Epigenetic regulation of nociceptin/orphanin FQ and corticotropin-releasing factor system genes in frustration stress-induced binge-like palatable food consumption. Addict Biol 21:1168–1185PubMedGoogle Scholar
  108. Raddad E, Chappell A, Meyer J, Wilson A, Ruegg CE, Tauscher J, Statnick MA, Barth V, Zhang X, Verfaille SJ (2016) Occupancy of nociceptin/orphanin FQ peptide receptors by the antagonist LY2940094 in rats and healthy human subjects. Drug Metab Dispos 44:1536–1542PubMedGoogle Scholar
  109. Reinscheid RK, Nothacker H-P, Bourson A, Ardati A, Henningsen RA, Bunzow JR, Grandy DK, Langen H, Monsma FJ Jr, Civelli O (1995) Orphanin FQ: a neuropeptide that activates an opioidlike G protein-coupled receptor. Science 270:792–794PubMedGoogle Scholar
  110. Reinscheid RK, Ardati A, Monsma FJ Jr, Civelli O (1996) Structure-activity relationship studies on the novel neuropeptide orphanin FQ. J Biol Chem 271:14163–14168PubMedGoogle Scholar
  111. Reinscheid RK, Higelin J, Henningsen RA, Monsma FJ Jr, Civelli O (1998) Structures that delineate orphanin FQ and dynorphin A pharmacological selectivities. J Biol Chem 273:1490–1495PubMedGoogle Scholar
  112. Reinscheid RK, Nothacker H, Civelli O (2000) The orphanin FQ/nociceptin gene: structure, tissue distribution of expression and functional implications obtained from knockout mice. Peptides 21:901–906PubMedGoogle Scholar
  113. Rekik K, Faria Da Silva R, Colom M, Pacifico S, Zaveri NT, Calò G, Rampon C, Frances B, Mouledous L (2017) Activation of nociceptin/orphanin FQ receptors inhibits contextual fear memory reconsolidation. Neuropharmacology 125:39–49PubMedGoogle Scholar
  114. Rizzi A, Molinari S, Marti M, Marzola G, Calò G (2011) Nociceptin/orphanin FQ receptor knockout rats: in vitro and in vivo studies. Neuropharmacology 60:572–579PubMedGoogle Scholar
  115. Rodi D, Polidori C, Bregola G, Zucchini S, Simonato M, Massi M (2002) Pro-nociceptin/orphanin FQ and NOP receptor mRNA levels in the forebrain of food deprived rats. Brain Res 957:354–361PubMedGoogle Scholar
  116. Romualdi P, Landuzzi D, D’Addario C, Candeletti S (2002) Modulation of proorphaninFQ/N gene expression by morphine in the rat mesocorticolimbic system. Neuroreport 13:645–648PubMedGoogle Scholar
  117. Rosenberger J, Petrovics G, Buzas B (2001) Oxidative stress induces proorphanin FQ and proenkephalin gene expression in astrocytes through p38- and ERK-MAP kinases and NF-kappaB. J Neurochem 79:35–44PubMedGoogle Scholar
  118. Rossi GC, Mathis JP, Pasternak GW (1998) Analgesic activity of orphanin FQ2, murine prepro-orphanin FQ141-157 in mice. Neuroreport 9:1165–1168PubMedGoogle Scholar
  119. Rouillé Y, Duguay SJ, Lund K, Furuta M, Gong Q, Lipkind G, Oliva AA Jr, Chan SJ, Steiner DF (1995) Proteolytic processing mechanisms in the biosynthesis of neuroendocrine peptides: the subtilisin-like proprotein convertases. Front Neuroendocrinol 16:322–361PubMedGoogle Scholar
  120. Ruggeri B, Macare C, Stopponi S, Jia T, Carvalho FM, Robert G, Banaschewski T, Bokde ALW, Bromberg U, Büchel C et al (2018) Methylation of OPRL1 mediates the effect of psychosocial stress on binge drinking in adolescents. J Child Psychol Psychiatry 59:650–658PubMedGoogle Scholar
  121. Rutten K, De Vry J, Bruckmann W, Tzschentke TM (2011) Pharmacological blockade or genetic knockout of the NOP receptor potentiates the rewarding effect of morphine in rats. Drug Alcohol Depend 114:253–256PubMedGoogle Scholar
  122. Saban MR, Nguyen NB, Hammond TG, Saban R (2002) Gene expression profiling of mouse bladder inflammatory responses to LPS, substance P, and antigen-stimulation. Am J Pathol 160:2095–2110PubMedPubMedCentralGoogle Scholar
  123. Saito Y, Maruyama K, Saido TC, Kawashima S (1995) N23K, a gene transiently up-regulated during neural differentiation, encodes a precursor protein for a newly identified neuropeptide nociceptin. Biochem Biophys Res Commun 217:539–545PubMedGoogle Scholar
  124. Saito Y, Maruyama K, Kawano H, Hagino-Yamagishi K, Kawamura K, Saido TC, Kawashima S (1996) Molecular cloning and characterization of a novel form of neuropeptide gene as a developmentally regulated molecule. J Biol Chem 271:15615–15622PubMedGoogle Scholar
  125. Saito Y, Maruyama K, Saido TC, Kawashima S (1997) Overexpression of a neuropeptide nociceptin/orphanin FQ precursor gene, N23K/N27K, induces neurite outgrowth in mouse NS20Y cells. J Neurosci Res 48:397–406PubMedGoogle Scholar
  126. Sakoori K, Murphy NP (2008) Endogenous nociceptin (orphanin FQ) suppresses basal hedonic state and acute reward responses to methamphetamine and ethanol, but facilitates chronic responses. Neuropsychopharmacology 33:877–891PubMedGoogle Scholar
  127. Sasaki A, Takasaki I, Andoh T, Shiraki K, Takeshima H, Takahata H, Kuraishi Y (2008) Nociceptin-receptor deficiency prevents postherpetic pain without effects on acute herpetic pain in mice. Neuroreport 19:83–86PubMedGoogle Scholar
  128. Schröder W, Lambert DG, Ko MC, Koch T (2014) Functional plasticity of the N/OFQ-NOP receptor system determines analgesic properties of NOP receptor agonists. Br J Pharmacol 171:3777–3800PubMedPubMedCentralGoogle Scholar
  129. Sirianni MJ, Fujimoto KI, Nelson CS, Pellegrino MJ, Allen RG (1999) Cyclic AMP analogs induce synthesis, processing, and secretion of prepro nociceptin/orphanin FQ-derived peptides by NS20Y neuroblastoma cells. DNA Cell Biol 18:51–58PubMedGoogle Scholar
  130. Sobczak M, Mokrowiecka A, Cygankiewicz AI, Zakrzewski PK, Sałaga M, Storr M, Kordek R, Małecka-Panas E, Krajewska WM, Fichna J (2014) Anti-inflammatory and antinociceptive action of an orally available nociceptin receptor agonist SCH 221510 in a mouse model of inflammatory bowel diseases. J Pharmacol Exp Ther 348:401–409PubMedGoogle Scholar
  131. Sossin WS, Fisher JM, Scheller RH (1989) Cellular and molecular biology of neuropeptide processing and packaging. Neuron 2:1407–1417PubMedGoogle Scholar
  132. Stamer UM, Book M, Comos C, Zhang L, Nauck F, Stüber F (2011) Expression of the nociceptin precursor and nociceptin receptor is modulated in cancer and septic patients. Br J Anaesth 106:566–572PubMedGoogle Scholar
  133. Statnick MA, Chen Y, Ansonoff M, Witkin JM, Rorick-Kehn L, Suter TM, Song M, Hu C, Lafuente C, Jiménez A, Benito A, Diaz N, Martínez-Grau MA, Toledo MA, Pintar JE (2016) A novel nociceptin receptor antagonist LY2940094 inhibits excessive feeding behavior in rodents: a possible mechanism for the treatment of binge eating disorder. J Pharmacol Exp Ther 356:493–502PubMedGoogle Scholar
  134. Szutorisz H, Hurd YL (2016) Epigenetic effects of cannabis exposure. Biol Psychiatry 79:586–594PubMedGoogle Scholar
  135. Tallent MK, Madamba SG, Siggins GR (2001) Nociceptin reduces epileptiform events in CA3 hippocampus via presynaptic and postsynaptic mechanisms. J Neurosci 21:6940–6948PubMedGoogle Scholar
  136. Tapocik JD, Ceniccola K, Mayo CL, Schwandt ML, Solomon M, Wang BD, Luu TV, Olender J, Harrigan T, Maynard TM, Elmer GI, Lee NH (2016) MicroRNAs are involved in the development of morphine-induced analgesic tolerance and regulate functionally relevant changes in Serpini1. Front Mol Neurosci 9:20. CrossRefPubMedPubMedCentralGoogle Scholar
  137. Toll L, Bruchas MR, Calò G, Cox BM, Zaveri NT (2016) Nociceptin/orphanin FQ receptor structure, signaling, ligands, functions, and interactions with opioid systems. Pharmacol Rev 68:419–457PubMedPubMedCentralGoogle Scholar
  138. Turunc Bayrakdar E, Bojnik E, Armagan G, Kanit L, Benyhe S, Borsodi A, Yalcin A (2013) Kainic acid-induced seizure activity alters the mRNA expression and G-protein activation of the opioid/nociceptin receptors in the rat brain cortex. Epilepsy Res 105:13–19PubMedGoogle Scholar
  139. Ueda H, Yamaguchi T, Tokuyama S, Inoue M, Nishi M, Takeshima H (1997) Partial loss of tolerance liability to morphine analgesia in mice lacking the nociceptin receptor gene. Neurosci Lett 237:136–138PubMedGoogle Scholar
  140. Ueda H, Inoue M, Takeshima H, Iwasawa Y (2000) Enhanced spinal nociceptin receptor expression develops morphine tolerance and dependence. J Neurosci 20:7640–7647PubMedGoogle Scholar
  141. Walker DM, Nestler EJ (2018) Neuroepigenetics and addiction. Handb Clin Neurol 148:747–765PubMedPubMedCentralGoogle Scholar
  142. Wang JB, Johnson PS, Imai Y, Persico AM, Ozenberger BA, Eppler CM, Uhl GR (1994) cDNA cloning of an orphan opiate receptor gene family member and its splice variant. FEBS Lett 348:75–79PubMedGoogle Scholar
  143. Wick MJ, Minnerath SR, Roy S, Ramakrishnan S, Loh HH (1995) Expression of alternate forms of brain opioid “orphan” receptor mRNA in activated human peripheral blood lymphocytes and lymphocytic cell lines. Mol Brain Res 32:342–347PubMedGoogle Scholar
  144. Wille-Bille A, Miranda-Morales RS, Pucci M, Bellia F, D’Addario C, Pautassi RM (2018) Prenatal ethanol induces an anxiety phenotype and alters expression of dynorphin & nociceptin/orphanin FQ genes. Prog Neuro-Psychopharmacol Biol Psychiatry 85:77–88Google Scholar
  145. Witkin JM, Statnick MA, Rorick-Kehn LM, Pintar JE, Ansonoff M, Chen Y, Tucker RC, Ciccocioppo R (2014) The biology of Nociceptin/Orphanin FQ (N/OFQ) related to obesity, stress, anxiety, mood, and drug dependence. Pharmacol Ther 141:283–299PubMedGoogle Scholar
  146. Wu Q, Liu L (2018) ORL1 activation mediates a novel ORL1 receptor agonist SCH221510 analgesia in neuropathic pain in rats. J Mol Neurosci 66:10–16PubMedGoogle Scholar
  147. Xie GX, Ito E, Maruyama K, Suzuki Y, Sugano S, Sharma M, Pietruck C, Palmer PP (1999a) The promoter region of human prepro-nociceptin gene and its regulation by cyclic AMP and steroid hormones. Gene 238:427–436PubMedGoogle Scholar
  148. Xie GX, Meuser T, Pietruck C, Sharma M, Palmer PP (1999b) Presence of opioid receptor-like (ORL1), receptor mRNA splice variants in peripheral sensory and sympathetic neuronal ganglia. Life Sci 64:2029–2037PubMedGoogle Scholar
  149. Xie GX, Ito E, Maruyama K, Pietruck C, Sharma M, Yu L, Pierce Palmer P (2000) An alternatively spliced transcript of the rat nociceptin receptor ORL1 gene encodes a truncated receptor. Mol Brain Res 77:1–9PubMedGoogle Scholar
  150. Xuei X, Flury-Wetherill L, Almasy L, Bierut L, Tischfield J, Schuckit M, Nurnberger JI Jr, Foroud T, Edenberg HJ (2008) Association analysis of genes encoding the nociceptin receptor (OPRL1) and its endogenous ligand (PNOC) with alcohol or illicit drug dependence. Addict Biol 13:80–87PubMedGoogle Scholar
  151. Yamamoto KK, Gonzalez GA, Biggs WH 3rd, Montminy MR (1988) Phosphorylation-induced binding and transcriptional efficacy of nuclear factor CREB. Nature 334:494–498PubMedGoogle Scholar
  152. Zaratin PF, Petrone G, Sbacchi M, Garnier M, Fossati C, Petrillo P, Ronzoni S, Giardina GA, Scheideler MA (2004) Modification of nociception and morphine tolerance by the selective opiate receptor-like orphan receptor antagonist(−)-cis-1-methyl-7-[[4-(26-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol(SB-612111). J Pharmacol Exp Ther 308:454–461PubMedGoogle Scholar
  153. Zaveri NT, Green CJ, Toll L (2000) Transcriptional regulation of the human prepronociceptin gene. Biochem Biophys Res Commun 276:710–717PubMedGoogle Scholar
  154. Zaveri NT, Green CJ, Polgar WE, Huynh N, Toll L (2002) Regulation of transcription of the human prepronociceptin gene by Sp1. Gene 290:45–52PubMedGoogle Scholar
  155. Zaveri NT, Waleh N, Toll L (2006) Regulation of the prepronociceptin gene and its effect on neuronal differentiation. Gene 384:27–36PubMedGoogle Scholar
  156. Zhang L, Stuber F, Stamer UM (2013a) Inflammatory mediators influence the expression of nociceptin and its receptor in human whole blood cultures. PLoS One 8:e74138PubMedPubMedCentralGoogle Scholar
  157. Zhang H, Wang F, Kranzler HR, Zhao H, Gelernter J (2013b) Profiling of childhood adversity-associated DNA methylation changes in alcoholic patients and healthy controls. PLoS One 8:e65648PubMedPubMedCentralGoogle Scholar
  158. 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 172:571–582PubMedGoogle Scholar
  159. Zhou MM, Yu CX, Wang MZ, Cao XD, Wu GC (2001) Alteration of orphanin FQ immunoreactivity and ppOFQ mRNA by combination of melatonin with electroacupuncture. Acupunct Electrother Res 26:49–58PubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Francesca Felicia Caputi
    • 1
  • Patrizia Romualdi
    • 1
    Email author
  • Sanzio Candeletti
    • 1
  1. 1.Department of Pharmacy and BiotechnologyAlma Mater Studiorum – University of BolognaBolognaItaly

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