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pp 1-14 | Cite as

The History of N/OFQ and the NOP Receptor

  • Rainer K. ReinscheidEmail author
  • Olivier Civelli
Chapter
First Online:
Part of the Handbook of Experimental Pharmacology book series

Abstract

The discovery of nociceptin/orphanin FQ (N/OFQ) marks the genuine start of the reverse pharmacology era, when systematic hunting for ligands of orphan receptors began. The choice of this particular target was no coincidence as the orphan receptor ORL-1 displayed high similarity to known opioid receptors, and thus its elusive ligand held promise to find more than a ligand but a missing opioid peptide. N/OFQ indeed turned out to belong to the opioid peptide family, but with significant pharmacological and functional distinctions. The quest for understanding N/OFQ’s physiological functions has produced some novel insights into stress regulation and many other body functions but is still ongoing almost 25 years after its discovery. This chapter highlights the early steps of orphan receptor research and some of the protagonists who helped to advance the field.

Keywords

Analgesia Bioassay G protein-coupled receptor Nociceptin/orphanin FQ Opioid peptide Orphan receptor Stress 
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References

  1. Bunzow JR, Van Tol HH, Grandy DK, Albert P, Salon J, Christie M, Machida CA, Neve KA, Civelli O (1988) Cloning and expression of a rat D2 dopamine receptor cDNA. Nature 336(6201):783–787. PubMed PMID: 2974511Google Scholar
  2. 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(2–3):284–288. PubMed PMID: 8034019Google Scholar
  3. Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, Richardson JA, Williams SC, Xiong Y, Kisanuki Y, Fitch TE, Nakazato M, Hammer RE, Saper CB, Yanagisawa M (1999) Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98(4):437–451. PubMed PMID: 10481909Google Scholar
  4. Chen Y, Mestek A, Liu J, Hurley JA, Yu L (1993) Molecular cloning and functional expression of a mu-opioid receptor from rat brain. Mol Pharmacol 44(1):8–12. PubMed PMID: 8393525Google Scholar
  5. 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(2–3):279–283. PubMed PMID: 8034018Google Scholar
  6. Chung S, Pohl S, Zeng J, Civelli O, Reinscheid RK (2006) Endogenous orphanin FQ/nociceptin is involved in the development of morphine tolerance. J Pharmacol Exp Ther 318(1):262–267. Epub 2006 Apr 4. PubMed PMID: 16595734Google Scholar
  7. 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 ociceptin/orphanin FQ receptor agonist, Ro 64-6198. Psychopharmacology (Berl) 161(2):113–119. Epub 2002 Mar 22. PubMed PMID: 11981590Google Scholar
  8. de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, Fukuhara C, Battenberg EL, Gautvik VT, Bartlett FS 2nd, Frankel WN, van den Pol AN, Bloom FE, Gautvik KM, Sutcliffe JG (1998) The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci U S A 95(1):322–327. PubMed PMID: 9419374; PubMed Central PMCID: PMC18213Google Scholar
  9. Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258(5090):1946–1949. PubMed PMID: 1470919Google Scholar
  10. Evans CJ, Keith DE Jr, Morrison H, Magendzo K, Edwards RH (1992) Cloning of a delta opioid receptor by functional expression. Science 258(5090):1952–1955. PubMed PMID: 1335167Google Scholar
  11. Fujii R, Hosoya M, Fukusumi S, Kawamata Y, Habata Y, Hinuma S, Onda H, Nishimura O, Fujino M (2000) Identification of neuromedin U as the cognate ligand of the orphan G protein-coupled receptor FM-3. J Biol Chem 275(28):21068–21074. PubMed PMID: 10783389Google Scholar
  12. Fujii R, Yoshida H, Fukusumi S, Habata Y, Hosoya M, Kawamata Y, Yano T, Hinuma S, Kitada C, Asami T, Mori M, Fujisawa Y, Fujino M (2002) Identification of a neuropeptide modified with bromine as an endogenous ligand for GPR7. J Biol Chem 277(37):34010–34016. Epub 2002 Jul 12. PubMed PMID: 12118011Google Scholar
  13. 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):42–46. PubMed PMID: 8163014Google Scholar
  14. Fukusumi S, Yoshida H, Fujii R, Maruyama M, Komatsu H, Habata Y, Shintani Y, Hinuma S, Fujino M (2003) A new peptidic ligand and its receptor regulating adrenal function in rats. J Biol Chem 278(47):46387–46395. Epub 2003 Sep 5. PubMed PMID: 12960173Google Scholar
  15. Gavioli EC, Calo G (2013) Nociceptin/orphanin FQ receptor antagonists as innovative antidepressant drugs. Pharmacol Ther 140(1):10–25.  https://doi.org/10.1016/j.pharmthera.2013.05.008. Epub 2013 May 24. Review. PubMed PMID: 23711793CrossRefGoogle Scholar
  16. 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(9):1987–1990. PubMed PMID: 12752799Google Scholar
  17. 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(6):547–553. Epub 2004 May 25. PubMed PMID: 15197534Google Scholar
  18. Günther T, Dasgupta P, Mann A, Miess E, Kliewer A, Fritzwanker S, Steinborn R, Schulz S (2018) Targeting multiple opioid receptors - improved analgesics with reduced side effects? Br J Pharmacol 175(14):2857–2868.  https://doi.org/10.1111/bph.13809. Epub 2017 May 26. Review PubMed PMID: 28378462; PubMed Central PMCID: PMC6016677CrossRefGoogle Scholar
  19. Hinuma S, Habata Y, Fujii R, Kawamata Y, Hosoya M, Fukusumi S, Kitada C, Masuo Y, Asano T, Matsumoto H, Sekiguchi M, Kurokawa T, Nishimura O, Onda H, Fujino M (1998) A prolactin-releasing peptide in the brain. Nature 393(6682):272–276. Erratum in: Nature 1998 Jul 16;394(6690):302. PubMed PMID: 9607765Google Scholar
  20. Hinuma S, Shintani Y, Fukusumi S, Iijima N, Matsumoto Y, Hosoya M, Fujii R, Watanabe T, Kikuchi K, Terao Y, Yano T, Yamamoto T, Kawamata Y, Habata Y, Asada M, Kitada C, Kurokawa T, Onda H, Nishimura O, Tanaka M, Ibata Y, Fujino M (2000) New neuropeptides containing carboxy-terminal RFamide and their receptor in mammals. Nat Cell Biol 2(10):703–708. PubMed PMID: 11025660Google Scholar
  21. Itoh Y, Kawamata Y, Harada M, Kobayashi M, Fujii R, Fukusumi S, Ogi K, Hosoya M, Tanaka Y, Uejima H, Tanaka H, Maruyama M, Satoh R, Okubo S, Kizawa H, Komatsu H, Matsumura F, Noguchi Y, Shinohara T, Hinuma S, Fujisawa Y, Fujino M (2003) Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40. Nature 422(6928):173–176. Epub 2003 Feb 23. PubMed PMID: 12629551Google Scholar
  22. 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 behavioral responses to stress. Proc Natl Acad Sci U S A 94(26):14854–14858. PubMed PMID: 9405703; PubMed Central PMCID: PMC25127Google Scholar
  23. 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(9):4938–4943. PubMed PMID: 10758169; PubMed Central PMCID: PMC18336Google Scholar
  24. Kawamata Y, Fujii R, Hosoya M, Harada M, Yoshida H, Miwa M, Fukusumi S, Habata Y, Itoh T, Shintani Y, Hinuma S, Fujisawa Y, Fujino M (2003) A G protein-coupled receptor responsive to bile acids. J Biol Chem 278(11):9435–9440. Epub 2003 Jan 10. PubMed PMID: 12524422Google Scholar
  25. Kieffer BL, Befort K, Gaveriaux-Ruff C, Hirth CG (1992) The delta-opioid receptor: isolation of a cDNA by expression cloning and pharmacological characterization. Proc Natl Acad Sci U S A 89(24):12048–12052. Erratum in: Proc Natl Acad Sci U S A 1994 Feb 1;91(3):1193. PubMed PMID: 1334555; PubMed Central PMCID: PMC50695Google Scholar
  26. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K (1999) Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402(6762):656–660. PubMed PMID: 10604470Google Scholar
  27. Köster A, Montkowski A, Schulz S, Stübe 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(18):10444–10449. PubMed PMID: 10468628; PubMed Central PMCID: PMC17908Google Scholar
  28. 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(1):34–40 PubMed PMID: 7798930Google Scholar
  29. Libert F, Parmentier M, Lefort A, Dinsart C, Van Sande J, Maenhaut C, Simons MJ, Dumont JE, Vassart G (1989) Selective amplification and cloning of four new members of the G protein-coupled receptor family. Science 244(4904):569–572. PubMed PMID: 2541503Google Scholar
  30. Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X, Qiu X, de Jong PJ, Nishino S, Mignot E (1999) The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98(3):365–376. PubMed PMID: 10458611Google Scholar
  31. Linz K, Christoph T, Tzschentke TM, Koch T, Schiene K, Gautrois M, Schröder W, Kögel BY, Beier H, Englberger W, Schunk S, De Vry J, Jahnel U, Frosch S (2014) Cebranopadol: a novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonist. J Pharmacol Exp Ther 349(3):535–548.  https://doi.org/10.1124/jpet.114.213694. Epub 2014 Apr 8. PubMed PMID: 24713140CrossRefGoogle Scholar
  32. Lutfy K, Hossain SM, Khaliq I, Maidment NT (2001) Orphanin FQ/nociceptin attenuates the development of morphine tolerance in rats. Br J Pharmacol 134(3):529–534. PubMed PMID: 11588106; PubMed Central PMCID: PMC1572978Google Scholar
  33. Masuda Y, Takatsu Y, Terao Y, Kumano S, Ishibashi Y, Suenaga M, Abe M, Fukusumi S, Watanabe T, Shintani Y, Yamada T, Hinuma S, Inatomi N, Ohtaki T, Onda H, Fujino M (2002) Isolation and identification of EG-VEGF/prokineticins as cognate ligands for two orphan G-protein-coupled receptors. Biochem Biophys Res Commun 293(1):396–402. PubMed PMID: 12054613Google Scholar
  34. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346(6284):561–564. PubMed PMID: 2165569Google Scholar
  35. Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, Gopher A, Almog S, Martin BR, Compton DR et al (1995) Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 50(1):83–90. PubMed PMID: 7605349Google Scholar
  36. 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(6549):532–535. PubMed PMID: 7566152Google Scholar
  37. Mogil JS, Grisel JE, Reinscheid RK, Civelli O, Belknap JK, Grandy DK (1996) Orphanin FQ is a functional anti-opioid peptide. Neuroscience 75(2):333–337. PubMed PMID: 8930999Google Scholar
  38. 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(1):33–38. PubMed PMID: 8137918Google Scholar
  39. Mollereau C, Mouledous L, Lapalu S, Cambois G, Moisand C, Butour JL, Meunier JC (1999) Distinct mechanisms for activation of the opioid receptor-like 1 and kappa-opioid receptors by nociceptin and dynorphin A. Mol Pharmacol 55(2):324–331. PubMed PMID: 9927625Google Scholar
  40. Mori M, Sugo T, Abe M, Shimomura Y, Kurihara M, Kitada C, Kikuchi K, Shintani Y, Kurokawa T, Onda H, Nishimura O, Fujino M (1999) Urotensin II is the endogenous ligand of a G-protein-coupled orphan receptor, SENR (GPR14). Biochem Biophys Res Commun 265(1):123–129Google Scholar
  41. Ohtaki T, Shintani Y, Honda S, Matsumoto H, Hori A, Kanehashi K, Terao Y, Kumano S, Takatsu Y, Masuda Y, Ishibashi Y, Watanabe T, Asada M, Yamada T, Suenaga M, Kitada C, Usuki S, Kurokawa T, Onda H, Nishimura O, Fujino M (2001) Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature 411(6837):613–617Google Scholar
  42. Okuda-Ashitaka E, Tachibana S, Houtani T, Minami T, Masu Y, Nishi M, Takeshima H, Sugimoto T, Ito S (1996) Identification and characterization of an endogenous ligand for opioid receptor homologue ROR-C: its involvement in allodynic response to innocuous stimulus. Brain Res Mol Brain Res 43(1–2):96–104. PubMed PMID: 9037523Google Scholar
  43. Pan YX, Cheng J, Xu J, Rossi G, Jacobson E, Ryan-Moro J, Brooks AI, Dean GE, Standifer KM, Pasternak GW (1995) Cloning and functional characterization through antisense mapping of a kappa 3-related opioid receptor. Mol Pharmacol 47(6):1180–1188. PubMed PMID: 7603458Google Scholar
  44. 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.  https://doi.org/10.1038/npp.2015.348 Epub 2015 Nov 20. PubMed PMID: 26585287; PubMed Central PMCID: PMC4869049CrossRefGoogle Scholar
  45. Reinscheid RK, Nothacker HP, 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(5237):792–794. PubMed PMID: 7481766Google Scholar
  46. Reinscheid RK, Ardati A, Monsma FJ Jr, Civelli O (1996) Structure-activity relationship studies on the novel neuropeptide orphanin FQ. J Biol Chem 271(24):14163–14168. PubMed PMID: 8662940Google Scholar
  47. 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(3):1490–1495. PubMed PMID: 9430687Google Scholar
  48. Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92(4):573–585. PubMed PMID: 9491897Google Scholar
  49. Scholz A, Bothmer J, Kok M, Hoschen K, Daniels S (2018) Cebranopadol: a novel, first-in-class, strong analgesic: results from a randomized phase IIA clinical trial in postoperative acute pain. Pain Physician 21(3):E193–E206. PubMed PMID: 29871387Google Scholar
  50. Sertürner FWA (1806) Darstellung der reinen Mohnsäure (Opiumsäure) nebst einer chemischen Untersuchung des Opiums mit vorzüglicher Hinsicht auf einen darin neu entdeckten Stoff und die dahin gehörigen Bemerkungen. J Pharm XIV:47–93. Leipzig: S.L. CrusinsGoogle Scholar
  51. Shimohigashi Y, Hatano R, Fujita T, Nakashima R, Nose T, Sujaku T, Saigo A, Shinjo K, Nagahisa A (1996) Sensitivity of opioid receptor-like receptor ORL1 for chemical modification on nociceptin, a naturally occurring nociceptive peptide. J Biol Chem 271(39):23642–23645. PubMed PMID: 8798582Google Scholar
  52. Shimomura Y, Mori M, Sugo T, Ishibashi Y, Abe M, Kurokawa T, Onda H, Nishimura O, Sumino Y, Fujino M (1999) Isolation and identification of melanin-concentrating hormone as the endogenous ligand of the SLC-1 receptor. Biochem Biophys Res Commun 261(3):622–626Google Scholar
  53. Shinohara T, Harada M, Ogi K, Maruyama M, Fujii R, Tanaka H, Fukusumi S, Komatsu H, Hosoya M, Noguchi Y, Watanabe T, Moriya T, Itoh Y, Hinuma S (2004) Identification of a G protein-coupled receptor specifically responsive to beta-alanine. J Biol Chem 279(22):23559–23564. Epub 2004 Mar 22. PubMed PMID: 15037633Google Scholar
  54. Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K, Yamashita A, Waku K (1995) 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun 215(1):89–97. PubMed PMID: 7575630Google Scholar
  55. Sugo T, Murakami Y, Shimomura Y, Harada M, Abe M, Ishibashi Y, Kitada C, Miyajima N, Suzuki N, Mori M, Fujino M (2003) Identification of urotensin II-related peptide as the urotensin II-immunoreactive molecule in the rat brain. Biochem Biophys Res Commun 310(3):860–868. PubMed PMID: 14550283Google Scholar
  56. Sundström G, Dreborg S, Larhammar D (2010) Concomitant duplications of opioid peptide and receptor genes before the origin of jawed vertebrates. PLoS One 5(5):e10512.  https://doi.org/10.1371/journal.pone.0010512 PubMed PMID: 20463905; PubMed Central PMCID: PMC2865548CrossRefGoogle Scholar
  57. Tatemoto K, Hosoya M, Habata Y, Fujii R, Kakegawa T, Zou MX, Kawamata Y, Fukusumi S, Hinuma S, Kitada C, Kurokawa T, Onda H, Fujino M (1998) Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochem Biophys Res Commun 251(2):471–476. PubMed PMID: 9792798Google Scholar
  58. 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(2–3):136–138. PubMed PMID: 9453234Google Scholar
  59. Ueda H, Inoue M, Takeshima H, Iwasawa Y (2000) Enhanced spinal nociceptin receptor expression develops morphine tolerance and dependence. J Neurosci 20(20):7640–7647. PubMed PMID: 11027224Google Scholar
  60. 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(1):75–79. PubMed PMID: 8026588Google Scholar
  61. 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 PMID: 10476866Google Scholar
  62. Yasuda K, Raynor K, Kong H, Breder CD, Takeda J, Reisine T, Bell GI (1993) Cloning and functional comparison of kappa and delta opioid receptors from mouse brain. Proc Natl Acad Sci U S A 90(14):6736–6740. PubMed PMID: 8393575; PubMed Central PMCID: PMC47007Google Scholar

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© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Institute of Pharmacology and ToxicologyUniversity Hospital Jena, Friedrich-Schiller-UniversitätJenaGermany
  2. 2.Institute of Physiology IUniversity Hospital Münster, Westfälische-Wilhelms-UniversitätMünsterGermany
  3. 3.Department of Pharmacology and Pharmaceutical SciencesUniversity of California IrvineIrvineUSA

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