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Endogenous Opioids

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The Opiate Receptors

Part of the book series: The Receptors ((REC))

Abstract

Most of the endogenous opioids that have been identified are peptides that originate from four distinct precursor proteins, proenkephalin, prodynorphin, proopiomelanocortin (POMC), and pronociceptin/orphanin FQ. All four of these precursors are differentially processed by endopeptidases and carboxypeptidases to give rise to a large number of peptides that have biological activity. In many cases, the amount of processing affects the bioactivity of the resulting peptides; in some cases the longer forms of a particular peptide bind with higher affinity to one of the opioid peptide receptors, in other cases the shorter forms bind with higher affinity to the receptor. Also, in the case of β-endorphin, one form of the peptide is an agonist at opioid peptide receptors while a shorter form lacking four C-terminal residues is an antagonist at the same receptor. Thus, processing of the endogenous opioid peptides plays a critical role in generating the bioactive form(s) of the peptide, and regulation of this processing can greatly influence the physiological activity of the peptide.

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References

  1. Hughes J, Smith TW, Kosterlitz HW, Fothergill LA, Morgan BA, Morris HR (1975) Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature 258(5536):577–580

    PubMed  CAS  Google Scholar 

  2. Li CH, Chung D (1976) Isolation and structure of an untriakontapeptide with opiate activity from camel pituitary glands. Proc Natl Acad Sci USA 73(4):1145–1148

    PubMed  CAS  Google Scholar 

  3. Goldstein A, Tachibana S, Lowney LI, Hunkapiller M, Hood L (1979) Dynorphin-(1-13), an extraordinarily potent opioid peptide. Proc Natl Acad Sci USA 76(12):6666–6670

    PubMed  CAS  Google Scholar 

  4. Goldstein A, Fishli W, Lowney LI, Hunkapiller M, Hood L (1981) Porcine pituitary dynorphin: complete amino acid sequence of the biologically active heptadecapeptide. Proc Natl Acad Sci USA 78:7219–7223

    PubMed  CAS  Google Scholar 

  5. Kangawa K, Matsuo H (1979) Alpha-neo-endorphin: a “big” Leu-enkephalin with potent opiate activity from porcine hypothalami. Biochem Biophys Res Commun 86(1):153–160

    PubMed  CAS  Google Scholar 

  6. Minamino N, Kangawa K, Fukuda A, Matsuo H, Igarashi M (1980) A new opioid octapeptide related to dynorphin from porcine hypothalamus. Biochem Biophys Res Commun 95:1475–1481

    PubMed  CAS  Google Scholar 

  7. Minamino N, Kangawa K, Chino N, Sakakibara S, Matsuo H (1981) Beta-neo-endorphin, a new hypothalamic “big” Leu-enkephalin of porcine origin: its purification and the complete amino acid sequence. Biochem Biophys Res Commun 99(3):864–870

    PubMed  CAS  Google Scholar 

  8. Mizuno K, Minamino N, Kangawa K, Matsuo H (1980) A new family of endogenous “big” Met-enkephalins from bovine adrenal medulla: purification and structure of docosa- (BAM-22P) and eicosapeptide (BAM-20P) with very potent opiate activity. Biochem Biophys Res Commun 97(4):1283–1290

    PubMed  CAS  Google Scholar 

  9. Kimura S, Lewis RV, Stern AS, Rossier J, Stein S, Udenfriend S (1980) Probable precursors of (Leu)enkephalin and (Met)enkephalin in adrenal medulla: peptides of 3–5 kilodaltons. Proc Natl Acad Sci USA 77(3):1681–1685

    PubMed  CAS  Google Scholar 

  10. Lewis RV, Stern AS, Kimura S, Stein S, Udenfriend S (1980) Enkephalin biosynthetic pathway: proteins of 8000 and 14, 000 daltons in bovine adrenal medulla. Proc Natl Acad Sci USA 77(8):5018–5020

    PubMed  CAS  Google Scholar 

  11. Lewis RV, Stern AS, Kimura S, Rossier J, Stein S, Udenfriend S (1980) An about 50, 000-dalton protein in adrenal medulla: a common precursor of (Met)- and (Leu)enkephalin. Science 208(4451):1459–1461

    PubMed  CAS  Google Scholar 

  12. Stern AS, Lewis RV, Kimura S, Rossier J, Stein S, Udenfriend S (1980) Opioid hexapeptides and heptapeptides in adrenal medulla and brain: possible implications on the biosynthesis of enkephalins. Arch Biochem Biophys 205:606–613

    PubMed  CAS  Google Scholar 

  13. Reinscheid RK, Nothacker H, Bourson A, Ardati A, Henningsen RA, Bunzow JR et al (1995) Orphanin FQ: a neuropeptide that activates an opioidlike G protein-coupled receptor. Science 270:792–794

    PubMed  CAS  Google Scholar 

  14. Meunier J, Mollereau C, Toll L, Suaudeau C, Moisand C, Alvinerie P et al (1995) Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor. Nature 377:532–534

    PubMed  CAS  Google Scholar 

  15. Goldstein A, Barrett RW, James IF, Lowney LI, Weitz CJ, Knipmeyer LL et al (1985) Morphine and other opiates from beef brain and adrenal. Proc Natl Acad Sci USA 82(15):5203–5207

    PubMed  CAS  Google Scholar 

  16. Weitz CJ, Lowney LI, Faull KF, Feistner G, Goldstein A (1988) 6-Acetylmorphine: a natural product present in mammalian brain. Proc Natl Acad Sci USA 85(14):5335–5338

    PubMed  CAS  Google Scholar 

  17. Weitz CJ, Lowney LI, Faull KF, Feistner G, Goldstein A (1986) Morphine and codeine from mammalian brain. Proc Natl Acad Sci USA 83(24):9784–9788

    PubMed  CAS  Google Scholar 

  18. Weitz CJ, Faull KF, Goldstein A (1987) Synthesis of the skeleton of the morphine molecule by mammalian liver. Nature 330(6149):674–677

    PubMed  CAS  Google Scholar 

  19. Zadina JE, Hackler L, Ge LJ, Kastin AJ (1997) A potent and selective endogenous agonist for the mu-opiate receptor. Nature 386(6624):499–502

    PubMed  CAS  Google Scholar 

  20. Brantl V, Gramsch C, Lottspeich F, Mertz R, Jaeger KH, Herz A (1986) Novel opioid peptides derived from hemoglobin: hemorphins. Eur J Pharmacol 125(2):309–310

    PubMed  CAS  Google Scholar 

  21. Karelin AA, Philippova MM, Karelina EV, Ivanov VT (1994) Isolation of endogenous hemorphin-related hemoglobin fragments from bovine brain. Biochem Biophys Res Commun 202(1):410–415

    PubMed  CAS  Google Scholar 

  22. Zhao Q, Garreau I, Sannier F, Piot JM (1997) Opioid peptides derived from hemoglobin: hemorphins. Biopolymers 43(2):75–98

    PubMed  CAS  Google Scholar 

  23. Rosen H, Douglass J, Herbert E (1984) Isolation and characterization of the rat proenkephalin gene. J Biol Chem 259:14309–14313

    PubMed  CAS  Google Scholar 

  24. Civelli O, Douglass J, Goldstein A, Herbert E (1985) Sequence and expression of the rat prodynorphin gene. Proc Natl Acad Sci USA 82:4291–4295

    PubMed  CAS  Google Scholar 

  25. Kakidani H, Furutani Y, Takahashi H, Noda M, Morimoto Y, Hirose T et al (1982) Cloning and sequence analysis of cDNA for porcine B-neo-endorphin/dynorphin precursor. Nature (Lund) 298(5871):245–249

    PubMed  CAS  Google Scholar 

  26. Nakanishi S, Inoue A, Kita T, Nakamura M, Chang AC, Cohen SN et al (1979) Nucleotide sequence of cloned cDNA for bovine corticotropin-beta-lipotropin precursor. Nature (Land) 278(5703):423–427

    PubMed  CAS  Google Scholar 

  27. Roberts JL, Herbert E (1977) Characterization of a common precursor to corticotropin and beta-lipotropin: identification of beta-lipotropin peptides and their arrangement relative to corticotropin in the precursor synthesized in a cell-free system. Proc Natl Acad Sci USA 74(12):5300–5304

    PubMed  CAS  Google Scholar 

  28. Roberts JL, Herbert E (1977) Characterization of a common precursor to corticotropin and beta-lipotropin: cell-free synthesis of the precursor and identification of corticotropin peptides in the molecule. Proc Natl Acad Sci USA 74(11):4826–4830

    PubMed  CAS  Google Scholar 

  29. Gubler U, Seeburg P, Hoffman BJ, Gage LP, Udenfriend S (1982) Molecular cloning establishes proenkephalin as precursor of enkephalin-containing peptides. Nature 295(5846):206–208

    PubMed  CAS  Google Scholar 

  30. Noda M, Teranishi Y, Takahashi H, Toyosato M, Notake M, Nakanishi S et al (1982) Isolation and structural organization of the human preproenkephalin gene. Nature 297(5865):431–434

    PubMed  CAS  Google Scholar 

  31. Noda M, Furutani Y, Takahashi H, Toyosato M, Hirose T, Inayama S et al (1982) Cloning and sequence analysis of cDNA for bovine adrenal preproenkephalin. Nature 295(5846):202–206

    PubMed  CAS  Google Scholar 

  32. Comb M, Rosen H, Seeburg P, Adelman J, Herbert E (1983) Primary structure of the human proenkephalin gene. DNA 2(3):213–229

    PubMed  CAS  Google Scholar 

  33. Comb M, Seeburg PH, Adelman J, Eiden L, Herbert E (1982) Primary structure of the human Met- and Leu-enkephalin precursor and its mRNA. Nature 295(5851):663–666

    PubMed  CAS  Google Scholar 

  34. Eipper BA, Mains RE (1980) Structure and biosynthesis of proACTH/endorphin and related peptides. Endocr Rev 1:1–27

    PubMed  CAS  Google Scholar 

  35. Hurlbut DE, Evans CJ, Barchas JD, Leslie FM (1987) Pharmacological properties of a proenkephalin A-derived opioid peptide: BAM 18. Eur J Pharmacol 138(3):359–366

    PubMed  CAS  Google Scholar 

  36. Mansour A, Hoversten MT, Taylor LP, Watson SJ, Akil H (1995) The cloned mu, delta and kappa receptors and their endogenous ligands: evidence for two opioid peptide recognition cores. Brain Res 700(1–2):89–98

    PubMed  CAS  Google Scholar 

  37. Blobel G (2000) Protein targeting. Biosci Rep 20(5):303–344

    PubMed  CAS  Google Scholar 

  38. Bennett HPJ (1991) Glycosylation, phosphorylation, and sulfation of peptide hormones and their precursors. In: Fricker LD (ed) Peptide biosynthesis and processing. CRC, Boca Raton, pp 111–140

    Google Scholar 

  39. Orci L, Ravazzola M, Storch MJ, Anderson RGW, Vassalli JD, Perrelet A (1987) Proteolytic maturation of insulin is a post-Golgi event which occurs in acidifying clathrin-coated vesicles. Cell 49:865–868

    PubMed  CAS  Google Scholar 

  40. Steiner DF (1998) The proprotein convertases. Curr Opin Chem Biol 2(1):31–39

    PubMed  CAS  Google Scholar 

  41. Zhou A, Webb G, Zhu X, Steiner DF (1999) Proteolytic processing in the secretory pathway. J Biol Chem 274:20745–20748

    PubMed  CAS  Google Scholar 

  42. Seidah NG, Chretien M (2004) Proprotein convertase I. In: Barrett AJ, Rawlings ND, Woessner JF (eds) Handbook of proteolytic enzymes. Academic, San Diego, pp 1861–1864

    Google Scholar 

  43. Seidah NG, Chretien M (2004) Proprotein convertase 2. In: Barrett AJ, Rawlings ND, Woessner JF (eds) Handbook of proteolytic enzymes. Academic, San Diego, pp 1865–1868

    Google Scholar 

  44. Scamuffa N, Calvo F, Chretien M, Seidah NG, Khatib AM (2006) Proprotein convertases: lessons from knockouts. FASEB J 20(12):1954–1963

    PubMed  CAS  Google Scholar 

  45. Fricker LD (1988) Carboxypeptidase E. Annu Rev Physiol 50:309–321

    PubMed  CAS  Google Scholar 

  46. Fricker LD, Evans CJ, Esch FS, Herbert E (1986) Cloning and sequence analysis of cDNA for bovine carboxypeptidase E. Nature 323:461–464

    PubMed  CAS  Google Scholar 

  47. Fricker LD, Snyder SH (1982) Enkephalin convertase: purification and characterization of a specific enkephalin-synthesizing carboxypeptidase localized to adrenal chromaffin granules. Proc Natl Acad Sci USA 79:3886–3890

    PubMed  CAS  Google Scholar 

  48. Song L, Fricker LD (1995) Purification and characterization of carboxypeptidase D, a novel carboxypeptidase E-like enzyme, from bovine pituitary. J Biol Chem 270:25007–25013

    PubMed  CAS  Google Scholar 

  49. Varlamov O, Eng FJ, Novikova EG, Fricker LD (1999) Localization of metallocarboxypeptidase D in AtT-20 cells: potential role in prohormone processing. J Biol Chem 274:14759–14767

    PubMed  CAS  Google Scholar 

  50. Eipper BA, Mains RE (1988) Peptide alpha-amidation. Annu Rev Physiol 50:333–344

    PubMed  CAS  Google Scholar 

  51. Prigge ST, Mains RE, Eipper BA, Amzel LM (2000) New insights into copper monooxygenases and peptide amidation: structure, mechanism and function. Cell Mol Life Sci 57(8–9):1236–1259

    PubMed  CAS  Google Scholar 

  52. Weber E, Esch FS, Bohlen P, Paterson S, Corbett AD, McKnight AT et al (1983) Metorphamide: isolation, structure, and biologic activity of an amidated opioid octapeptide from bovine brain. Proc Natl Acad Sci USA 80(23):7362–7366

    PubMed  CAS  Google Scholar 

  53. Seizinger BR, Liebisch DC, Gramsch C, Herz A, Weber E, Evans CJ et al (1985) Isolation and structure of a novel C-terminally amidated opioid peptide, amidorphin, from bovine adrenal medulla. Nature 313(5997):57–59

    PubMed  CAS  Google Scholar 

  54. Liebisch DC, Weber E, Kosicka B, Gramsch C, Herz A, Seizinger BR (1986) Isolation and structure of a C-terminally amidated nonopioid peptide, amidorphin-(8-26) from bovine striatum: a major product of proenkephalin in brain but not in adrenal medulla. Proc Natl Acad Sci USA 83:1936–1940

    PubMed  CAS  Google Scholar 

  55. Bradbury AF, Smyth DG (1991) Modification of the N- and C-termini of bioactive peptides: amidation and acetylation. In: Fricker LD (ed) Peptide biosynthesis and processing. CRC, Boca Raton, pp 231–250

    Google Scholar 

  56. Dennis M, Seidah NG, Chretien M (1983) Regional heterogeneity in the processing of pro-opiomelanocortin in rat brain. Life Sci 33(suppl 1):49–52

    PubMed  CAS  Google Scholar 

  57. Smyth DG, Massey DE, Zakarian S, Finnie MD (1979) Endorphins are stored in biologically active and inactive forms: isolation of alpha-N-acetyl peptides. Nature 279(5710):252–254

    PubMed  CAS  Google Scholar 

  58. Chard T (1987) An introduction to radioimmunoassay and related techniques, 3rd edn. Elsevier, Amsterdam

    Google Scholar 

  59. Baggerman G, Verleyen P, Clynen E, Huybrechts J, De Loof A, Schoofs L (2004) Peptidomics. J Chromatogr B Analyt Technol Biomed Life Sci 803(1):3–16

    PubMed  CAS  Google Scholar 

  60. Clynen E, De Loof A, Schoofs L (2003) The use of peptidomics in endocrine research. Gen Comp Endocrinol 132(1):1–9

    PubMed  CAS  Google Scholar 

  61. Fricker LD, Lim J, Pan H, Che F-Y (2006) Peptidomics: identification and quantification of endogenous peptides in neuroendocrine tissues. Mass Spectrom Rev 25:327–344

    PubMed  CAS  Google Scholar 

  62. Fricker LD (2007) Neuropeptidomics to study peptide processing in animal models of obesity. Endocrinology 148(9):4185–4190

    PubMed  CAS  Google Scholar 

  63. Svensson M, Skold K, Svenningsson P, Andren PE (2003) Peptidomics-based discovery of novel neuropeptides. J Proteome Res 2(2):213–219

    PubMed  CAS  Google Scholar 

  64. Svensson M, Skold K, Nilsson A, Falth M, Svenningsson P, Andren PE (2007) Neuropeptidomics: expanding proteomics downwards. Biochem Soc Trans 35(pt 3):588–593

    PubMed  CAS  Google Scholar 

  65. Hummon AB, Amare A, Sweedler JV (2006) Discovering new invertebrate neuropeptides using mass spectrometry. Mass Spectrom Rev 25:77–98

    PubMed  CAS  Google Scholar 

  66. Che F-Y, Fricker LD (2005) Quantitative peptidomics of mouse pituitary: comparison of different stable isotopic tags. J Mass Spectrom 40:238–249

    PubMed  CAS  Google Scholar 

  67. Che F-Y, Lim J, Biswas R, Pan H, Fricker LD (2005) Quantitative neuropeptidomics of microwave-irradiated mouse brain and pituitary. Mol Cell Proteomics 4:1391–1405

    PubMed  CAS  Google Scholar 

  68. Zhang X, Che FY, Berezniuk I, Sonmez K, Toll L, Fricker LD (2008) Peptidomics of Cpe fat/fat mouse brain regions: implications for neuropeptide processing. J Neurochem 107(6):1596–1613

    PubMed  CAS  Google Scholar 

  69. D’Souza NB, Lindberg I (1988) Evidence for the phosphorylation of a proenkephalin-derived peptide, peptide B. J Biol Chem 263(5):2548–2552

    PubMed  Google Scholar 

  70. Lindberg I, Shaw E, Finley J, Leone D, Deininger P (1991) Posttranslational modifications of rat proenkephalin overexpressed in Chinese hamster ovary cells. Endocrinology 128(4):1849–1856

    PubMed  CAS  Google Scholar 

  71. Watkinson A, Dockray GJ (1989) Identification and characterization of N-glycosylated and phosphorylated variants of proenkephalin A-derived peptides in bovine adrenal medulla, spinal cord and ileum. Regul Pept 26(3):313–322

    PubMed  CAS  Google Scholar 

  72. Liston DR, Vanderhaeghen JJ, Rossier J (1983) Presence in brain of synenkephalin, a proenkephalin-immunoreactive protein which does not contain enkephalin. Nature 302(5903):62–65

    PubMed  CAS  Google Scholar 

  73. de Wied D, Van Ree JM (1987) Non-opiate effects of neuropeptides derived from beta-endorphin. Pol J Pharmacol Pharm 39(5):623–632

    PubMed  Google Scholar 

  74. Deakin JF, Dostrovsky JO, Smyth DG (1980) Influence of N-terminal acetylation and C-terminal proteolysis on the analgesic activity of beta-endorphin. Biochem J 189(3):501–506

    PubMed  CAS  Google Scholar 

  75. Goldstein A, Ghazarossian VE (1980) Immunoreactive dynorphin in pituitary and brain. Proc Natl Acad Sci USA 77(10):6207–6210

    PubMed  CAS  Google Scholar 

  76. Kangawa H, Minamino N, Chino N, Sakakibara S, Matsuo H (1981) The complete amino acid sequence of -neo-endorphin. Biochem Biophys Res Commun 99:871–878

    PubMed  CAS  Google Scholar 

  77. Reed B, Bidlack JM, Chait BT, Kreek MJ (2008) Extracellular biotransformation of beta-endorphin in rat striatum and cerebrospinal fluid. J Neuroendocrinol 20(5):606–616

    PubMed  CAS  Google Scholar 

  78. Hammonds RG Jr, Nicolas P, Li CH (1984) Beta-endorphin-(1-27) is an antagonist of beta-endorphin analgesia. Proc Natl Acad Sci USA 81(5):1389–1390

    PubMed  CAS  Google Scholar 

  79. Nicolas P, Li CH (1985) Beta-endorphin-(1–27) is a naturally occurring antagonist to etorphine-induced analgesia. Proc Natl Acad Sci USA 82(10):3178–3181

    PubMed  CAS  Google Scholar 

  80. Okuda-Ashitaka E, Minami T, Tachibana S, Yoshihara Y, Nishiuchi Y, Kimura T et al (1998) Nocistatin, a peptide that blocks nociceptin action in pain transmission. Nature 392(6673):286–289

    PubMed  CAS  Google Scholar 

  81. Mathis JP, Rossi GC, Pellegrino MJ, Jimenez C, Pasternak GW, Allen RG (2001) Carboxyl terminal peptides derived from prepro-orphanin FQ/nociceptin (ppOFQ/N) are produced in the hypothalamus and possess analgesic bioactivities. Brain Res 895(1–2):89–94

    PubMed  CAS  Google Scholar 

  82. Rossi GC, Mathis JP, Pasternak GW (1998) Analgesic activity of orphanin FQ2, murine prepro-orphanin FQ141-157 in mice. Neuroreport 9(6):1165–1168

    PubMed  CAS  Google Scholar 

  83. Rossi GC, Leventhal L, Bolan E, Pasternak GW (1997) Pharmacological characterization of orphanin FQ/nociceptin and its fragments. J Pharmacol Exp Ther 282(2):858–865

    PubMed  CAS  Google Scholar 

  84. Pan YX, Xu J, Pasternak GW (1996) Cloning and expression of a cDNA encoding a mouse brain orphanin FQ/nociceptin precursor. Biochem J 315(pt 1):11–13

    PubMed  CAS  Google Scholar 

  85. Rossi GC, Pellegrino M, Shane R, Abbadie CA, Dustman J, Jimenez C et al (2002) Characterization of rat prepro-orphanin FQ/nociceptin(154-181): nociceptive processing in supraspinal sites. J Pharmacol Exp Ther 300(1):257–264

    PubMed  CAS  Google Scholar 

  86. Seidah NG, Prat A (2002) Precursor convertases in the secretory pathway, cytosol and extracellular milieu. Essays Biochem 38:79–94

    PubMed  CAS  Google Scholar 

  87. Nakayama K (1997) Furin: a mammalian subtilisin/Kex2p-like endoprotease involved in processing of a wide variety of precursor proteins. Biochem J 327:625–635

    PubMed  CAS  Google Scholar 

  88. Thomas G (2002) Furin at the cutting edge: from protein traffic to embryogenesis and disease. Nat Rev Mol Cell Biol 3:753–766

    PubMed  CAS  Google Scholar 

  89. Che F-Y, Yan L, Li H, Mzhavia N, Devi L, Fricker LD (2001) Identification of peptides from brain and pituitary of Cpe fat /Cpe fat mice. Proc Natl Acad Sci USA 98:9971–9976

    PubMed  CAS  Google Scholar 

  90. Lembo PMC, Grazzini E, Groblewski T, O’Donnell D, Roy M, Zhang J et al (2002) Proenkephalin A gene products activate a new family of sensory neuron-specific GPCRs. Nat Neurosci 5:201–209

    PubMed  CAS  Google Scholar 

  91. Pohl T, Zimmer M, Mugele K, Spiess J (1991) Primary structure and functional expression of a glutaminyl cyclase. Proc Natl Acad Sci USA 88(22):10059–10063

    PubMed  CAS  Google Scholar 

  92. Hook VY (2006) Unique neuronal functions of cathepsin L and cathepsin B in secretory vesicles: biosynthesis of peptides in neurotransmission and neurodegenerative disease. Biol Chem 387(10–11):1429–1439

    PubMed  CAS  Google Scholar 

  93. Ahn K (1998) Endothelin-converting enzyme 2. In: Barrett AJ, Rawlings ND, Woessner JF (eds) Handbook of proteolytic enzymes. Academic, San Diego, pp 1090–1091

    Google Scholar 

  94. Emoto N, Yanagisawa M (1995) Endothelin-converting enzyme-2 is a membrane-bound, phosphoramidon-sensitive metalloprotease with acidic pH optimum. J Biol Chem 270:15262–15268

    PubMed  CAS  Google Scholar 

  95. Mzhavia N, Pan H, Che F-Y, Fricker LD, Devi LA (2003) Characterization of endothelin-converting enzyme-2. Implication for a role in the nonclassical processing of regulatory peptides. J Biol Chem 278(17):14704–14711

    PubMed  CAS  Google Scholar 

  96. Fricker LD (1985) Neuropeptide biosynthesis: focus on the carboxypeptidase processing enzyme. Trends Neurosci 8:210–214

    CAS  Google Scholar 

  97. Arolas JL, Vendrell J, Aviles FX, Fricker LD (2007) Metallocarboxypeptidases: emerging drug targets in biomedicine. Curr Pharm Des 13(4):349–366

    PubMed  CAS  Google Scholar 

  98. Fricker LD (2004) Metallocarboxypeptidase D. In: Barrett AJ, Rawlings ND, Woessner JF (eds) Handbook of proteolytic enzymes. Academic, San Diego, pp 848–851

    Google Scholar 

  99. Sidyelyeva G, Baker NE, Fricker LD (2006) Characterization of the molecular basis of the Drosophila mutations in carboxypeptidase D. Effect on enzyme activity and expression. J Biol Chem 281(19):13844–13852

    PubMed  CAS  Google Scholar 

  100. Rioli V, Kato A, Portaro FC, Cury GK, te Kaat K, Vincent B et al (1998) Neuropeptide specificity and inhibition of recombinant isoforms of the endopeptidase 3.4.24.16 family: comparison with the related recombinant endopeptidase 3.4.24.15. Biochem Biophys Res Commun 250(1):5–11

    PubMed  CAS  Google Scholar 

  101. Massarelli EE, Casatti CA, Kato A, Camargo AC, Bauer JA, Glucksman MJ et al (1999) Differential subcellular distribution of neurolysin (EC 3.4.24.16) and thimet oligopeptidase (EC 3.4.24.15) in the rat brain. Brain Res 851(1–2):261–265

    PubMed  CAS  Google Scholar 

  102. Ferro ES, Tullai JW, Glucksman MJ, Roberts JL (1999) Secretion of metalloendopeptidase 24.15 (EC 3.4.24.15). DNA Cell Biol 18(10):781–789

    PubMed  CAS  Google Scholar 

  103. Ferro ES, Carreno FR, Goni C, Garrido PA, Guimaraes AO, Castro LM et al (2004) The intracellular distribution and secretion of endopeptidases 24.15 (EC 3.4.24.15) and 24.16 (EC 3.4.24.16). Protein Pept Lett 11(5):415–421

    PubMed  CAS  Google Scholar 

  104. Malfroy B, Swerts JP, Guyon A, Roques BP, Schwartz JC (1978) High-affinity enkephalin-degrading peptidase in brain is increased after morphine. Nature 276(5687):523–526

    PubMed  CAS  Google Scholar 

  105. Gorenstein C, Snyder SH (1980) Enkephalinases. Proc R Soc Lond B Biol Sci 210(1178):123–132

    PubMed  CAS  Google Scholar 

  106. Schwartz JC, de la Baume S, Malfroy B, Patey G, Perdrisot R, Swerts JP et al (1980) “Enkephalinase”: a newly characterised dipeptidyl carboxypeptidase: properties and possible role in enkephalinergic transmission. Int J Neurol 14(2–4):195–204

    PubMed  CAS  Google Scholar 

  107. Sullivan S, Akil H, Blacker D, Barchas JD (1980) Enkephalinase: selective inhibitors and partial characterization. Peptides 1(1):31–35

    PubMed  CAS  Google Scholar 

  108. Roques BP, Fournie-Zaluski MC, Soroca E, Lecomte JM, Malfroy B, Llorens C et al (1980) The enkephalinase inhibitor thiorphan shows antinociceptive activity in mice. Nature 288(5788):286–288

    PubMed  CAS  Google Scholar 

  109. Wong-Leung YL, Kenny AJ (1968) Some properties of a microsomal peptidase in rat kidney. Biochem J 110(2):5P

    Google Scholar 

  110. Turner AJ (1998) Membrane alanyl aminopeptidases. In: Barrett AJ, Rawlings ND, Woessner JF (eds) Handbook of proteolytic enzymes. Academic, San Diego, pp 996–1000

    Google Scholar 

  111. Montiel JL, Cornille F, Roques BP, Noble F (1997) Nociceptin/orphanin FQ metabolism: role of aminopeptidase and endopeptidase 24.15. J Neurochem 68(1):354–361

    PubMed  CAS  Google Scholar 

  112. Noble F, Roques BP (2007) Protection of endogenous enkephalin catabolism as natural approach to novel analgesic and antidepressant drugs. Expert Opin Ther Targets 11(2):145–159

    PubMed  CAS  Google Scholar 

  113. Corvol P, Williams TA (1998) Peptidyl-dipeptidase A/angiotensin I-converting enzyme. In: Barrett AJ, Rawlings ND, Woessner JF (eds) Handbook of proteolytic enzymes. Academic, San Diego, pp 1066–1076

    Google Scholar 

  114. Norman JA, Autry WL, Barbaz BS (1985) Angiotensin-converting enzyme inhibitors potentiate the analgesic activity of (Met)-enkephalin-Arg6-Phe7 by inhibiting its degradation in mouse brain. Mol Pharmacol 28(6):521–526

    PubMed  CAS  Google Scholar 

  115. Turner AJ, Hooper NM (2002) The angiotensin-converting enzyme gene family: genomics and pharmacology. Trends Pharmacol Sci 23(4):177–183

    PubMed  CAS  Google Scholar 

  116. Wei S, Segura S, Vendrell J, Aviles FX, Lanoue E, Day R et al (2002) Identification and characterization of three members of the human metallocarboxypeptidase gene family. J Biol Chem 277:14954–14964

    PubMed  CAS  Google Scholar 

  117. Fontenele-Neto JD, Kalinina E, Feng Y, Fricker LD (2005) Identification and distribution of mouse carboxypeptidase A-6. Mol Brain Res 137:132–142

    PubMed  CAS  Google Scholar 

  118. Lyons PJ, Callaway MB, Fricker LD (2008) Characterization of carboxypeptidase A6, an extracellular-matrix peptidase. J Biol Chem 283(11):7054–7063

    PubMed  CAS  Google Scholar 

  119. Patey G, Cupo A, Chaminade M, Morgat JL, Rossier J (1983) Release of the heptapeptide Met-enkephalin-Arg6-Phe7 and of the octapeptide Met-enkephalin-Arg6-Gly7-Leu8 from rat striatum in vitro and their rapid inactivation. Life Sci 33(suppl 1):117–120

    PubMed  CAS  Google Scholar 

  120. Khachaturian H, Schafer MKH, Lewis ME (1993) Anatomy and function of the endogenous opioid system. In: Herz A, Akil H, Simon EJ (eds) Opioids I. Springer, Berlin, pp 471–497

    Google Scholar 

  121. Akil H, Watson SJ, Young E, Lewis ME, Khachaturian H, Walker JM (1984) Endogenous opioids: biology and function. Annu Rev Neurosci 7:223–255

    PubMed  CAS  Google Scholar 

  122. Harlan RE, Shivers BD, Romano GJ, Howells RD, Pfaff DW (1987) Localization of preproenkephalin mRNA in the rat brain and spinal cord by in situ hybridization. J Comp Neurol 258(2):159–184

    PubMed  CAS  Google Scholar 

  123. Spruce BA, Curtis R, Wilkin GP, Glover DM (1990) A neuropeptide precursor in cerebellum: proenkephalin exists in subpopulations of both neurons and astrocytes. EMBO J 9:1787–1795

    PubMed  CAS  Google Scholar 

  124. Shinoda H, Marini AM, Cosi C, Schwartz JP (1989) Brain region and gene specificity of neuropeptide gene expression in cultured astrocytes. Science 245:415–417

    PubMed  CAS  Google Scholar 

  125. Klein RS, Fricker LD (1992) Heterogeneous expression of carboxypeptidase E and proenkephalin mRNAs by cultured astrocytes. Brain Res 569:300–310

    PubMed  CAS  Google Scholar 

  126. Polakiewicz RD, Rosen H (1990) Regulated expression of proenkephalin A during ontogenic development of mesenchymal derivative tissues. Mol Cell Biol 10(2):736–742

    PubMed  CAS  Google Scholar 

  127. Bicknell AB (2008) The tissue-specific processing of pro-opiomelanocortin. J Neuroendocrinol 20(6):692–699

    PubMed  CAS  Google Scholar 

  128. Smith AI, Funder JW (1988) Proopiomelanocortin processing in the pituitary, central nervous system, and peripheral tissues. Endocr Rev 9(1):159–179

    PubMed  CAS  Google Scholar 

  129. Wikberg JE, Muceniece R, Mandrika I, Prusis P, Lindblom J, Post C et al (2000) New aspects on the melanocortins and their receptors. Pharmacol Res 42(5):393–420

    PubMed  CAS  Google Scholar 

  130. Civelli O (2008) The orphanin FQ/nociceptin (OFQ/N) system. Results Probl Cell Differ 46:1–25

    PubMed  CAS  Google Scholar 

  131. 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(4):503–547

    PubMed  CAS  Google Scholar 

  132. Houtani T, Nishi M, Takeshima H, Nukada T, Sugimoto T (1996) Structure and regional distribution of nociceptin/orphanin FQ precursor. Biochem Biophys Res Commun 219(3):714–719

    PubMed  CAS  Google Scholar 

  133. Ikeda K, Watanabe M, Ichikawa T, Kobayashi T, Yano R, Kumanishi T (1998) Distribution of prepro-nociceptin/orphanin FQ mRNA and its receptor mRNA in developing and adult mouse central nervous systems. J Comp Neurol 399(1):139–151

    PubMed  CAS  Google Scholar 

  134. Konig M, Zimmer AM, Steiner H, Holmes PV, Crawley JN, Brownstein MJ et al (1996) Pain responses, anxiety and aggression in mice deficient in pre-proenkephalin. Nature 383(6600):535–538

    PubMed  CAS  Google Scholar 

  135. Ragnauth A, Schuller A, Morgan M, Chan J, Ogawa S, Pintar J et al (2001) Female preproenkephalin-knockout mice display altered emotional responses. Proc Natl Acad Sci USA 98(4):1958–1963

    PubMed  CAS  Google Scholar 

  136. Bilkei-Gorzo A, Racz I, Michel K, Zimmer A, Klingmuller D, Zimmer A (2004) Behavioral phenotype of pre-proenkephalin-deficient mice on diverse congenic backgrounds. Psychopharmacology 176(3–4):343–352

    PubMed  CAS  Google Scholar 

  137. Bilkei-Gorzo A, Michel K, Noble F, Roques BP, Zimmer A (2007) Preproenkephalin knockout mice show no depression-related phenotype. Neuropsychopharmacology 32(11):2330–2337

    PubMed  CAS  Google Scholar 

  138. Berrendero F, Mendizabal V, Robledo P, Galeote L, Bilkei-Gorzo A, Zimmer A et al (2005) Nicotine-induced antinociception, rewarding effects, and physical dependence are decreased in mice lacking the preproenkephalin gene. J Neurosci 25(5):1103–1112

    PubMed  CAS  Google Scholar 

  139. Wang Z, Gardell LR, Ossipov MH, Vanderah TW, Brennan MB, Hochgeschwender U et al (2001) Pronociceptive actions of dynorphin maintain chronic neuropathic pain. J Neurosci 21(5):1779–1786

    PubMed  CAS  Google Scholar 

  140. Zimmer A, Valjent E, Konig M, Zimmer AM, Robledo P, Hahn H et al (2001) Absence of delta-9-tetrahydrocannabinol dysphoric effects in dynorphin-deficient mice. J Neurosci 21(23):9499–9505

    PubMed  CAS  Google Scholar 

  141. Sainsbury A, Lin S, McNamara K, Slack K, Enriquez R, Lee NJ et al (2007) Dynorphin knockout reduces fat mass and increases weight loss during fasting in mice. Mol Endocrinol 21(7):1722–1735

    PubMed  CAS  Google Scholar 

  142. Galeote L, Berrendero F, Andreea BS, Zimmer A, Maldonado R (2008) Prodynorphin gene disruption increases the sensitivity to nicotine self-administration in mice. Int J Neuropsychopharmacol 12(5):1–11

    Google Scholar 

  143. Yaswen L, Diehl N, Brennan MB, Hochgeschwender U (1999) Obesity in the mouse model of pro-piomelanocortin deficiency responds to peripheral melanocortin. Nat Med 5(9):1066–1070

    PubMed  CAS  Google Scholar 

  144. Rubinstein M, Mogil JS, Japon M, Chan EC, Allen RG, Low MJ (1996) Absence of opioid stress-induced analgesia in mice lacking beta-endorphin by site-directed mutagenesis. Proc Natl Acad Sci USA 93(9):3995–4000

    PubMed  CAS  Google Scholar 

  145. Grisel JE, Mogil JS, Grahame NJ, Rubinstein M, Belknap JK, Crabbe JC et al (1999) Ethanol oral self-administration is increased in mutant mice with decreased beta-endorphin expression. Brain Res 835(1):62–67

    PubMed  CAS  Google Scholar 

  146. Appleyard SM, Hayward M, Young JI, Butler AA, Cone RD, Rubinstein M et al (2003) A role for the endogenous opioid beta-endorphin in energy homeostasis. Endocrinology 144(5):1753–1760

    PubMed  CAS  Google Scholar 

  147. Koster A, Montkowski A, Schulz S, Stube EM, Knaudt K, Jenck F et al (1999) Targeted disruption of the orphanin FQ/nociceptin gene increases stress susceptibility and impairs stress adaptation in mice. Proc Natl Acad Sci USA 96(18):10444–10449

    PubMed  CAS  Google Scholar 

  148. Reinscheid RK, Civelli O (2002) The orphanin FQ/nociceptin knockout mouse: a behavioral model for stress responses. Neuropeptides 36(2–3):72–76

    PubMed  CAS  Google Scholar 

  149. Depner UB, Reinscheid RK, Takeshima H, Brune K, Zeilhofer HU (2003) Normal sensitivity to acute pain, but increased inflammatory hyperalgesia in mice lacking the nociceptin precursor polypeptide or the nociceptin receptor. Eur J Neurosci 17(11):2381–2387

    PubMed  Google Scholar 

  150. 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

    PubMed  CAS  Google Scholar 

  151. Binaschi A, Zucchini S, Bregola G, Rodi D, Mazzuferi M, Reinscheid RK et al (2003) Delayed epileptogenesis in nociceptin/orphanin FQ-deficient mice. Neuroreport 14(6):825–827

    PubMed  CAS  Google Scholar 

  152. Berman Y, Mzhavia N, Polonskaia A, Furuta M, Steiner DF, Pintar JE et al (2000) Defective prodynorphin processing in mice lacking prohormone convertase PC2. J Neurochem 75(4):1763–1770

    PubMed  CAS  Google Scholar 

  153. Allen RG, Peng B, Pellegrino MJ, Miller ED, Grandy DK, Lundblad JR et al (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(16):5864–5870

    PubMed  CAS  Google Scholar 

  154. Miller R, Aaron W, Toneff T, Vishnuvardhan D, Beinfeld MC, Hook VY (2003) Obliteration of alpha-melanocyte-stimulating hormone derived from POMC in pituitary and brains of PC2-deficient mice. J Neurochem 86(3):556–563

    PubMed  CAS  Google Scholar 

  155. Pan H, Che FY, Peng B, Steiner DF, Pintar JE, Fricker LD (2006) The role of prohormone convertase-2 in hypothalamic neuropeptide processing: a quantitative neuropeptidomic study. J Neurochem 98(6):1763–1777

    PubMed  CAS  Google Scholar 

  156. Johanning K, Juliano MA, Juliano L, Lazure C, Lamango NS, Steiner DF et al (1998) Specificity of prohormone convertase 2 on proenkephalin and proenkephalin-related substrates. J Biol Chem 273(35):22672–22680

    PubMed  CAS  Google Scholar 

  157. Zhang X, Pan H, Peng B, Steiner DF, Pintar JE, Fricker LD (2010) Neuropeptidomic analysis establishes a major role for prohormone convertase-2 in neuropeptide biosynthesis. J Neurochem 112(5):1168–1179

    PubMed  CAS  Google Scholar 

  158. Cain BM, Connolly K, Blum AC, Vishnuvardhan D, Marchand JE, Zhu X et al (2004) Genetic inactivation of prohormone convertase (PC1) causes a reduction in cholecystokinin (CCK) levels in the hippocampus, amygdala, pons and medulla in mouse brain that correlates with the degree of colocalization of PC1 and CCK mRNA in these structures in rat brain. J Neurochem 89(2):307–313

    PubMed  CAS  Google Scholar 

  159. Dey A, Norrbom C, Zhu X, Stein J, Zhang C, Ueda K et al (2004) Furin and prohormone convertase 1/3 are major convertases in the processing of mouse pro-growth hormone-releasing hormone. Endocrinology 145(4):1961–1971

    PubMed  CAS  Google Scholar 

  160. Hardiman A, Friedman TC, Grunwald WC Jr, Furuta M, Zhu Z, Steiner DF et al (2005) Endocrinomic profile of neurointermediate lobe pituitary prohormone processing in PC1/3- and PC2-Null mice using SELDI-TOF mass spectrometry. J Mol Endocrinol 34(3):739–751

    PubMed  CAS  Google Scholar 

  161. Marzban L, Trigo-Gonzalez G, Zhu X, Rhodes CJ, Halban PA, Steiner DF et al (2004) Role of beta-cell prohormone convertase (PC)1/3 in processing of pro-islet amyloid polypeptide. Diabetes 53(1):141–148

    PubMed  CAS  Google Scholar 

  162. Pan H, Nanno D, Che FY, Zhu X, Salton SR, Steiner DF et al (2005) Neuropeptide processing profile in mice lacking prohormone convertase-1. Biochemistry 44(12):4939–4948

    PubMed  CAS  Google Scholar 

  163. Ugleholdt R, Zhu X, Deacon CF, Orskov C, Steiner DF, Holst JJ (2004) Impaired intestinal proglucagon processing in mice lacking prohormone convertase 1. Endocrinology 145(3):1349–1355

    PubMed  CAS  Google Scholar 

  164. Zhu X, Orci L, Carroll R, Norrbom C, Ravazzola M, Steiner DF (2002) Severe block in processing of proinsulin to insulin accompanied by elevation of des-64, 65 proinsulin intermediates in islets of mice lacking prohormone convertase 1/3. Proc Natl Acad Sci USA 99:10299–10304

    PubMed  CAS  Google Scholar 

  165. Breslin MB, Lindberg I, Benjannet S, Mathis JP, Lazure C, Seidah NG (1993) Differential processing of proenkephalin by prohormone convertases 1(3) and 2 and furin. J Biol Chem 268(36):27084–27093

    PubMed  CAS  Google Scholar 

  166. Dupuy A, Lindberg I, Zhou Y, Akil H, Lazure C, Chretien M et al (1994) Processing of prodynorphin by the prohormone convertase PC1 results in high molecular weight intermediate forms: cleavage at a single arginine residue. FEBS Lett 337(1):60–65

    PubMed  CAS  Google Scholar 

  167. Lim J, Berezniuk I, Che F-Y, Parikh R, Biswas R, Pan H et al (2006) Altered neuropeptide processing in prefrontal cortex of Cpe fat/fat mice: implications for neuropeptide discovery. J Neurochem 96:1169–1181

    PubMed  CAS  Google Scholar 

  168. Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A, Bernard A et al (2007) Genome-wide atlas of gene expression in the adult mouse brain. Nature 445(7124):168–176

    PubMed  CAS  Google Scholar 

  169. Tuteja R (2005) Type I signal peptidase: an overview. Arch Biochem Biophys 441(2):107–111

    PubMed  CAS  Google Scholar 

  170. Fricker LD (2004) Carboxypeptidase E. In: Barrett AJ, Rawlings ND, Woessner JF (eds) Handbook of proteolytic enzymes. Academic, San Diego, pp 840–844

    Google Scholar 

  171. Richter F, Meurers BH, Zhu C, Medvedeva VP, Chesselet M-F. Neurons express hemoglobin alpha and beta chains in rat and human brains. J Comp Neurol 2009; 51:538–547

    Google Scholar 

  172. Biagioli M, Pinto M, Cesselli D, Zaninello M, Lazarevic D, Roncaglia P et al. Unexpected expression of alpha- and beta-globin in mesencephalic dopaminergic neurons and glial cells. Proc Natl Acad Sci USA 2009; 106(36):15454–15459.

    Google Scholar 

  173. Gelman JS, Sironi J, Castro LM, Ferro ES, Fricker LD. Hemopressins and other hemoglobin-derived peptides in mouse brain: Comparison between brain, blood, and heart peptidome and regulation in Cpefat/fat mice. J Neurochem 2010; 113:871–880

    Google Scholar 

  174. Gomes I, et al. Hemoglobin-derived peptides as novel type of bioactive signaling molecules. AAPS J 2010; in press

    Google Scholar 

  175. Gelman JS, Fricker LD. Hemopressin and Other Bioactive Peptides from Cytosolic Proteins: Are These Non-Classical Neuropeptides? AAPS J 2010; 12:279–289

    Google Scholar 

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  1. Departments of Molecular Pharmacology and Neuroscience, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, 10461, USA

    Lloyd D. Fricker

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Berezniuk, I., Fricker, L.D. (2011). Endogenous Opioids. In: Pasternak, G. (eds) The Opiate Receptors. The Receptors. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-993-2_5

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