Opioids pp 393-421 | Cite as

Proopiomelanocortin Biosynthesis, Processing, and Secretion: Functional Implications

  • E. Young
  • D. Bronstein
  • H. Akil
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 104 / 1)


Peptide hormones and transmitters are synthesized as large molecular weight precursors, prohormones (Herbert and Uhler 1982; Steiner and Oyer 1967), which are processed intracellularly in neurotransmitter- or hormone-secreting cells to yield smaller active fragments. Within the structure of the hormone are processing “signals” that direct cellular enzymes to cut out or “cleav” the peptide hormones. Although the amino acid sequence of the prohormone determines the placement of processing signals, the particular signals recognized and consequently cleaved vary between types of cells. This cell-specific processing gives rise to different end products from the identical prohormone in different cells. It also results in biologically active sequences buried within the sequence of other end products in some tissues. In addition, different tissues can chemically modify the peptides posttranslationally, often producing substantial changes in the biological activity of the peptide products. All of the above variations can be combined to produce very different mixtures of biologically active products from different cell types. Finally, chronic activation of any cell may alter the mixture of secreted peptides, endowing these neurosecretory cells with a flexibility to meet the demands for one peptide hormone without shifting the homeostatic balance for its co-secreted peptide partner.


Opioid Peptide Anterior Lobe Nucleus Tractus Solitarius Opiate Receptor Intermediate Lobe 
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  1. Akil H, Mayer DJ, Liebeskind JC (1976a) Antagonism of stimulation-produced analgesia by naloxone, a narcotic antagonist. Science 191: 961PubMedGoogle Scholar
  2. Akil H, Madden J, Patrick RL, Barchas JD (1976b) Stress-induced increase in endogenous opiate peptides: concurrent analgesia and its partial reversal by naloxone. In: Kosterlitz HW (ed) Opiates and endogenous opioid peptides. Elsevier, Amsterdam, p 63Google Scholar
  3. Akil H, Watson SJ, Berger PA, Barchas JD (1978a) Endorphins, beta-lipotropin and ACTH: biochemical, pharmacological and anatomical studies. In: Trabucchi M, Costa E (eds) The endorphins: advances in biochemistry and psychopharmacology. Raven, New York, p 125Google Scholar
  4. Akil H, Richardson DE, Barchas JD, Li CH (1978b) Appearance of beta-endorphin- like immunoreactivity in human ventricular cerebrospinal fluid upon analgesic electrical stimulation. Proc Natl Acad Sci USA 75: 5170PubMedGoogle Scholar
  5. Akil H, Young E, Watson SJ, Coy D (1981a) Opiate binding properties of naturally occurring N- and C-terminus modified beta-endorphin. Peptides 2: 289PubMedGoogle Scholar
  6. Akil H, Ueda Y, Lin H-L, Lewis JW, Walker JM, Shiomi H, Liebeskind JC, Watson SJ (1981b) Multiple forms of beta-endorphin (βE) in pituitary and brain: effects of stress. In: Takagi H, Simon E (eds) Advances in endogenous and exogenous opioids. Kodansha, Tokyo, p 116Google Scholar
  7. Akil H, Shiomi H, Matthews J (1985) Induction of the intermediate pituitary by stress: synthesis and release of a nonopiod form of beta-endorphin. Science 227: 424PubMedGoogle Scholar
  8. Amalric M, Cline EJ, Martinez JL Jr, Bloom FE, Koob GF (1987) Rewarding properties of B-endorphin as measured by conditioned place preference. Psychopharmacology 91: 14PubMedGoogle Scholar
  9. Austen BM, Smyth DG (1977) The NH2-terminus of C-fragment is resistant to the action of aminopeptidases. Biochem Biophys Res Commun 76: 477Google Scholar
  10. Autelitano DJ, Smith Al, Lolait SJ, Funder JW (1985) Dopaminergic agents differentially alter beta-endorphin processing patterns in the rat pituitary neurointermediate lobe. Neurosci Lett 59: 141PubMedGoogle Scholar
  11. Bals-Kubik R, Herz A, Shippenberg TS (1988) p-endorphin-(1–27) is a naturally occurring antagonist of the reinforcing effects of opioids. Naunyn Schmiedebergs Arch Pharmacol 338:392PubMedGoogle Scholar
  12. Bals-Kubik R, Shippenberg TS, Herz A (1990) Involvement of central μ and δ opioid receptors in mediating the reinforcing effects of P-endorphin in the rat. Eur J Pharmacol 175: 63PubMedGoogle Scholar
  13. Belluzzi JD, Stein L (1977) Enkephalins may mediate euphoria and drive-reduction reward. Nature 266: 556PubMedGoogle Scholar
  14. Bennett HPJ, Browne CA, Solomon S (1981) Biosynthesis of phosphorylated forms of corticotropin related peptides. Proc Natl Acad Sci USA 78: 4713PubMedGoogle Scholar
  15. Bennett HPJ, Brubacker PL, Seger MA, Solomon S (1983) Human phosphoserine 31 corticotropin 1–39: isolation and characterization. J Biol Chem 258: 8108PubMedGoogle Scholar
  16. Bjorklund A, Moore RV, Nobin A, Stenevi U (1973) The organization of tubero-hypophyseal and reticulo-infundibular catecholamine neuron systems in the rat brain. Brain Res 51: 171PubMedGoogle Scholar
  17. Bloch B, Bugnon C, Fellman D, Lenys D (1978) Immunocytochemical evidence that the same neurons in the human infundibular nucleus are stained with anti-endorphins and antisera of other related peptides. Neurosci Lett 10: 147PubMedGoogle Scholar
  18. Bloom F, Battenberg E, Rossier J, Ling N, Guillemin R (1978) Neurons containing beta-endorphin in rat brain exist separately from those containing enkephalin: immunocytochemical studies. Proc Natl Acad Sci USA 75: 1591PubMedGoogle Scholar
  19. Bradbury AF, Finnie MDA, Smyth DG (1982) Mechanisms of C-terminal amide formation by pituitary enzymes. Nature 198: 686Google Scholar
  20. Bronstein DM, Schäfer MKH, Trujillo KA, Watson SJ, Akil H (1990a) Pro-opiomelanocortin ( POMC) mRNA in the nucleus tractus solitarius and other extrahypothalamic brain regions. Soc Neurosci Abstr 16: 1026Google Scholar
  21. Bronstein DM, Przewlocki R, Akil H (1990b) Effects of morphine treatment on proopiomelanocortin systems in rat brain. Brain Res 519: 102PubMedGoogle Scholar
  22. Bronstein DM, Kelsey JE, Akil H. Regulation of β-endorphin biosynthesis in the brain: different effects of morphine pelleting and repeated stress. In: Molecular approaches to drug abuse research. US Department of Health and Human Services (in press)Google Scholar
  23. Burbach JPH (1984) Action of proteolytic enzymes on lipotropins and endorphins: biosynthesis, biotransformation and fate. Pharmacol Ther 24: 321PubMedGoogle Scholar
  24. Burbach JPH, Wiegant VM (1984) Isolation and characterization of a-endorphin and γ-endorphin from single human pituitary gland. FEBS Lett 166: 267PubMedGoogle Scholar
  25. Burbach JPH, Loeber JG, Verhoef J, Wiegant VM, De Kloet ER, De Wied D (1980) Selective conversion of β-endorphin into peptides related to γ- and α-endorphins. Nature 283: 96PubMedGoogle Scholar
  26. Burbach JPH, De Kloet ER, Schotman P, De Wied D (1981) Proteolytic conversion of β-endorphin by brain synaptic membranes: characterization of generated β-endorphin fragments and proposed metabolic pathway. J Biol Chem 256: 12463PubMedGoogle Scholar
  27. Chen C-LC, Mather JP, Morris PL, Bardin CW (1984) Expression of proopiomelanocortin-like gene in the testis and epididymis. Proc Natl Acad Sci USA 81: 5672PubMedGoogle Scholar
  28. Chrétien M, Seidah NG, Dennis M (1984) Processing of precursor polyproteins in rat brain: regional differences in acetylation of POMC peptides. In: Muller EE, Genazzani AR (eds) Central and peripheral endorphins: basic and clinical aspects. Raven, New York, p 27Google Scholar
  29. Christie MJ, Chesher GB, Bird KD (1981) The correlation between swim-stress induced antinociception and [3H] leu-enkephalin binding to brain homogenates in mice. Pharmacol Biochem Behav 15: 853PubMedGoogle Scholar
  30. Civelli O, Brinberg N, Herbert E (1982) Detection and quantitation of proopiomelanocortin mRNA in pituitary and brain tissues from different species. J Biol Chem 257: 6783PubMedGoogle Scholar
  31. Cromlish JA, Seidah NG, Chrétien M (1986) Selective cleavage of human ACTH, beta-lipotropin, and the N-terminal glycopeptide at pairs of basic residues by IRCM-serine proteasel. Subcellular localization in small and large vesicles. J Biol Chem 261: 10859Google Scholar
  32. Deakin JF, Dostrovsky JO, Smyth D (1980) Influence of N-terminal acetylation and C-terminal proteolysis on the analgesic activity of beta-endorphin. Biochem J 189: 501PubMedGoogle Scholar
  33. DeSouza EB, Van Loon GR (1985) Differential plasma β-endorphin, β-lipotropin, and adrenocorticotropin responses to stress in rats. Endocrinology 116: 1577PubMedGoogle Scholar
  34. De Wied D, Jolles J (1990) Neuropeptides derived from pro-opiocortin: behavioral, physiological and neurochemical effects. Physiol Rev 72: 976Google Scholar
  35. Dickerson IM, Mains RE (1990) Cell-type specific post-transloational processing of peptides by different pituitary cell lines. Endocrinology 127: 133PubMedGoogle Scholar
  36. Dores RM, Jain M, Akil H (1986) Characterization of the forms of β-endorphin and α-MSH in the caudal medulla of the rat and guinea pig. Brain Res 377: 251PubMedGoogle Scholar
  37. Dum J, Gramsch C, Herz A (1983) Activation of hypothalamic β-endorphin pools by reward induced by highly palatable food. Pharmacol Biochem Behav 18: 443PubMedGoogle Scholar
  38. Eipper BA, Mains RE (1980) Structure and biosynthesis of proadrenocorticotropin/endorphin and related peptides. Endocr Rev 1: 1PubMedGoogle Scholar
  39. Eipper BA, Mains RE (1981) Further analysis of post-translational processing of beta-endorphin in rat intermediate pituitary. J Biol Chem 256: 5689PubMedGoogle Scholar
  40. Eipper BA, Mains RE (1982) Phosphorylation of pro-adrenocorticotroin/endorphin- derived peptides. J Biol Chem 257: 4907PubMedGoogle Scholar
  41. Eipper BA, Mains RE, Glembotski CC (1983) Identification in pituitary tissue of a peptide alpha-amidation activity that acts on glycine-extended peptides and requires molecular oxygen, copper and ascorbic acid. Proc Natl Acad Sci USA 80: 5144PubMedGoogle Scholar
  42. Eipper BA, Park L, Keutmann HT, Mains RE (1986) Amidation of joining peptide, a mauor pro-ACTH/endorphin-derived product peptide. J Biol Chem 261: 8686PubMedGoogle Scholar
  43. Eipper BA, Park LP, Dickerson IM, Keutmann HT, Thiele EA, Rodriguez H, Schoefield PR, Mains RE (1987) Structure of the precursor to an enzyme mediating COOH-terminal amidation in peptide biosynthesis. Mol Endocrinol 1: 777PubMedGoogle Scholar
  44. Emeson RB, Eipper BA (1986) Characterization of pro-ACTH/endorphin-derived peptides in rat hypothalamus. J Neurosci 6: 837PubMedGoogle Scholar
  45. Froni G, Bindoni M, Santoni A, Belluardo N, Marchese AE, Giovarelli M (1983) Radiofrequency destruction of the tuberoinfundibular region of the hypothalamus permanently abrogates NK cell activity in mice. Nature 306: 181Google Scholar
  46. Gianoulakis C, Angelogianni P (1989) Characterization of B-endorphin peptides in the spinal cord of the rat. Peptides 10: 1049PubMedGoogle Scholar
  47. Gilman SC, Schwartz JM, Milner AJ, Bloom FE, Feldman JD (1982) P-Endorphin enhances lymphocyte proliferative responses. Proc Natl Acad Sci USA 79: 4226PubMedGoogle Scholar
  48. Glembotski CC (1982a) Characterization of the peptide acetyl transferase activity in bovine and rat intermediate pituitaries responsible for the acetylation of beta- endorphin and alpha-melanotropin. J Biol Chem 257: 10501PubMedGoogle Scholar
  49. Glembotski CC (1982b) Acetylation of alpha-melanotropin and beta-endorphin in the rat intermediate pituitary. J Biol Chem 257: 10493PubMedGoogle Scholar
  50. Gramsch C, Kleber G,. Höllt V, Pasi A, Mehraein P, Herz A (1980) Pro-opiocortin fragments in human and rat brain: β-endorphin and α-MSH are the predominant peptides. Brain Res 192: 109PubMedGoogle Scholar
  51. Ham J, Smyth DG (1985a) β-Endorphin processing in pituitary and brain is sensitive to haloperidol. Neuropeptides 5:497Google Scholar
  52. Ham J, Smyth DJ (1985b) β-Endorphin and ACTH related peptides in primary cultures of rat anterior pituitary cells: evidence for different intracellular pools. FEBS Lett 190:253Google Scholar
  53. Ham J, Smyth DG (1986) Chronic stimulation of anterior pituitary cell cultures with CRF leads to the secretin of liptropin. Neuroendocrinology 44: 533Google Scholar
  54. Hammonds RG Jr, Nicolas P, Li CH (1984) β-Endorphin-(1–27) is an antagonist of P-endorphin analgesia. Proc Natl Acad Sci USA 81:1389PubMedGoogle Scholar
  55. Hazum E, Chang KJ, Cuatrecasas P (1979) Specific nonopiate receptors for beta-endorphin. Science 205: 1033PubMedGoogle Scholar
  56. Herbert E, Uhler M (1982) Biosynthesis of polyprotein precursors to regulatory peptides. Cell 30:1PubMedGoogle Scholar
  57. Hirsch MD, Millington WR, McKenzie JE, Mueller GP (1988) β-Endorphin-(1–27) is a potent endogenous hypotensive agent. Soc Neurosci Abstr 14:465Google Scholar
  58. Hirsch MD, Villavicencio AE, McKenzie JE, Millington WR (1990) C-terminal proteolysis modifies cardioregulation by P-endorphin. Soc Neurosci Abstr 16: 1025Google Scholar
  59. Holaday JW (1983) Cardiovascular effects of endogenous opiate systems. Annu Rev Pharmacol Toxicol 23: 541PubMedGoogle Scholar
  60. Holaday JW (1985) Endogenous opioids and their receptors. Upjohn, KalamazooGoogle Scholar
  61. Holaday JW, Loh HH (1981) Neurobiology of β-endorphin and related peptides. In: Li CH (ed) Hormonal proteins and peptides: p-endorphin. Academic, New York, p 204Google Scholar
  62. Höllt V, Bergmann M (1982) Effects of acute and chronic haloperiodol treatment on the concentrations of immunoreactive beta-endorphin in plasma, pituitary and brain of rats. Neuropharmacology 21: 147PubMedGoogle Scholar
  63. Hong M, Jhamandas K (1989) Actions of β-endorphin and related peptide fragments on a pressor response induced by cholinergic stimulation. Prog Clin Biol Res 328: 371Google Scholar
  64. Hosobuchi Y, Rossier J, Bloom FE, Guillemin R (1979) Stimulation of human periaqueductal gray for pain relief increases immunoreactive B-endorphin in ventricular fluid. Science 203: 279PubMedGoogle Scholar
  65. Jenks BG, Verburg Van Kemenade BML, Tonon MC, Vaudry H (1985) Regulation of biosynthesis and release of pars intermedia peptides in Rana ridibunda: dopamine affects both acetylation and release of α-MSH. Peptides 6: 913PubMedGoogle Scholar
  66. Joseph SA, Michael GJ (1988) Efferent ACTH-IR opiocortin projections from nucleus tractus solitarius: a hypothalamic deafferentation study. Peptides 9: 193PubMedGoogle Scholar
  67. Joseph SA, Pilcher WH, Bennet-Clarke C (1983) Immunocytochemical localization of ACTH perikerya in nucleus tractus solitarius: evidence for a second opiocortin neuronal system. Neurosci Lett 38: 221PubMedGoogle Scholar
  68. Katopodis AG, Ping D, May SW (1990) A novel enzyme from bovine neuro-intermediate pituitary catalyzes dealkylation of a-hydroxyglycine derivatives, thereby functioning sequentially with peptidylglycine a-amidating monooxygenase in peptide amidation. Biochemistry 29: 6115PubMedGoogle Scholar
  69. Khachaturian H, Alessi NE, Munfakh N, Watson SJ (1983) Ontogeny of opioid and related peptides in the rat CNS and pituitary: an immunocytochemical study. Life Sci 33 (Suppl I): 61PubMedGoogle Scholar
  70. Khachaturian H, Lewis ME, Tsou K, Watson SJ (1985) β-Endorphin, α-MSH, ACTH, and related peptides. In: Bjoorklund A, Hokfelt T (eds) Handbook of chemical neuroanatomy, vol 4: GABA and neuropeptides in the CNS, part I. Elsevier Science, Amsterdam, p 216Google Scholar
  71. Kizer JS, Bateman RC Jr, Miller RC, Humm J, Busby WH Jr, Youngblood WW (1986) Purification and characterization of peptidyl glycine monooxygenase from porcine pituitary. Endocrinology 118: 2262PubMedGoogle Scholar
  72. Krieger DT, Liotta AS, Brownstein MJ, Zimmerman EA (1980) ACTH, β- lipotropin, and related peptides in brain, pituitary, and blood. Rec Prog Horm Res 36: 277PubMedGoogle Scholar
  73. Lagaze-Masmontei CT, De Keyser Y, Luton JP, Kahin A, Bertagna X (1987) Characterization of proopiomelanocortin transcripts in human non-pituitary tissues. Proc Natl Acad Sci USA 84: 7261Google Scholar
  74. Lebouille JLM, Burbach JPH, De Kloet ER (1984) Quantitation of the endopeptidase activity generating γ-endorphin from β-endorphin in rat brain synaptic membranes by a radiometric assay. Anal Biochem 141: 1PubMedGoogle Scholar
  75. Lebouille JLM, Burbach JPH, De Kloet ER (1985) γ-Endorphin generating endopeptidase in rat brain: subcellular and regional distribution. Biochem Biophys Res Commun 127:44PubMedGoogle Scholar
  76. Lennarz WJ (1980) The biochemistry of glycoproteins and proteoglycans. Plenum, New YorkGoogle Scholar
  77. Lewis JW, Cannon JT, Liebeskind JC (1980) Opioid and non-opioid mechanisms of stress analgesia. Science 208: 623PubMedGoogle Scholar
  78. Lewis JW, Shavit Y, Terman GW, Nelson LR, Gale RP, Liebeskind JC (1983) Apparent involvement of opioid peptides in stress-induced enhancement of tumor growth. Peptides 4: 635PubMedGoogle Scholar
  79. Lewis JW, Shavit Y, Terman GW, Nelson LR, Martin FC, Gale RP, Liebeskind JC (1985) Involvement of opioid peptides in the analgesic, immunoscuppressive, and tumor-enhancing effects of stress. Psychopharmacol Bull 21: 479PubMedGoogle Scholar
  80. Lewis JW, Baldrighi G, Akil H (1987) A possible interface between autonomic function and pain control: opioid analgesia and the nucleus tractus solitarius. Brain Res 424: 65PubMedGoogle Scholar
  81. Li CH, Tseng L-F, Ferrara P, Yamashiro D (1980a) β-Endorphin: dissociation of receptor binding activity from analgesic potency. Proc Natl Acad Sci USA 77:2303Google Scholar
  82. Li CH, Yamashiro D, Tseng L-F, Chang W-C, Ferrara P (1980b) β-Endorphin omission analogs: dissociation of immunoreactivity from other biological activities. Proc Natl Acad Sci USA 77:3211Google Scholar
  83. Liotta AS, Loudes C, McKelvy JF, Krieger DT (1980) Biosynthesis of precursor corticotropin/endorphin-, corticotropin-, α-melanotropin-, β-lipotropin-, and β-endorphin-loke material by cultured rat hypothalamic neurons. Proc Natl Acad Sci USA 77: 1880PubMedGoogle Scholar
  84. Liotta AS, Advis JP, Krause JE, McKelvy JF, Krieger DT (1984) Demonstration of in vivo synthesis of pro-opiomelanocortin-, β-endorphin, and α-melanotropin- like species in the adult rat brain. J Neurosci 4: 956PubMedGoogle Scholar
  85. Loh H, Tseng LF, Wei E, Li CH (1976) P-Endorphin is a potent analgesic agent. Proc Natl Acad Sci USA 73: 2895PubMedGoogle Scholar
  86. Loh YP (1986) Kinetic studies on the processing of human beta-lipotropin by bovine pituitary intermediate lobe pro-opiomelanocortin-converting enzyme. J Biol Chem 261: 11949PubMedGoogle Scholar
  87. Loh YP, Jenks BG (1981) Evidence for two different turnover pools of adrenocorticotropin, α-melanocyte stimulating hormone and endorphin-related peptides released by the frog pituitary neurointermediate lobe. Endocrinology 109: 54PubMedGoogle Scholar
  88. Loh YP, Eskay RL, Brownstein M (1980) α-MSH-like peptides in rat brain: identification and changes during development. Biochem Biophys Res Commun 94:916PubMedGoogle Scholar
  89. Loh YP, Parish DC, Tuteja R (1985) Purification and characterization of a paired basic residue-specific pro-opiomelanocortin converting enzyme from bovine pituitary intermediate lobe secretory vesicle. J Biol Chem 260: 7194PubMedGoogle Scholar
  90. Lolait SJ, Lim ATW, Toh BH, Funder JW (1984) Immunoactive β-endorphin in a subpopulation of mouse spleen macrophages. J Clin Invest 73: 277PubMedGoogle Scholar
  91. Lolait SJ, Clements JA, Markwick AJ, Cheng MC, McNally M, Smith Al, Funder JW (1986) Pro-opiomelanocortin synthesis and post-translational processing of β-endorphin in spleen macrophages. J Clin Invest 77: 1776PubMedGoogle Scholar
  92. Lopker A, Abood LG, Hoss W, Lionetti FJ (1980) Stereoselective muscarinic acetylcholine and opiate receptors in human phagocytic leukocytes. Biochem Pharmacol 29: 1361PubMedGoogle Scholar
  93. Lowy MT, Maickel RP, Yim GK (1980) Naloxone reduction of stress-related feeding. Life Sci 26: 2113PubMedGoogle Scholar
  94. Lowy MT, Starkey C, Yim GK (1981) Stereoselective effects of opiate agonists and antagonists on ingestive behavior in rats. Pharmacol Biochem Behav 15: 591PubMedGoogle Scholar
  95. Madden J, Akil H, Tsou K, Watson SJ (1977) Stress-induced parallel changes in central opioid levels and pain responsiveness in the rat. Nature 265: 358PubMedGoogle Scholar
  96. Mains RE, Eipper BA (1976) Biosynthesis of ACTH in mouse pituitary tumor cells. J Biol Chem 251: 4115PubMedGoogle Scholar
  97. Mains RE, Eipper BA, Ling N (1977) Common precursor to corticotropins and endorphins. Proc Natl Acad Sci USA 74: 3014PubMedGoogle Scholar
  98. Mandler RN, Bididson WE, Mandler R, Serrate SA (1986) P-Endorphin augments the cytolytic activity and interferon production of natural killer cells. J Immunol 136: 934PubMedGoogle Scholar
  99. Mathews PM, Froelich CJ, Sibbit WL Jr, Bankhurst AD (1983) Enhancement of natural cytotoxicity by P-endorphin. J Immunol 130: 1658PubMedGoogle Scholar
  100. Mayer DJ, Hayes RL (1975) Stimulation-produced analgesia: development of tolerance and cross-tolerance. Science 188: 941PubMedGoogle Scholar
  101. Mayer DJ, Liebeskind JC (1974) Pain relief by focal electrical stimulation of the brain: anatomical and behavioral analysis. Brain Res 68: 73PubMedGoogle Scholar
  102. Mayer DJ, Wolfe TL, Akil H, Carder B, Liebeskind JC (1971) Analgesia from electrical stimulation in the brainstem of the rat. Science 174: 1351PubMedGoogle Scholar
  103. Meador-Woodruff JH, Pellerito B, Vaudry H, Jegou S, Seidah NG, Watson SJ, Akil H (1988) Regional processing of the N- and C-terminal domains of proopiomelanocortin in monkey pituitary and brain. Neuropeptides 11: 111PubMedGoogle Scholar
  104. Millan MJ, Millan MJ, Herz A (1986) Depletion of central β-endorphin blocks midbrain stimulation-produced analgesia in the freely-moving rat. Neuroscience 18: 641PubMedGoogle Scholar
  105. Millan MJ, Przewlocki R, Jerlicz M, Gramsch C, Höllt V, Herz A (1981) Stress- induced release of brain and pituitary β-endorphin: major role of endorphins in generation of hyperthermia, not analgesia. Brain Res 208: 325PubMedGoogle Scholar
  106. Millan MJ, Czlonkowski A, Millan MH, Herz A (1987) Activation of periaqueductal grey pools of β-endorphin by analgetic electrical stimulation in freely moving rats. Brain Res 407: 199PubMedGoogle Scholar
  107. Millington WR, Mueller GP, O’Donohue TL (1984) Regional heterogeneity in the ratio of a-MSH: β-endorphin in rat brain. Peptides 5: 841PubMedGoogle Scholar
  108. Millington WR, O’Donohue TL, Chappell MC, Roberts JL, Mueller GP (1986) Coordinate regulation of peptide acetyltransferase activity and pro-piomelanocortin gene expression in the intermediate lobe of the rat pituitary. Endocrinology 118: 2024PubMedGoogle Scholar
  109. Mochetti I, Costa E (1986) Down regulation of hypothalamic pro-opiomelanocortin system during morphine tolerance. Neuropharmacology 9 (Suppl 1): 125Google Scholar
  110. Mochetti I, Ritter A, Costa E (1989) Down-regulation of pro-opiomelanocortin synthesis and beta-endorphin utilization in hypothalamus of morphine-tolerant rats. J Mol Neurosci 1: 33Google Scholar
  111. Moss IR, Friedman E (1978) β-Endorphin — effects on respiratory regulation. Life Sci 23:1271PubMedGoogle Scholar
  112. Murthy ASN, Mains RE, Eipper BA (1986) Purification and characterizatioon of peptidylglycine α-amidating monooxygenase from bovine neurointermediate pituitary. J Biol Chem 261: 1851Google Scholar
  113. Nakanishi S, Inoue A, Kita T, Nakamura M, Chang ACY, Cohen SN, Numa S (1979) Nucleotide sequence of cloned cDNA for bovine corticotropin-beta-lipotropin precursor. Nature 278: 423PubMedGoogle Scholar
  114. Nicolas P, Hammonds RG Jr, Li CH (1984) P-Endorphin-induced analgesia is inhibited by synthetic analogs of B-endorphin. Proc Natl Acad Sci USA 81: 3074PubMedGoogle Scholar
  115. Oates EL, Allaway GP, Armstrong GR, Boyajian RA, Kehrl JH, Pranhakar BS (1988) Human lymphocytes produce pro-opiomelanocortin gene-related transcripts. J Biol Chem 263: 10041PubMedGoogle Scholar
  116. O’Donohue TL, Charlton CG, Helke CJ, Miller RJ, Jacobowitz DM (1979) Identification of α-MSH immunoreactivity in rat and human brain and CSF. In: Gross E, Meinhoffer J (eds) Peptide structure and biological functioning. Pierce Chemical, p 897Google Scholar
  117. Orth DN, Nicholson WE, Mitchell WM, Island DP, Shapiro M, Byyny RL (1973) ACTH and MSH production by a single cloned mouse pituitary tumor cell line. Endocrinology 92: 385PubMedGoogle Scholar
  118. Palkovits M, Eskay RL (1987) Distribution and possible origin of β-endorphin and ACTH in discrete brainstem nuclei of rats. Neuropeptides 9: 123PubMedGoogle Scholar
  119. Palkovits M, Mezey E, Eskay RL (1987) Pro-opiomelanocortin-derived peptiddes ( ACTH/β-endorphin/α-MSH) in brainstem baroreceptor areas of the rat. Brain Res 436: 323Google Scholar
  120. Perkins SN, Husten EJ, Eipper BA (1990) The 108-kDA peptidylglycine α-amidating monoxygenase precursor contains two separable enzymatic activities involved in peptide amidation. Biochem Biophys Res Commun 171: 926PubMedGoogle Scholar
  121. Pilcher WH, Joseph SA (1986) Differential sensitivity of hypothalamic and medullary opiocortin and tyrosine hydroxylase neurons to the neurotoxic effects of monsodium glutamate ( MSG ). Peptides 7: 783Google Scholar
  122. Pintar JE, Schacter BS, Herman AB, Durgerian S, Krieger DT (1984) Characterization and localization of proopiomelanocortin messenger RNA in the adult rat testis. Science 225: 632PubMedGoogle Scholar
  123. Plotnikoff NP, Miller GC (1983) Enkephalins as immunomodulators. J Immunopharmacol 5: 437Google Scholar
  124. Przewlocki R, Millan MJ, Gramsch C, Millan MH, Herz A (1982) The influence of selective adeno- and neurointermedio-hypophysectomy upon plasma and brain levels of β-endorphin and their response to stress in rats. Brain Res 242: 107PubMedGoogle Scholar
  125. Przewlocki R, Lason W, Höllt V, Silberring J, Herz A (1987) The influence of chronic stress on multiple opioid peptide systems in the rat: pronounced effects upon dynorphin in spinal cord. Brain Res 413: 213PubMedGoogle Scholar
  126. Reynolds DV (1969) Surgery in the rat during electrical analgesia induced by focal brain stimulation. Science 164: 444PubMedGoogle Scholar
  127. Rivier C, Vale W (1983) Modulation of stress-induced ACTH release by corticotropin-releasing factor, catecholamines and vasopressin. Nature 305: 325PubMedGoogle Scholar
  128. 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: 4826PubMedGoogle Scholar
  129. Rossier J, French ED, Rivier C, Ling N, Guillemin R, Bloom FE (1977) Foot-shock induced stress increases B-endorphin levels in blood nut not brain. Nature 270: 618PubMedGoogle Scholar
  130. Sapru HN, Willette RN, Krieger AJ (1981) Stimulation of pulmonary J receptors by an enkephalin analog. J Pharmacol Exp Ther 217: 228Google Scholar
  131. Schwartzberg DG, Nakane PK (1983) ACTH-related peptide containing neurons within the medulla oblongata of the rat. Brain Res 276: 351PubMedGoogle Scholar
  132. Schweigerer L, Bhakdi S, Teschemacher H (1982) Specific non-opiate binding sites for human β-endorphin on the terminal complex of human complement. Nature 296: 572PubMedGoogle Scholar
  133. Seeger TF, Sforzo GA, Pert CB, Pert A (1984) In vivo autoradiography: visualization of stress-induced changes in opiate receptor occupancy in the rat brain. Brain Res 305: 303PubMedGoogle Scholar
  134. Seidah NG, Chrétien M (1981) Complete amino acid sequence of a human pituitary glycopeptide: an important maturation produce of pro-opiomelanocortin. Proc Natl Acad Sci USA 78: 4236PubMedGoogle Scholar
  135. Seidah NG, Rochemont J, Hamelin J, Benjannet S, Chrétien M (1981) The missing fragment of the pro-sequence of human proopiomelanocortin: sequence and evidence for C-terminal amidation. Biochem Biophys Res Commun 102: 710PubMedGoogle Scholar
  136. Seidah NG, Gaspar L, Mion P, Marcinkiewicz M, Mbikay M, Chrétien M (1990) cDNA sequence of two distinct pituitary proteins homologous to Kex2 and furin gene products: tissue-specific mRN As encoding candidates for pro-hormone processing proteinases. DNA Cell Biol 9:415PubMedGoogle Scholar
  137. Seidah NG, Marcinkiewicz M, Benjannet S, Gaspar L, Beaubien G, Mattei MG, Lazure C, Mbikay M, Chrétien M (1991) Cloning and primary sequence of a mouse candidate prohormone convertase PCI homologous to PC2, furin, and kex2: distinct chromosomal localization and messenger RNA distribution in brain and pituitary compared to PC2. Mol Endocrinol 5: 111PubMedGoogle Scholar
  138. Shavit Y, Lewis JW, Terman GW, Gale RP, Liebeskind JC (1984) Opioid peptides mediate the suppressive effects of stress on natural killer cell cytotoxicity. Science 223: 188PubMedGoogle Scholar
  139. Shavit Y, Terman GW, Martin FC, Lewis JW, Liebeskind JC, Gale RP (1985) Stress, opioid-peptides, the immune system, and cancer. J Immunol (Suppl) 135: 834Google Scholar
  140. Shavit Y, Depaulis A, Martin FC, Terman GW, Pechnick RN, Zane CJ, Gale, RP, Liebeskind JC (1986) Involvement of brain opiate receptors in the immune- suppressive effect of morphine. Proc Natl Acad Sci USA 83: 7114PubMedGoogle Scholar
  141. Shiomi H, Watson SJ, Kelsey JE, Akil H (1986) Pretranslational and post- translational mechanisms for regulating β-endorphin-adrenocorticotropin of the anterior pituitary lobe. Endocrinology 119: 1793PubMedGoogle Scholar
  142. Smeekens SP, Steiner DF (1990) Identification of a human insulinoma cDNA encoding a novel mammalian protein structurally related to the yeast dibasic processing protease Kex2. J Biol Chem 265: 2997PubMedGoogle Scholar
  143. Smeekens SP, Avruch AS, LaMendola J, Chan SJ, Steiner DF (1991) Identification of a cDNA encoding a second putative prohormone convertase related to PC2 in AtT20 cells and islets of Langerhans. Proc Natl Acad Sci USA 88: 340PubMedGoogle Scholar
  144. Smith EM, Blalock EJ (1981) Human lymphocyte production of corticotropin and endorphin like substances: association with leukocyte interferon. Proc Natl Acad Sci USA 77: 7530Google Scholar
  145. Smyth DG, Zakarian Z (1980) Selective processing of P-endorphin in regions of porcine pituitary. Nature 288: 613PubMedGoogle Scholar
  146. Smyth DG, Massey DE, Zakarian S (1979) Endorphins are stored in biologically active and inactive forms: isolation of α-N-acetyl peptides. Nature 279: 252PubMedGoogle Scholar
  147. Smyth DG, Zakarian S (1982) α-N-Acetyl derivatives of β-endorphin in rat pituitary: chromatographic evidence for processed forms of beta-endorphin in pancreas and brain. Life Sci 31:1887PubMedGoogle Scholar
  148. Steiner DF, Oyer PE (1967) The biosynthesis of insulin and a probable precursor of insulin by a human islet cell adenoma. Proc Natl Acad Sci USA 57: 473PubMedGoogle Scholar
  149. Stoffers DA, Green CB, Eipper BA (1989) Alternative mRNA splicing generates multiple forms of peptidyl-glycine alpha-amidating monooxygenase in rat atrium. Proc Natl Acad Sci USA 86: 735PubMedGoogle Scholar
  150. Takahashi H, Hakamata Y, Watanabe Y, Kikuno R, Miyata T, Numa S (1983) Complete nucleotide sequence of the human corticotropin-beta-lipotropin precursor gene. Nucleic Acids Res 11:6847 Takahashi K, Okamoto H, Seino H, Noguchi M (1990) Peptidylglycine α-amidating reaction: evidence for a two-step mechanism involving a stable intermediate at neutral pH. Biochem Biophys Res Commun 169: 524Google Scholar
  151. Tilders FJH, Mulder AH (1975) In vitro demonstration of melanocyte-stimulating hormone release inhibiting action of dopaminergic nerve fibres. J Endocrinol 64: 63Google Scholar
  152. Trujillo KA, Belluzzi JD, Stein L (1989) Opiate antagonists and self-stimulation: extinction-like response patterns suggest selective reward deficit. Brain Res 492: 15PubMedGoogle Scholar
  153. Tsou K, Khachaturian H, Akil H, Watson SJ (1986) Immunocytochemical localization of proopiomelanocortin-derived peptides in the adult rat spinal cord. Brain Res 378: 28PubMedGoogle Scholar
  154. Turner JD, Keith AB, Smith Al, Mcdermott JR, Biggins JA, Edwardson JA (1983) Studies on the characterization of α-MSH-like immunoreactivity in rat hypothalamus. Regul Pept 5: 283PubMedGoogle Scholar
  155. Van Loon GR, Appel NM, Ho D (1981a) β-Endorphin-induced increases in plasma epinephrine, norepinephrine and dopamine in rats: inhibition of adreno-medullary response by intracisternal somatostatin. Brain Res 212:207Google Scholar
  156. Van Loon GR, Appel NM, Ho D (1981b) β-Endorphin-induced stimulation of central sympathetic outflow: β-endorphin increases plasma concentrations of epinephrine, norepinephrine and dopamine in rats. Endocrinology 109:46Google Scholar
  157. Van Ree JM, Smyth DG, Colpaert FC (1979) Dependence creating properties of lipotropin C-fragment (β-endorphin): evidence for its internal control of behavior. Life Sci 24: 495PubMedGoogle Scholar
  158. Vaudry H, Jenks BG, van Overbeeke AP (1983) The frog pars intermedia contains only the non-acetylated form of α-MSH: acetylation to generate α-MSH occurs during the release process. Life Sci 33 (Suppl 1): 97PubMedGoogle Scholar
  159. Wand GS, May V, Eipper BA (1988) Comparison of acute and chronic secretagogue regulation of proadrenocorticotropin/endorphin synthesis, secretion and messenger ribonucleic acid production in primary cultures of rat anterior pituitary. Endocrinology 123: 1153PubMedGoogle Scholar
  160. Watson SJ, Barchas JD, Li CH (1977) Beta-lipotropin: localization in cells and axons in rat brain by immunocytochemistry. Proc Natl Acad Sci USA 74: 5155PubMedGoogle Scholar
  161. Watson SJ, Akil H, Richard CW, Barchas JD (1978a) Evidence for two separate opiate peptide neuronal systems and the coexistence of beta-lipotropin, beta- endorphin and ACTH immunoreactivities in the same hypothalamic neurons. Nature 275: 226PubMedGoogle Scholar
  162. Watson SJ, Richard CW, Barchas JD (1978b) Adrenocorticotropin in rat brain: immunocytochemical localization in the cells and axons. Science 200: 1180PubMedGoogle Scholar
  163. Watson SJ, Lopez J, Young EA, Vale W, Rivier J, Akil H (1987) Effects of low dose α-CRF in humans: endocrine relationships and β-endorphin/β-lipotropin response. J Clin Endocrinol Metab 66: 10Google Scholar
  164. Westly HJ, Kleiss AJ, Kelley KW, Wong PK, Yuen P-H (1986) Newcastle disease virus-infected splenocytes express the pro-opiomelanocortin gene. J Exp Med 163: 1589PubMedGoogle Scholar
  165. Westphal M, Li CH (1984a) β-Endorphin: evidence for the existence of opioid and non-opioid binding components for the tritiated human hormone in NG108-15 cells. Biochem Biophys Res Commun 122:428Google Scholar
  166. Westphal M, Li CH (1984b) β-Endorphin: demonstration of binding sites in three human neuroblastoma cell lines specific for the COOH-terminal segment of the human hormone. Biochem Biophys Res Commun 120:873Google Scholar
  167. Wybran J, Appelboom T, Famaly JP, Govaerts A (1979) Suggestive evidence for receptors for morphine and methionine-enkephalin on normal human blood T lymphocytes. J Immunol 123: 1068PubMedGoogle Scholar
  168. Yoshida M, Taniguchi Y (1988) Projection of pro-opiomelanocortin neurons from the rat arcuate nucleus to the midbrain central gray as demonstrated by double staining with retrograde labeling and immunohistochemistry. Arch Histol Cytol 51: 175PubMedGoogle Scholar
  169. Young EA (1989) Adrenalectomy increases β-lipotropin secretion over β-endorphin secretion from anterior pituitary corticotrophs. Life Sci 45: 2233PubMedGoogle Scholar
  170. Young EA (1990) Induction of the intermediate lobe POMC system with chronic swim stress and B-adrenergic modulation of this induction. Neuroendocrinology 52: 405PubMedGoogle Scholar
  171. Young EA, Akil H (1985) Corticotropin-releasing factor stimulation of adrenocorticotropin and P-endorphin release: effects of acute and chronic stress. Endocrinology 117: 23PubMedGoogle Scholar
  172. Young EA, Lewis J, Akil H (1986) The preferential release of β-endorphin from the anterior pituitary lobe by corticotropin releasing factor ( CRF ). Peptides 7: 603PubMedGoogle Scholar
  173. Zakarian S, Smyth DG (1982a) Distribution of β-endorphin-related peptides in rat pituitary and brain. Biochem J 202: 561PubMedGoogle Scholar
  174. Zakarian S, Smyth DG (1982b) β-Endorphin is processed differently in specific regions of rat pituitary and brain. Nature 296:250Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1993

Authors and Affiliations

  • E. Young
  • D. Bronstein
  • H. Akil

There are no affiliations available

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