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Neuropeptides as synaptic transmitters


Neuropeptides are small protein molecules (composed of 3–100 amino-acid residues) that have been localized to discrete cell populations of central and peripheral neurons. In most instances, they coexist with low-molecular-weight neurotransmitters within the same neurons. At the subcellular level, neuropeptides are selectively stored, singularly or more frequently in combinations, within large granular vesicles. Release occurs through mechanisms different from classical calcium-dependent exocytosis at the synaptic cleft, and thus they account for slow synaptic and/or non-synaptic communication in neurons. Neuropeptide co-storage and coexistence can be observed throughout the central nervous system and are responsible for a series of functional interactions that occur at both pre- and post-synaptic levels. Thus, the subcellular site(s) of storage and sorting mechanisms into different neuronal compartments are crucial to the mode of release and the function of neuropeptides as neuronal messengers.

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Fig. 3



5-hydroxytryptamine or serotonin




agouti gene-related protein


cocaine- and amphetamine-regulated transcript




calcitonin gene-related peptide


central nervous system


corticotropin-releasing hormone


dorsal root ganglion


delta sleep-inducing peptide


γ-amino-butyric acid


glucagon-like peptide 1


G-protein-coupled receptor


islet amyloid polypeptide


large granular vesicle


luteinizing hormone-releasing hormone


α-melanocyte-stimulating hormone


nitric oxide


neuropeptide tyrosine


pituitary adenylyl cyclase-activating peptide


peptide histidine isoleucine


pancreatic polypeptide


polymerase chain reaction


peripheral nervous system


peptide tyrosine tyrosine


substance P


small synaptic vesicle


trans-Golgi network


thyrotropin-releasing hormone


vasoactive intestinal polypeptide


  1. Agnati LF, Fuxe K, Benfenati F, Battistini N, Harfstrand A, Hökfelt T, Cavicchioli L, Tatemoto K, Mutt V (1983) Failure of neuropeptide Y in vitro to increase the number of alpha 2-adrenergic binding sites in membranes of medulla oblongata of the spontaneous hypertensive rat. Acta Physiol Scand 119:309–312

  2. Aimar P, Pasti L, Carmignoto G, Merighi A (1998) Nitric oxide-producing islet cells modulate the release of sensory neuropeptides in the rat substantia gelatinosa. J Neurosci 18:10375–10388

  3. Amara SG, Jonas V, Rosenfeld MG, Ong ES, Evans RM (1982) Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature 298:240–244

  4. Amara SG, Arriza JL, Leff SE, Swanson LW, Evans RM, Rosenfeld MG (1985) Expression in brain of a messenger RNA encoding a novel neuropeptide homologous to calcitonin gene-related peptide. Science 229:1094–1097

  5. Angulo JA, McEwen BS (1994) Molecular aspects of neuropeptide regulation and function in the corpus striatum and nucleus accumbens. Brain Res Brain Res Rev 19:1–28

  6. Aoki C, Pickel VM (1990) Neuropeptide Y in cortex and striatum. Ultrastructural distribution and coexistence with classical neurotransmitters and neuropeptides. Ann N Y Acad Sci 611:186–205

  7. Artalejo CR, Elhamdani A, Palfrey HC (1998) Secretion: dense-core vesicles can kiss-and-run too. Curr Biol 8:R62–R65

  8. Arvidsson U, Cullheim S, Ulfhake B, Bennett GW, Fone KCF, Cuello AC, Verhofstad AAJ, Visser TJ, Hökfelt T (1990a) 5-Hydroxytryptamine, substance P, and thyrotropin-releasing hormone in the adult cat spinal cord segment L7: immunohistochemical and chemical studies. Synapse 6:237

  9. Arvidsson U, Schalling M, Cullheim S, Ulfhake B, Terenius L, Verhofstad A, Hökfelt T (1990b) Evidence for coexistence between calcitonin gene-related peptide and serotonin in the bulbospinal pathway in the monkey. Brain Res 532:47–57

  10. Arvidsson U, Cullheim S, Ulfhake B, Luppi PH, Kitahama K, Jouvet M, Hökfelt T (1994) Quantitative and qualitative aspects on the distribution of 5-HT and its coexistence with substance P and TRH in cat ventral medullary neurons. J Chem Neuroanat 7:3–12

  11. Arvieu L, Mauborgne A, Bourgoin S, Oliver C, Feltz P, Hamon M, Cesselin F (1996) Sumatriptan inhibits the release of CGRP and substance P from the rat spinal cord. Neuroreport 7:1973–1976

  12. Balkowiec A, Katz DM (2000) Activity-dependent release of endogenous brain-derived neurotrophic factor from primary sensory neurons detected by ELISA in situ. J Neurosci 20:7417–7423

  13. Baranano DE, Ferris CD, Snyder SH (2001) Atypical neural messengers. Trends Neurosci 24:99–106

  14. Barg S, Olofsson CS, Schriever-Abeln J, Wendt A, Gebre-Medhin S, Renstrom E, Rorsman P (2002) Delay between fusion pore opening and peptide release from large dense-core vesicles in neuroendocrine cells. Neuron 33:287–299

  15. Baulieu EE, Robel P, Schumacher M (2001) Neurosteroids: beginning of the story. Int Rev Neurobiol 46:1–32

  16. Bean AJ, Zhang X, Hökfelt T (1994) Peptide secretion: what do we know? FASEB J 8:630–638

  17. Bock MG, DiPardo R, Evans BE, Rittle KE, Whitter WL, Veber DE, Anderson PS, Freidinger RM (1989) Benzodiazepine gastrin and brain cholecystokinin receptor ligands: L-365,260. J Med Chem 32:13–16

  18. Bockstaele EJ van, Saunders A, Commons KG, Liu XB, Peoples J (2000) Evidence for coexistence of enkephalin and glutamate in axon terminals and cellular sites for functional interactions of their receptors in the rat locus coeruleus. J Comp Neurol 417:103–114

  19. Bondy CA, Whitnall MH, Brady LS, Gainer H (1989) Coexisting peptides in hypothalamic neuroendocrine systems: some functional implications. Cell Mol Neurobiol 9:427–446

  20. Brezina V, Weiss KR (1997) Analyzing the functional consequences of transmitter complexity. Trends Neurosci 20:538–543

  21. Brigadski T, Hartmann M, Lessmann V (2005) Differential vesicular targeting and time course of synaptic secretion of the mammalian neurotrophins. J Neurosci 25:7601–7614

  22. Buijs RM, Wortel J, Hou YX (1995) Colocalization of gamma-amino butyric acid with vasopressin, vasoactive intestinal peptide, and somatostatin in the rat suprachiasmatic nucleus. J Comp Neurol 358:343–352

  23. Buma P (1988) Synaptic and nonsynaptic release of neuromediators in the central nervous system. Acta Morphol Nederl-Scand 26:81–113

  24. Burgen A, Kosterlitz HW, Iversen LL (1980) Neuroactive peptides. Royal Society, London

  25. Calo’ G, Guerrini R, Rizzi A, Salvadori S, Regoli D (2000) Pharmacology of nociceptin and its receptor: a novel therapeutic target. Br J Pharmacol 129:1261–1283

  26. Caruso DM, Owczarzak MT, Pourcho RG (1990) Colocalization of substance P and GABA in retinal ganglion cells: a computer-assisted visualization. Vis Neurosci 5:389–394

  27. Cauli B, Tong XK, Rancillac A, Serluca N, Lambolez B, Rossier J, Hamel E (2004) Cortical GABA interneurons in neurovascular coupling: relays for subcortical vasoactive pathways. J Neurosci 24:8940–8949

  28. Chan-Palay V (1988) Neurons with galanin innervate cholinergic cells in the human basal forebrain and galanin and acetylcholine coexist. Brain Res Bull 21:465–472

  29. Chan-Palay V, Palay SL (1984) Coexistence of neuroactive substances in neurons. Wiley, New York

  30. Charlton CG, Helke CJ (1986) Ontogeny of substance P receptors in rat spinal cord: quantitative changes in receptor number and differential expression in specific loci. Brain Res 394:81–91

  31. Charnay Y, Paulin C, Chayvialle JA, Dubois PM (1983) Distribution of substance P-like immunoreactivity in the spinal cord and dorsal root ganglia of the human foetus and infant. Neuroscience 10:41–55

  32. Civelli O, Nothacker H-P, Saito Y, Wang Z, Lin SHS, Reinscheid RK (2001) Novel neurotransmitters as natural ligands of orphan g-protein coupled receptors. Trends Neurosci 24:230–237

  33. Collin E, Mantelet S, Frechilla D, Pohl M, Bourgoin S, Hamon M, Cesselin F (1993) Increased in vivo release of calcitonin gene-related peptide-like material from the spinal cord in arthritic rats. Pain 54:203–211

  34. Collin E, Frechilla D, Pohl M, Bourgoin S, Mauborgne A, Hamon M, Cesselin F (1994) Differential effects of the novel analgesic, S 12813–4, on the spinal release of substance P- and calcitonin gene-related peptide-like materials in the rat. Naunyn-Schmiedebergs Arch Pharmacol 349:387–393

  35. Consolo S, Palazzi E, Bertorelli R, Fisone G, Crawley J, Hökfelt T, Bartfai T (1990) Functional aspects of acetylcholine-galanin coexistence in the brain. Prog Brain Res 84:279–287

  36. Coulouarn Y, JS, Tostivint H, Vaudry H, Lihrmann I (1999) Cloning, sequence analysis and tissue distribution of the mouse and rat urotensin II precursors. FEBS Lett 457:28–32

  37. Crawley JN (1990) Coexistence of neuropeptides and “classical” neurotransmitters. Functional interactions between galanin and acetylcholine. Ann N Y Acad Sci 579:233–245

  38. Crawley JN (1993) Functional interactions of galanin and acetylcholine: relevance to memory and Alzheimer’s disease. Behav Brain Res 57:133–141

  39. Cuello AC (1982) Co-transmission. McMillan, London

  40. Cuello AC, Polak JM, Pearse AGE (1976) Substance P: a naturally occurring transmitter in human spinal cord. Lancet II:1054–1056

  41. Dalkin AC, Haisenleder DJ, Ortolano GA, Ellis TR, Marshall JC (1989) The frequency of gonadotropin-releasing-hormone stimulation differentially regulates gonadotropin subunit messenger ribonucleic acid expression. Endocrinology 125:917–924

  42. Dalsgaard CJ, Jernbeck J, Stain W, Kjartansson J, Haegerstrand A, Hökfelt T, Brodin E, Cuello AC, Brown JC (1989) Calcitonin gene-related peptide-like immunoreactivity in nerve fibres in the human skin: relation to fibres containing substance P-, somatostatin- and vasoactive intestinal polypeptide-like immunoreactivity. Histochemistry 91:35–38

  43. Darland T, Heinricher MM, Grandy DK (1998) Orphanin FQ/nociceptin: a role in pain and analgesia, but so much more. Trends Neurosci 21:215–221

  44. De Biasi S, Rustioni A (1988) Glutamate and substance P coexist in primary afferent terminals in the superficial laminae of the spinal cord. Proc Natl Acad Sci USA 85:7820–7824

  45. De Biasi S, Rustioni A (1991) Ultrastructural immunocytochemical localization of excitatory amino acids in the somatosensory system. J Histochem Cytochem 38:1745–1754

  46. De Camilli P, Jahn R (1990) Pathways to regulated exocytosis in neurons. Annu Rev Physiol 52:625–645

  47. De Felipe C, Herrero JF, O’Brien JA, Palmer JA, Doyle CA, Smith AJ, Laird JMA, Ben-Ari Y, Cervero F, Hunt SP (1998) Altered nociception, analgesia and aggression in mice lacking the receptor for substance P. Nature 392:394–397

  48. Delander GE, Schott E, Brodin E, Fredholm BB (1997) Temporal changes in spinal cord expression of mRNA for substance P, dynorphin and enkephalin in a model of chronic pain. Acta Physiol Scand 161:509–516

  49. Doods HN, Wieland HA, Engel W, Eberlein W, Willim KD, Entzeroth M, Wienen W, Rudolf K (1996) BIBP 226, the first selective neuropeptide Y1 receptor antagonist: a review of its pharmacological properties. Regul Pept 65:71–77

  50. Dun NJ, Dun SL, Wong RK, Forstermann U (1994) Colocalization of nitric oxide synthase and somatostatin immunoreactivity in rat dentate hilar neurons. Proc Natl Acad Sci USA 91:2955–2959

  51. Elhamdani A, Palfrey HC, Artalejo CR (2001) Quantal size is dependent on stimulation frequency and calcium entry in calf chromaffin cells. Neuron 31:819–830

  52. Emson PC, Lindvall O (2001) Distribution of putative neurotransmitters in the neocortex. Neuroscience 79:1–30

  53. Erspamer V (1981) The tachykinin peptide family. Trends Neurosci 4:267–269

  54. Euler US von, Gaddum J (1931) An unidentified depressor substance in certain tissue extracts. J Physiol (Lond) 72:74–81

  55. Fisher JM, Sossin W, Newcomb R, Scheller RH (1988) Multiple neuropeptides derived from a common precursor are differentially packaged and transported. Cell 54:813–822

  56. Fitzpatrick-McElligott S, Card JP, O’Kane TM, Baldino F (1991) Ontogeny of somatostatin mRNA-containing perikarya in the rat central nervous system. Synapse 7:123–134

  57. Folkers K, Hörig J, Rampold G, Lane P, Rosell S, Björkroth U (1982) Design and synthesis of effective antagonists of substance P. Acta Chem Scand 36:389–395

  58. Folkers K, Feng DM, Asano N, Håkanson R, Wiesenfeld-Hallin Z, Leander S (1990) Spantide II, an effective tachykinin antagonist having high potency and negligible neurotoxicity. Proc Natl Acad Sci USA 87:4833–4835

  59. Fried G (1982) Neuropeptide storage in vesicles. In: Klein RL, Lagercrantz H, Zimmermann H (eds) Neurotransmitter vesicles. Academic Press, London New York, pp 361–374

  60. Fried G, Terenius L, Hökfelt T, Goldstein M (1985) Evidence for differential localization of noradrenaline and neuropeptide Y (NPY) in neuronal storage vesicles isolated from rat vas deferens. J Neurosci 5:450–458

  61. Garry MG, Hargreaves KM (1992) Enhanced release of immunoreactive CGRP and substance P from spinal dorsal horn slices occurs during carrageenan inflammation. Brain Res 582:139–142

  62. Garry MG, Richardson JD, Hargreaves KM (1994) Sodium nitroprusside evokes the release of immunoreactive calcitonin gene-related peptide and substance P from dorsal horn slices via nitric oxide-dependent and nitric oxide-independent mechanisms. J Neurosci 14:4329–4337

  63. Giachetti A, Said SI, Reynolds RC, Koniges FC (1977) Vasoactive intestinal polypeptide in brain: localization in and release from isolated nerve terminals. Proc Natl Acad Sci USA 74:3424–3428

  64. Gibson CL, Clowry GJ (1999) Transient expression of calcitonin gene-related peptide immunoreactivity in the ventral horn of the post-natal rat cervical spinal cord. Brain Res Dev Brain Res 115:93–96

  65. Gibson SJ, Polak JM, Bloom SR, Sabate IM, Mulderry PM, Ghatei MA, McGregor GP, Morrison JFB, Kelly JS, Evans RM, Rosenfeld MG (1984) Calcitonin gene-related peptide immunoreactivity in the spinal cord of man and of eight other species. J Neurosci 4:3101–3111

  66. Glasgow E, Kusano K, Chin H, Mezey E, Young WS, Gainer H (1999) Single cell reverse transcription-polymerase chain reaction analysis of rat supraoptic magnocellular neurons: neuropeptide phenotypes and high voltage-gated calcium channel subtypes. Endocrinology 140:5391–5401

  67. Glowinski J, Kemel ML, Desban M, Gauchy C, Lavielle S, Chassaing G, Beaujouan JC, Tremblay L (1993) Distinct presynaptic control of dopamine release in striosomal- and matrix-enriched areas of the rat striatum by selective agonists of NK1, NK2 and NK3 tachykinin receptors. Regul Pept 46:124–128

  68. Gray TS, Morley JE (1986) Neuropeptide Y: anatomical distribution and possible function in mammalian nervous system. Life Sci 38:389–401

  69. Guillemin R (2005) Hypothalamic hormones a.k.a. hypothalamic releasing factors. J Endocrinol 184:11–28

  70. Gulbenkian S, Merighi A, Wharton J, Varndell IM, Polak JM (1986) Ultrastructural evidence for the coexistence of calcitonin gene-related peptide and substance P in secretory vesicles of peripheral nerves in the guinea pig. J Neurocytol 15:535–542

  71. Halliday GM, Li YW, Joh TH, Cotton RG, Howe PR, Geffen LB, Blessing WW (1988) Distribution of substance P-like immunoreactive neurons in the human medulla oblongata: co-localization with monoamine-synthesizing neurons. Synapse 2:353–370

  72. Hannibal J, Moller M, Ottersen OP, Fahrenkrug J (2000) PACAP and glutamate are co-stored in the retinohypothalamic tract. J Comp Neurol 418:147–155

  73. Harata N, Pyle JL, Aravanis AM, Mozhayeva M, Kavalali ET, Tsien RW (2001) Limited numbers of recycling vesicles in small CNS nerve terminals: implications for neural signaling and vesicular cycling. Trends Neurosci 24:637–643

  74. Harling H, Messell T, Poulsen SS, Rasmussen TN, Holst JJ (1991) Galanin and vasoactive intestinal polypeptide: coexistence and corelease from the vascularly perfused pig ileum during distension and chemical stimulation of the mucosa. Digestion 50:61–71

  75. Henry JN, Manaker S (1998) Colocalization of substance P or enkephalin in serotoninergic neuronal afferents to the hypoglossal nucleus in the rat. J Comp Neurol 391:491–505

  76. Hershey AD, Krause JE (1990) Molecular characterization of a functional cDNA encoding the rat substance P receptor. Science 247:958–962

  77. Heym C, Kummer W (1989) Immunohistochemical distribution and colocalization of regulatory peptides in the carotid body. J Electron Microsc Tech 12:331–342

  78. Hill R (2000) NK1 (substance P) receptor antagonists—why are they not analgesic in humans? Trends Physiol Sci 21:244–246

  79. 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 393:272–276

  80. Hinuma S, Onda H, Fujino M (1999) The quest for novel bioactive peptides utilizing orphan seven-transmembrane-domain receptors. J Mol Med 77:495–504

  81. Hisano S, Daikoku S, Yanaihara N, Shibasaki T (1986) Intragranular colocalization of CRF and Met-Enk-8 in nerve terminals in the rat median eminence. Brain Res 370:321–326

  82. Hisano S, Tsuruo Y, Katoh S, Daikoku S, Yanaihara N, Shibasaki T (1987) Intragranular colocalization of arginine vasopressin and methionine-enkephalin-octapeptide in CRF-axons in the rat median eminence. Cell Tissue Res 249:497–507

  83. Hökfelt T (1991) Neuropeptides in perspective: the last ten years. Neuron 7:867–879

  84. Hökfelt T, Johansson O, Ljungdahl A, Lundberg JM, Schultzberg M (1980) Peptidergic neurones. Nature 284:515–521

  85. Hökfelt T, Johansson O, Goldstein M (1984) Chemical anatomy of the brain. Science 225:1326–1334

  86. Hökfelt T, Millhorn D, Seroogy K, Tsuruo Y, Ceccatelli S, Lindh B, Meister B, Melander T, Schalling M, Bartfai T (1987) Coexistence of peptides with classical neurotransmitters. Experientia 43:768–780

  87. Hökfelt T, Zhang X, Verge V, Villar M, Elde R, Bartfai T, Xu XJ, Wiesenfeld-Hallin Z (1993) Coexistence and interaction of neuropeptides with substance P in primary sensory neurons, with special reference to galanin. Regul Pept 46:76–80

  88. Hökfelt T, Zhang X, Wiesenfeld-Hallin Z (1994) Messenger plasticity in primary sensory neurons following axotomy and its functional implications. Trends Neurosci 17:22–30

  89. Hökfelt T, Arvidsson U, Cullheim S, Millhorn D, Nicholas AP, Pieribone V, Seroogy K, Ulfhake B (2000a) Multiple messengers in descending serotonin neurons: localization and functional implications. J Chem Neuroanat 18:75–86

  90. Hökfelt T, Broberger C, Xu ZQ, Sergeyev V, Ubink R, Diez M (2000b) Neuropeptides—an overview. Neuropharmacology 39:1337–1356

  91. Holst JJ, Fahrenkrug J, Knuhtsen S, Jensen SL, Nielsen OV, Lundberg JM, Hökfelt T (1987) VIP and PHI in the pig pancreas: coexistence, corelease, and cooperative effects. Am J Physiol 252:G182–G189

  92. Holtback U, Brismar H, DiBona GF, Fu M, Greengard P, Aperia A (1999) Receptor recruitment: a mechanism for interactions between G protein-coupled receptors. Proc Natl Acad Sci USA 96:7271–7275

  93. Horvath TL, Bechmann I, Naftolin F, Kalra SP, Leranth C (1997) Heterogeneity in the neuropeptide Y-containing neurons of the rat arcuate nucleus: GABAergic and non-GABAergic subpopulations. Brain Res 756:283–286

  94. Huang LY, Neher E (1996) Ca(2+)-dependent exocytosis in the somata of dorsal root ganglion neurons. Neuron 17:135–145

  95. 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 258:577–579

  96. Illes P, Regenold JT (1990) Interaction between neuropeptide Y and noradrenaline on central catecholamine neurons. Nature 344:62–63

  97. Isaac JT, Nicoll RA, Malenka RC (1999) Silent glutamatergic synapses in the mammalian brain. Can J Physiol Pharmacol 77:735–737

  98. Jirikowski GF, Ramalho-Ortigao FJ, Caldwell JD (1991) Transitory coexistence of oxytocin and vasopressin in the hypothalamo neurohypophysial system of parturient rats. Horm Metab Res 23:476–480

  99. Johnson H, Hökfelt T, Ulfhake B (1992) Galanin- and CGRP-like immunoreactivity coexist in rat spinal motoneurons. Neuroreport 3:303–306

  100. Jones EG, Hendry SH (1986) Peptide-containing neurons of the primate cerebral cortex. Res Publ Assoc Res Nerv Ment Dis 64:163–178

  101. Juaneda C, Dubourg P, Ciofi P, Corio M, Tramu G (1999) Ultrastructural colocalization of vesicular cholecystokinin and corticoliberin in the periportal nerve terminals of the rat median eminence. J Neuroendocrinol 11:203–209

  102. Karhunen T, Vilim FS, Alexeeva V, Weiss KR, Church PJ (2001) Targeting of peptidergic vesicles in cotransmitting terminals. J Neurosci 21:RC127

  103. Kawai Y, Emson PC, Hillyard CJ, Girgis S, MacIntyre I, Oertel WH, Tohyama M (1987) Immunohistochemical evidence for the coexistence of calcitonin gene-related peptide and glutamate decarboxylase-like immunoreactivities in the Purkinje cells of the rat cerebellum. Brain Res 409:371–373

  104. Kessler JA (1985) Differential regulation of peptide and catecholamine characters in cultured sympathetic neurons. Neuroscience 15:827–839

  105. Kits KS, Mansvelder HD (2000) Regulation of exocytosis in neuroendocrine cells: spatial organization of channels and vesicles, stimulus-secretion coupling, calcium buffers and modulation. Brain Res Brain Res Rev 33:78–94

  106. Kits KS, Dreijer AM, Lodder JC, Borgdorff A, Wadman WJ (1997) High intracellular calcium levels during and after electrical discharges in molluscan peptidergic neurons. Neuroscience 79:275–284

  107. Klumperman J, Spijker S, van Minnan J, Sharp-Baker H, Smit AB, Geraerts WP (1996) Cell type-specific sorting of neuropeptides: a mechanism to modulate peptide composition of large dense-core vesicles. J Neurosci 16:7930–7940

  108. Kojima M, Kangawa K (2005) Ghrelin: structure and function. Physiol Rev 85:495–522

  109. Kojima M, Hosoda H, Kangawa K (2001) Purification and distribution of ghrelin: the natural endogenous ligand for the growth hormone secretagogue receptor. Horm Res 56(Suppl 1):93–97

  110. Kosaka T, Kosaka K, Tateishi K, Hamaoka Y, Yanaihara N, Wu JY, Hama K (1985) GABAergic neurons containing CCK-8-like and/or VIP-like immunoreactivities in the rat hippocampus and dentate gyrus. J Comp Neurol 239:420–430

  111. Kupfermann I (1991) Functional studies of cotransmission. Physiol Rev 71:683–732

  112. Laing I, Todd AJ, Heizmann CW, Schmidt HHHW (1994) Subpopulations of GABAergic neurons in laminae I–III of rat spinal dorsal horn defined by coexistence with classical transmitters, peptides, nitric oxide synthase or parvalbumin. Neuroscience 61:123–132

  113. Landgraf R, Neumann ID (2004) Vasopressin and oxytocin release within the brain: a dynamic concept of multiple and variable modes of neuropeptide communication. Front Neuroendocrinol 25:150–176

  114. Leibowitz SF (1989) Hypothalamic neuropeptide Y, galanin, and amines. Concepts of coexistence in relation to feeding behavior. Ann N Y Acad Sci 575:221–233

  115. Lessmann V, Gottmann K, Malcangio M (2003) Neurotrophin secretion: current facts and future prospects. Prog Neurobiol 69:341–374

  116. Lin CS, Lu SM, Schmechel DE (1986) Glutamic acid decarboxylase and somatostatin immunoreactivities in rat visual cortex. J Comp Neurol 244:369–383

  117. Liposits Z, Reid JJ, Negro-Vilar A, Merchenthaler I (1995) Sexual dimorphism in copackaging of luteinizing hormone-releasing hormone and galanin into neurosecretory vesicles of hypophysiotropic neurons: estrogen dependency. Endocrinology 136:1987–1992

  118. Liu Y, Waites C, Krantz D, Tan P, Edwards RH (1996) Molecular analysis of neurotransmitter transport into secretory vesicles. Cold Spring Harb Symp Quant Biol 61:747–758

  119. Lossi L, Bottarelli L, Candusso ME, Leiter AB, Rindi G, Merighi A (2004) Transient expression of secretin in serotoninergic neurons of mouse brain during development. Eur J Neurosci 20:3259–3269

  120. Ludwig M, Leng G (2006) Dendritic peptide release and peptide-dependent behaviours. Nat Rev Neurosci 7:126–136

  121. Lundberg JM (1996) Pharmacology of cotransmission in the autonomic nervous system: integrative aspects on amines, neuropeptides, adenosine triphosphate, amino acids and nitric oxide. Pharmacol Rev 48:113–178

  122. Ma W, Bisby MA (1998) Increase of preprotachykinin mRNA and substance P immunoreactivity in spared dorsal root ganglion neurons following partial sciatic nerve injury. Eur J Neurosci 10:2388–2399

  123. Maggi CA, Santicioli P, Geppetti P, Patacchini R, Frilli S, Astolfi M, Fusco B, Meli A (1988) Simultaneous release of substance P- and calcitonin gene-related peptide (CGRP)-like immunoreactivity from isolated muscle of the guinea pig urinary bladder. Neurosci Lett 87:163–167

  124. Malcangio M, Bowery NG (1999) Peptide autoreceptors: does an autoreceptor for substance P exist? Trends Pharmacol Sci 20:405–407

  125. Mantyh PW, Allen CJ, Ghilardi JR, Rogers SD, Mantyh CR, Liu H, Basbaum AI, Vigna SR, Maggio JE (1995) Rapid endocytosis of a G protein-coupled receptor: substance P-evoked internalization of its receptor in the rat striatum in vivo. Proc Natl Acad Sci USA 92:2622–2626

  126. Marco N, Thirion A, Mons G, Bougault I, Le FG, Soubrie P, Steinberg R (1998) Activation of dopaminergic and cholinergic neurotransmission by tachykinin NK3 receptor stimulation: an in vivo microdialysis approach in guinea pig. Neuropeptides 32:481–488

  127. Marson L (1989) Evidence for colocalization of substance P and 5-hydroxytryptamine in spinally projecting neurons from the cat medulla oblongata. Neurosci Lett 96:54–59

  128. Martinez-Rodriguez R, Martinez-Murillo R (1994) Molecular and cellular aspects of neurotransmission and neuromodulation. Int Rev Cytol 149:217–292

  129. Martire M, Pistritto G (1992) Neuropeptide Y interaction with the adrenergic transmission line: a study of its effect on alpha-2 adrenergic receptors. Pharmacol Res 25:203–215

  130. Maubert E, Slama A, Ciofi P, Viollet C, Tramu G, Dupouy JP, Epelbaum J (1994) Developmental patterns of somatostatin-receptors and somatostatin-immunoreactivity during early neurogenesis in the rat. Neuroscience 62:317–325

  131. Mcdonald AJ, Pearson JC (1989) Coexistence of GABA and peptide immunoreactivity in non-pyramidal neurons of the basolateral amygdala. Neurosci Lett 100:53–58

  132. Meister B, Hökfelt T (1988) Peptide- and transmitter-containing neurons in the mediobasal hypothalamus and their relation to GABAergic systems: possible roles in control of prolactin and growth hormone secretion. Synapse 2:585–605

  133. Melander T, Hökfelt T, Rokaeus A (1986) Distribution of galanin like immunoreactivity in the rat central nervous system. J Comp Neurol 248:475–517

  134. Mens WB, Witter A, Wimersma Greidanus TB (1983) Penetration of neurohypophyseal hormones from plasma into cerebrospinal fluid (CSF): half-times of disappearance of these neuropeptides from CSF. Brain Res 262:143–149

  135. Merighi A (2002) Costorage and coexistence of neuropeptides in the mammalian CNS. Prog Neurobiol 66:161–190

  136. Merighi A, Polak JM, Gibson SJ, Gulbenkian S, Valentino KL, Peirone SM (1988) Ultrastructural studies on calcitonin gene-related peptide-, tachykinins- and somatostatin-immunoreactive neurones in rat dorsal root ganglia: evidence for the colocalisation of different peptides in single secretory granules. Cell Tissue Res 254:101–109

  137. Merighi A, Polak JM, Fumagalli G, Theodosis DT (1989) Ultrastructural localisation of neuropeptides and GABA in the rat dorsal horn: a comparison of different immunogold labelling techniques. J Histochem Cytochem 37:529–540

  138. Merighi A, Polak JM, Theodosis DT (1991) Ultrastructural visualization of glutamate and aspartate immunoreactivities in the rat dorsal horn with special reference to the co-localization of glutamate, substance P and calcitonin gene-related peptide. Neuroscience 40:67–80

  139. Merighi A, Cruz F, Coimbra A (1992) Immunocytochemical staining of neuropeptides in terminal arborization of primary afferent fibers anterogradely labeled and identified at light and electron microscopic levels. J Neurosci Meth 42:105–113

  140. Mezey E, Kiss JZ (1991) Coexpression of vasopressin and oxytocin in hypothalamic supraoptic neurons of lactating rats. Endocrinology 129:1814–1820

  141. Mijnster MJ, Raimundo AG, Koskuba K, Klop H, Docter GJ, Groenewegen HJ, Voorn P (1997) Regional and cellular distribution of serotonin 5-hydroxytryptamine2a receptor mRNA in the nucleus accumbens, olfactory tubercle, and caudate putamen of the rat. J Comp Neurol 389:1–11

  142. Miller MA, Kolb PE, Planas B, Raskind MA (1998) Few cholinergic neurons in the rat basal forebrain coexpress galanin messenger RNA. J Comp Neurol 391:248–258

  143. Millhorn DE, Hökfelt T, Verhofstad AA, Terenius L (1989) Individual cells in the raphe nuclei of the medulla oblongata in rat that contain immunoreactivities for both serotonin and enkephalin project to the spinal cord. Exp Brain Res 75:536–542

  144. Mondal MS, Nakazato M, Matsukura S (2000) Orexins (hypocretins): novel hypothalamic peptides with divergent functions. Biochem Cell Biol 78:299–305

  145. Monks DA, Vanston CM, Watson NV (1999) Direct androgenic regulation of calcitonin gene-related peptide expression in motoneurons of rats with mosaic androgen insensitivity. J Neurosci 19:5597–5601

  146. Mutt V (1979) Some contributions to the chemistry of the gastrointestinal hormones. Fed Proc 38:2309–2314

  147. Mutt V (1980a) Chemistry, isolation and purification of gastrointestinal hormones. Biochem Soc Trans 8:11–14

  148. Mutt V (1980b) Cholecystokinin: isolation, structure and functions. In: Glass GBJ (ed) Gastrointestinal hormones. Raven, New York, pp 85–126

  149. Nicoll RA, Malenka RC (1999) Leaky synapses. Neuron 23:197–198

  150. Nicoll RA, Schenker C, Leeman SE (1980) Substance P as a transmitter candidate. Annu Rev Neurosci 3:227–268

  151. Nitsch R, Leranth C (1994) Substance P-containing hypothalamic afferents to the monkey hippocampus: an immunocytochemical, tracing, and coexistence study. Exp Brain Res 101:231–240

  152. Nusbaum MP, Blitz DM, Swensen AM, Wood D, Marder E (2001) The roles of co-transmission in neural network modulation. Trends Neurosci 24:146–154

  153. Ohno K, Takeda N, Yamano M, Matsunaga T, Tohyama M (1991) Coexistence of acetylcholine and calcitonin gene-related peptide in the vestibular efferent neurons in the rat. Brain Res 566:103–107

  154. Okuda-Ashitaka E, Ito S (2000) Nocistatin: a novel neuropeptide encoded by the gene for the nociceptin/orphanin FQ precursor. Peptides 21:1101–1109

  155. Pelletier G, Steinbusch HWM, Verhofstad AAJ (1981) Immunoreactive substance P and serotonin present in the same dense-core vesicles. Nature 293:71–72

  156. Penny GR, Afsharpour S, Kitai ST (1986) The glutamate decarboxylase-, leucine enkephalin-, methionine enkephalin- and substance P-immunoreactive neurons in the neostriatum of the rat and cat: evidence for partial population overlap. Neuroscience 17:1011–1045

  157. Peters A, Palay SL, Webster H deF (1976) The fine structure of the nervous system. Saunders, Philadelphia

  158. Polak JM, Bloom SR (1984) Regulatory peptides—the distribution of two newly discovered peptides: PHI and NPY. Peptides 5:79–89

  159. Pow DV, Morris JF (1989) Dendrites of hypothalamic magnocellular neurons release neurohypophysial peptides by exocytosis. Neuroscience 32:435–439

  160. Rahman MA, Ashton AC, Meunier FA, Davletov BA, Dolly JO, Ushkaryov YA (1999) Norepinephrine exocytosis stimulated by alpha-latrotoxin requires both external and stored Ca2+ and is mediated by latrophilin, G proteins and phospholipase C. Philos Trans R Soc Lond Biol 354:379–386

  161. Reimer RJ, Fon EA, Edwards RH (1998) Vesicular neurotransmitter transport and the presynaptic regulation of quantal size. Curr Opin Neurobiol 8:405–412

  162. Renda T, D’Este L, Fasolo A, Lazarus LH, Erspamer V (1989) Brain-gut-skin peptides: an update overview. Arch Histol Cytol 52S:317–323

  163. Ribeiro-Da-Silva A (1995) Ultrastructural features of the colocalization of calcitonin gene related peptide with substance P or somatostatin in the dorsal horn of the spinal cord. Can J Physiol Pharmacol 73:940–944

  164. Ribeiro-Da-Silva A, Hökfelt T (2000) Neuroanatomical localisation of substance P in the CNS and sensory neurons. Neuropeptides 34:256–271

  165. Rokaeus A (1987) Galanin: a newly isolated biologically active neuropeptide. Trends Neurosci 10:158–164

  166. Rossier J, Liston D, Patey G, Chaminade M, Foutz AS, Cupo A, Giraud P, Roisin MP, Henry JP, Verbanck P (1983) The enkephalinergic neuron: implications of a polyenkephalin precursor. Cold Spring Harb Symp Quant Biol 48:393–404

  167. Rowan S, Todd AJ, Spike RC (1993) Evidence that neuropeptide Y is present in GABAergic neurons in the superficial dorsal horn of the rat spinal cord. Neuroscience 53:537–545

  168. Safieddine S, Prior AM, Eybalin M (1997) Choline acetyltransferase, glutamate decarboxylase, tyrosine hydroxylase, calcitonin gene-related peptide and opioid peptides coexist in lateral efferent neurons of rat and guinea-pig. Eur J Neurosci 9:356–367

  169. Salio C, Lossi L, Ferrini F, Merighi A (2005) Ultrastructural evidence for a pre- and post-synaptic localization of full length trkB receptors in substantia gelatinosa (lamina II) of rat and mouse spinal cord. Eur J Neurosci 22:1951–1966

  170. Saria A, Gamse R, Petermann JB, Fischer JA, Theodorsson-Norheim E, Lundberg JM (1986) Simultaneous release of several tachykinins and calcitonin gene-related peptide from rat spinal cord slices. Neurosci Lett 63:310–314

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

  172. Schwartz JP, Epelbaum J (1998) Somatostatin as a neurotrophic factor. Which receptor/second messenger transduction system is involved? Prespect Dev Neurobiol 5:427–435

  173. Simmons DR, Spike RC, Todd AJ (1995) Galanin is contained in GABAergic neurons in the rat spinal dorsal horn. Neurosci Lett 187:119–122

  174. Skofitsch G, Jacobowitz DM (1985) Immunohistochemical mapping of galanin-like neurons in the rat central nervous system. Peptides 6:509–546

  175. Snider RM, Constantine JW, Lowe JA, III, Longo KP, Lebel WS, Woody HA, Dorzda SF, Desai MC, Vinik FJ, Spencer RW, Hess HJ (1991) A potent non peptide antagonist of the SP (NK-1) receptor. Science 251:435–437

  176. Sossin WS, Scheller RH (1991) Biosynthesis and sorting of neuropeptides. Curr Opin Neurobiol 1:79–83

  177. Sossin WS, Sweet-Cordero A, Scheller RH (1990) Dale’s hypothesis revisited: different neuropeptides derived from a common prohormone are targeted to different processes. Proc Natl Acad Sci USA 87:4845–4848

  178. Takano M, Takano Y, Yaksh TL (1993) Release of calcitonin gene-related peptide (CGRP), substance P (SP), and vasoactive intestinal polypeptide (VIP) from rat spinal cord: modulation by α2 agonists. Peptides 14:371–378

  179. Tanaka K, Masu M, Nakanishi S (1990) Structure and functional expression of the cloned rat neurotensin receptor. Neuron 4:847–854

  180. Tatemoto K, Carlquist M, Mutt V (1982) Neuropeptide Y—a novel brain peptide with structural similarities to peptide YY and pancreatic polypeptide. Nature 296:659–660

  181. Theodosis DT, Montagnese C, Rodriguez F, Vincent JD, Poulain DA (1986) Oxytocin induces morphological plasticity in the adult hypothalamo-neurohypophysial system. Nature 322:738–740

  182. Thor KB, Helke CJ (1989) Serotonin and substance P colocalization in medullary projections to the nucleus tractus solitarius: dual-colour immunohistochemistry combined with retrograde tracing. J Chem Neuroanat 2:139–148

  183. Thureson-Klein ÅK, Klein RL, Zhu PC, Kong J-Y (1988) Differential release of transmitters and neuropeptides co-stored in central and peripheral neurons. In: Zimmermann H (ed) Cellular and molecular basis of synaptic transmission. Springer, Berlin Heidelberg New York, pp 171–183

  184. Tsuboi T, Rutter GA (2003) Insulin secretion by “kiss-and-run” exocytosis in clonal pancreatic islet beta-cells. Biochem Soc Trans 31:833–836

  185. Vallet PG, Charnay Y, Boura C, Kiss JZ (1991) Colocalization of delta sleep inducing peptide and luteinizing hormone releasing hormone in neurosecretory vesicles in rat median eminence. Neuroendocrinology 53:103–106

  186. Vanner S (1994) Corelease of neuropeptides from capsaicin-sensitive afferents dilates submucosal arterioles in guinea pig ileum. Am J Physiol 267:G650–G655

  187. Verge VM, Richardson PM, Wiesenfeld-Hallin Z, Hökfelt T (1995) Differential influence of nerve growth factor on neuropeptide expression in vivo: a novel role in peptide suppression in adult sensory neurons. J Neurosci 15:2081–2096

  188. Verhage M, McMahon HT, Ghijsen WE, Boomsma F, Scholten G, Wiegant VM, Nicholls DG (1991) Differential release of amino acids, neuropeptides, and catecholamines from isolated nerve terminals. Neuron 6:517–524

  189. Wang R, Shoenfeld R (1987) Cholecystokinin antagonists. Liss, New York

  190. Wang TC, Dockray GJ (1999) Lessons from genetically engineered animal models. I. Physiological studies with gastrin in transgenic mice. Am J Physiol 277:G6–G11

  191. Ward RP, Dorsa DM (1996) Colocalization of serotonin receptor subtypes 5-HT2A, 5-HT2C, and 5-HT6 with neuropeptides in rat striatum. J Comp Neurol 370:405–414

  192. Whitnall MH (1993) Regulation of the hypothalamic corticotropin-releasing hormone neurosecretory system. Prog Neurobiol 40:573–629

  193. Whitnall MH, Gainer H, Cox BM, Molineaux CJ (1983) Dynorphin-A-(1–8) is contained within vasopressin neurosecretory vesicles in rat pituitary. Science 222:1137–1139

  194. Whitnall MH, Key S, Ben-Barak Y, Ozato K, Gainer H (1985a) Neurophysin in the hypothalamo-neurohypophysial system. II. Immunocytochemical studies of the ontogeny of oxytocinergic and vasopressinergic neurons. J Neurosci 5:98–109

  195. Whitnall MH, Mezey E, Gainer H (1985b) Co-localization of corticotropin-releasing factor and vasopressin in median eminence neurosecretory vesicles. Nature 317:248–250

  196. Woolf CJ, Mannion RJ, Neuman S (1998) Null mutations lacking substance: elucidating pain mechanisms by genetic pharmacology. Neuron 20:1063–1066

  197. Wouterlood FG, Pothuizen H (2000) Sparse colocalization of somatostatin- and GABA-immunoreactivity in the entorhinal cortex of the rat. Hippocampus 10:77–86

  198. Wynick D, Small CJ, Bloom SR, Pachnis V (1998) Targeted disruption of the murine galanin gene. Ann N Y Acad Sci 863:22–47

  199. Xu ZQ, Hökfelt T (1997) Expression of galanin and nitric oxide synthase in subpopulations of serotonin neurons of the rat dorsal raphe nucleus. J Chem Neuroanat 13:169–187

  200. Yaksh TL (1999) Spinal systems and pain processing: development of novel analgesic drugs with mechanistically defined models. Trends Physiol Sci 20:329–337

  201. Yamashita A, Shimizu K, Hayashi M (1990) Ontogeny of substance P-immunoreactive structures in the primate cerebral neocortex. Brain Res Dev Brain Res 57:197–207

  202. Yan XX, Toth Z, Schultz L, Ribak CE, Baram TZ (1998) Corticotropin-releasing hormone (CRH)-containing neurons in the immature rat hippocampal formation: light and electron microscopic features and colocalization with glutamate decarboxylase and parvalbumin. Hippocampus 8:231–243

  203. Yang L, Thomas ND, Helke CJ (1996) Characterization of substance P release from the intermediate area of rat thoracic spinal cord. Synapse 23:265–273

  204. Yang Y, Ozawa H, Yuri K, Kawata M (2000) Postnatal development of NADPH-diaphorase activity in the rat: the role of nitric oxide in the ontogeny of arginine vasopressin and oxytocin. Endocr J 47:601–613

  205. Yew DT, Chan WY (1999) Early appearance of acetylcholinergic, serotoninergic, and peptidergic neurons and fibers in the developing human central nervous system. Microsc Res Tech 45:389–400

  206. Yokota Y, Sasai Y, Tanaka K, Fujiwara T, Tsuchida K, Shigemoto R, Kakizuka A, Ohkubo H, Nakanishi S (1989) Molecular characterization of a functional cDNA for rat substance P receptor. J Biol Chem 264:17649–17652

  207. Zahm DS, Zaborszky L, Alones VE, Heimer L (1985) Evidence for the coexistence of glutamate decarboxylase and Met-enkephalin immunoreactivities in axon terminals of rat ventral pallidum. Brain Res 325:317–321

  208. Zee EA van der, Benoit R, Strosberg AD, Luiten PG (1991) Coexistence of muscarinic acetylcholine receptors and somatostatin in nonpyramidal neurons of the rat dorsal hippocampus. Brain Res Bull 26:343–351

  209. Zhang X, Nicholas AP, Hökfelt T (1993) Ultrastructural studies on peptides in the dorsal horn of the spinal cord. I. Co-existence of galanin with other peptides in primary afferents in normal rats. Neuroscience 57:365–384

  210. Zhu PC, Thureson-Klein ÅK, Klein RL (1986) Exocytosis from large dense cored vesicles outside the active synaptic zones of terminals within the trigeminal subnucleus caudalis: a possible mechanism for neuropeptide release. Neuroscience 19:43–54

  211. Zimmer A, Zimmer AM, Baffi J, Usdin T, Reynolds K, Konig M, Palkovits M, Mezey E (1998) Hypoalgesia in mice with a targeted deletion of the tachykinin 1 gene. Proc Natl Acad Sci USA 95:2630–2635

  212. Zoli M, Agnati LF, Jansson A, Fuxe K, Syková E (1999) Volume transmission in the CNS and its relevance for neurophyschopharmacology. Trends Physiol Sci 20:142–150

  213. Zsarnovszky A, Horvath TL, Naftolin F, Leranth C (2000) AMPA receptors colocalize with neuropeptide-Y- and galanin-containing, but not with dopamine neurons of the female rat arcuate nucleus: a semiquantitative immunohistochemical colocalization study. Exp Brain Res 133:532–537

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Correspondence to Adalberto Merighi.

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The original work described here was supported by local grants from the University of Torino, Regione Piemonte and Compagnia di San Paolo.

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Salio, C., Lossi, L., Ferrini, F. et al. Neuropeptides as synaptic transmitters. Cell Tissue Res 326, 583–598 (2006).

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  • Neurotransmission
  • Synapses
  • Neuropeptides
  • Large granular vesicles
  • Ultrastructure
  • Colocalization