Digestive Diseases and Sciences

, Volume 47, Issue 10, pp 2336–2348 | Cite as

REVIEW: Gastrointestinal Melatonin: Localization, Function, and Clinical Relevance

  • George A. Bubenik


The gastrointestinal tract of vertebrate species is a rich source of extrapineal melatonin. The concentration of melatonin in the gastrointestinal tissues surpasses blood levels by 10–100 times and there is at least 400× more melatonin in the gastrointestinal tract than in the pineal gland. The gastrointestinal tract contributes significantly to circulating concentrations of melatonin, especially during the daytime and melatonin may serve as an endocrine, paracrine, or autocrine hormone influencing the regeneration and function of epithelium, enhancing the immune system of the gut, and reducing the tone of gastrointestinal muscles. As binding sites for melatonin exhibit circadian variation in various species, it has been hypothesized that some melatonin found in the gastrointestinal tract might be of pineal origin. Unlike the photoperiodically regulated production of melatonin in the pineal, the release of gastrointestinal melatonin seems to be related to the periodicity of food intake. Phylogenetically, melatonin and its binding sites were detected in the gastrointestinal tract of lower vertebrates, birds, and mammals. Melatonin was found also in large quantities in the embryonic tissue of the mammalian and avian gastrointestinal tract. Food intake and, paradoxically, also long-term food deprivation resulted in an increase of tissue and plasma concentrations of melatonin. Melatonin release may have a direct effect on many gastrointestinal tissues but may also well influence the digestive tract indirectly, via the central nervous system and the sympathetic and parasympathetic nerves. Melatonin prevents ulcerations of gastrointestinal mucosa by an antioxidant action, reduction of secretion of hydrochloric acid, stimulation of the immune system, fostering epithelial regeneration, and increasing microcirculation. Because of its unique properties, melatonin could be considered for prevention or treatment of colorectal cancer, ulcerative colitis, gastric ulcers, irritable bowel syndrome, and childhood colic.

melatonin gastrointestinal tract physiology binding sites periodicity ontogeny phylogeny digestion food intake clinical relevance 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Reiter RJ: Pineal melatonin: cell biology of its synthesis and its physiological interactions. Endocrinol Rev 12:151–180, 1991Google Scholar
  2. 2.
    Lerner AB, Case JD, Lee TH, Mori W: Isolation of melatonin, the pineal factor that lightens melanocytes. J Am Chem Soc 80:2587, 1958Google Scholar
  3. 3.
    Reiter R: The melatonin rhythm: both a clock and a calendar. Experientia 49:654–664, 1993Google Scholar
  4. 4.
    Zhdanova IV, Wurtman RJ, Lynch HJ, Yves JR, Dollins AB, Morabito C, Matheson JK, Schomer DL: Sleep-inducing effect of low doses of melatonin ingested in the evening. Clin Pharmacol Ther 57:552–558, 1995Google Scholar
  5. 5.
    Poeggeler B, Reiter RJ, Tan D-X, Chen L-D, Manchester LC: Melatonin, hydroxyl-radical-mediated oxidative damage, and aging: a hypothesis. J Pineal Res 14:151–168, 1993Google Scholar
  6. 6.
    Pieri C, Marra M, Moroni F, Recchioni R, Marcheselli F: Melatonin: A peroxyl radical scavenger more effective than vitamin E. Life Sci 15:271–276, 1994Google Scholar
  7. 7.
    Reiter RJ: Melatonin: Lowering the high price of free radicals. News Physiol Sci 15:246–250, 2000Google Scholar
  8. 8.
    Reiter R, Tan D, Manchester L, Qi W: Biochemical reactivity of melatonin with reactive oxygen and nitrogen species. Cell Biochem Biophys 34:237–256, 2001Google Scholar
  9. 9.
    Reiter R, Tan D-X, Cabrera J, D'Arpa D, Sainz R, Mayo J, Ramon S: The oxidant/antioxidant network: role of melatonin. Biol Signal Recept 8:56–63, 1999Google Scholar
  10. 10.
    Reppert SM, Klein DC: Transport of maternal [3H]melatonin to suckling rats and the fate of [3H]melatonin in the neonatal rats. Endocrinology 102:582–588, 1978Google Scholar
  11. 11.
    Bubenik GA, Brown GM, Uhlir I, Grota LJ: Immunohistological localization of N-acetylindolealkylamines in the pineal gland, retina and cerebellum. Brain Res 81:233–242, 1974Google Scholar
  12. 12.
    Bubenik GA, Brown GM, Grota LJ: Differential localization of N-acetylated indolealkylamines in CNS and the Harderian gland using immunohistology. Brain Res 118:417–427, 1976Google Scholar
  13. 13.
    Bubenik GA, Purtill RA, Brown GM, Grota LJ: Melatonin in the retina and the Harderian gland. Ontogeny, diurnal variations and melatonin treatment. Exp Eye Res 27:323–333, 1978Google Scholar
  14. 14.
    Bubenik GA, Brown GM, Grota LJ: Immunohistological localization of melatonin in the rat digestive tract. Experientia 33:662–663, 1977Google Scholar
  15. 15.
    Bubenik GA: Immunohistological localization of melatonin in the salivary glands of the rat. Adv Biosci 29:95–112, 1980Google Scholar
  16. 16.
    Bubenik GA: Localization of melatonin in the digestive tract of the rat. Effect of maturation, diurnal variation, melatonin treatment and pinealectomy. Hormone Res 12:313–323, 1980Google Scholar
  17. 17.
    Raikhlin NT, Kvetnoy IM: Lightening effect of the extract of human appendix mucosa on frog skin melanophores. Bull Exp Biol Med 8:114–116, 1974 (in Russian)Google Scholar
  18. 18.
    Raikhlin NT, Kvetnoy IM: Melatonin and enterochromaffine cells. Acta Histochem 55:19–25, 1976Google Scholar
  19. 19.
    Holloway WR, Grota LJ, Brown GM: Determination of immunoreactive melatonin in the colon of rat by immunocytochemistry. J Histochem Cytochem 28:255–262, 1980Google Scholar
  20. 20.
    Reiter RJ, Richardson BA, Hurlbut EC: Pineal, retinal and Harderian gland melatonin in a diurnal species, the Richardson's ground squirrel (Spermophilus richardsonii). Neurosci Lett 22:285–288, 1981Google Scholar
  21. 21.
    Bubenik GA, Brown GM: Pinealectomy reduces melatonin levels in the serum but not in the gastrointestinal tract of the rat. Biol Signals 6:40–44, 1997Google Scholar
  22. 22.
    Kvetnoy IM, Raikhlin NT, Tolkachev VN: Chromatographical detection of melatonin (5-methoxy-N-acetylserotonin) and its biological precursors in enterochromaffine cells. Dokl Acad Nauk SSSR 221:226–227, 1975 (in Russian)Google Scholar
  23. 23.
    Rakhlin NT, Kvetnoy IM, Tolkachev VN: Melatonin may be synthesized in enterochromafinne cells. Nature 255:344–345, 1975Google Scholar
  24. 24.
    Lee PP, Hong GX, Pang SF: Melatonin in the gastrointestinal tract. In Role of Melatonin and Pineal Peptides in Neuroimmunomodulation. F Fraschini, RJ Reiter (eds). New York, Plenum Press, 1991, pp 127–136Google Scholar
  25. 25.
    Chow PH, Lee PPN, Poon AMS, Shiu SYW, Pang SF: The gastrointestinal system: A site of melatonin paracrine action. 21:123–132, 1996Google Scholar
  26. 26.
    Martin MT, Azpiroz F, Malagelada JR: Melatonin and the gastrointestinal system. Therapie 53:453–458, 1998Google Scholar
  27. 27.
    Bubenik GA, Ayles HL, Ball RO, Friendship RM, Brown GM: Relationship between melatonin levels in plasma and gastrointestinal tissues and the incidence and severity of gastric ulcers in pigs. J Pineal Res 24:62–66, 1998Google Scholar
  28. 28.
    Bubenik GA: Localization and physiological significance of gastrointestinal melatonin. In Melatonin in Health Promotion. R Watson (ed). Boca Raton, Florida, CRC press, 1999, pp 21–39Google Scholar
  29. 29.
    Bubenik GA: Localization, physiological significance and possible clinical implication of gastrointestinal melatonin. Biol Signals Recept 10:350–366, 2001Google Scholar
  30. 30.
    Kachi T, Kurushima M: Pineal-digestive organ relations: Physiological and pathophysiological significance of melatonin in the digestive system. Hirosaki Med J 51:93–108, 2000Google Scholar
  31. 31.
    Motilva V, Cabeza C, Alarcon de la Lastra C: New issues about melatonin and its effects on the digestive system. Curr Pharm Design 7:909–933, 2001Google Scholar
  32. 32.
    Raikhlin NT, Kvetnoy IM, Kadagidze ZG, Sokolov AV: Immunomorphological studies on synthesis of melatonin in enterochromaffine cells. Acta Histochem Cytochem 11:75–77, 1978Google Scholar
  33. 33.
    Hong GX, Pang SF: N-acetyltransferase activity in the quail (Coturnix coturnix jap) duodenum. Com Biochem Physiol 112B:251–255, 1995Google Scholar
  34. 34.
    Quay WB, Ma YH: Demonstration of gastrointestinal hydroxyindole-O-methyl transferase. IRCS Med Sci 4:563, 1976Google Scholar
  35. 35.
    Vakkuri O, Rintamaki H, Leppaluoto J: Presence of immunoreactive melatonin in different tissues of the pigeon. Gen Comp Endocrinol 58:69–75, 1985Google Scholar
  36. 36.
    Vakkuri O, Rintamaki H, Leppaluoto J: Plasma and tissue concentrations of melatonin after midnight light exposure and pinealectomy in the pigeon. J Endocrinol 105:263–268, 1985Google Scholar
  37. 37.
    Huether G, Poegeller B, Reimer R, George A: Effect of tryptophan administration on circulating melatonin levels in chicks and rats: evidence for stimulation of melatonin synthesis and release in the gastrointestinal tract. Life Sci 51:945–953, 1992Google Scholar
  38. 38.
    Bubenik GA, Pang SF, Hacker RR, Smith PS: Melatonin concentrations in serum and tissues of porcine gastrointestinal tract and their relationship to the intake and passage of food. J Pineal Res 21:251–256, 1996Google Scholar
  39. 39.
    Huether G: Melatonin synthesis in the gastrointestinal tract and the impact of nutritional factors on circulating melatonin. Ann NY Acad Sci 719:146–158, 1994Google Scholar
  40. 40.
    Bubenik GA, Hacker RR, Brown GM, Bartos L: Melatonin concentrations in the luminal fluid, mucosa and muscularis of the bovine and porcine gastrointestinal tract. J Pineal Res 29:56–63, 1999Google Scholar
  41. 41.
    Vician M, Zeman M, Herichova I, Blazicek P, Matis P: Melatonin content in plasma and large intestine of patients with colorectal carcinoma before and after surgery. J Pineal Res 27:164–169, 1999Google Scholar
  42. 42.
    Tan D-X, Manchester LC, Reiter RJ, Qi W, Hanes M, Farley NJ: High physiological levels of melatonin in the bile of mammals. Life Sci 65:2523–2529, 1999Google Scholar
  43. 43.
    Huether G: The contribution of extrapineal sites of melatonin synthesis to circulating melatonin levels in higher vertebrates. Experientia 49:665–670, 1993Google Scholar
  44. 44.
    Bubenik GA, Pang SF: Melatonin levels in the gastrointestinal tissue of fish, amphibians and a reptile. Gen Comp Endocrinol 106:415–419, 1997Google Scholar
  45. 45.
    Bubenik GA, Niles LO, Pang SF, Pentney PJ: Diurnal variations and binding characteristics of melatonin in the mouse brain and gastrointestinal tissues. Comp Biochem Physiol 104A:377–380, 1993Google Scholar
  46. 46.
    Bubenik GA, Brown GM, Hacker RR, Bartos L: Melatonin concentration in the gastrointestinal tissues of bovine fetuses. Acta Vet Brno 69:177–182, 2000Google Scholar
  47. 47.
    Bubenik GA, Pang SF, Cockshut JR, Smith PS, Grovum LW, Friendship RM, Hacker RR: Circadian variation of portal, arterial and venous blood levels of melatonin in pigs and its relationship to food intake and sleep. J Pineal Res 28:9–15, 2000Google Scholar
  48. 48.
    Pontoire C, Bernard M, Silvain C, Collin J-P, Voissin P: Characterization of melatonin binding sites in chicken and human intestines. Eur J Pharmacol 247:111–118, 1993Google Scholar
  49. 49.
    Poon AMS, Mak ASY, Luk HT: Melatonin and 2[125I]iodomelatonin binding sites in the human colon. Endocrine Res 22:77–94, 1996Google Scholar
  50. 50.
    Poon AMS, Chow PH, Mak ASY, Pang SF: Autoradiographic localization of 2[125I]iodomelatonin binding sites in the gastrointestinal tract of mammals including humans and birds. J Pineal Res 23:5–14, 1997Google Scholar
  51. 51.
    Thomas L, Drew JE, Abramovich DR, Williams LM: The role of melatonin in the human fetus. Int J Mol Med 1:539–543, 1998Google Scholar
  52. 52.
    Williams LM, Hannah LT, Adam CL, Bourke DA: Melatonin receptors in red deer fetuses (Cervus elaphus). J Reprod Fertil 110:145–151, 1997Google Scholar
  53. 53.
    Bubenik GA, Pang SF: The role of serotonin and melatonin in the gastrointestinal physiology: ontogeny, regulation of food intake and mutual 5-HT, melatonin feedbacks. J Pineal Res 16:91–99, 1994Google Scholar
  54. 54.
    Illnerova H: The effect of light on the development of hydroxyindole-O-methyltransferase activity in the rat pineal gland. Acta Nerv Super Prague 14:130–131, 1972Google Scholar
  55. 55.
    Illnerova H: Melatonin rhythm in the human milk. J Clin Endocrinol Metab 77:838–841, 1993Google Scholar
  56. 56.
    Herichova I, Zeman M: Perinatal development of melatonin production in gastrointestinal tract of domestic chicken. In Investigations of Perinatal Development of Birds. H Toenhardt, R Lewin (eds). Berlin, Free University, 1996, pp 109–116Google Scholar
  57. 57.
    Cardinali DP, Rosner JM: Metabolism of serotonin by the rat retina in vitro. J Neurochem 18:1769–1770, 1971Google Scholar
  58. 58.
    Kopin IJ, Pare CMB, Axelrod J, Weissbach: The fate of melatonin in animals. J Biol Chem 236:3072–3075, 1961Google Scholar
  59. 59.
    DeBoer H: The influence of photoperiod and melatonin on hormone levels and operand light demand in the pig. PhD thesis. University of Guelph, Ontario, Canada, 1988Google Scholar
  60. 60.
    Huether G, Hajak G, Reimer A, Poeggeler B, Bloomer M, Rodenback A, Ruuther E: The metabolic fate of infused L-tryptophan in men: possible clinical implications of the accumulation of circulating tryptophan and tryptophan metabolites. Psychopharmacology 106:422–432, 1992Google Scholar
  61. 61.
    Herichova I, Zeman M: Rhythmic changes of melatonin in the circulation and tissues of broiler chickens. Vet Med Czech 44:263–267, 1999Google Scholar
  62. 62.
    Huether G, Messner M, Rodenback A, Hardeland R: Effects of continuous infusion on steady state plasma melatonin levels under near physiological conditions. J Pineal Res 24:146–151, 1998Google Scholar
  63. 63.
    Messner M, Hardeland R, Rodenbeck A, Huether G: Tissue retention and subcellular distribution of continuously infused melatonin in rats under near physiological conditions. J Pineal Res 25:251–259, 1998Google Scholar
  64. 64.
    Kennaway DJ, Firth RJ, Philipou G, Matthews CD, Seamark RF: A specific radioimmunoassay for melatonin in biological tissue and fluids and its validation by gas chromatographymass spectrometry. Endocrinology 101:119–127, 1977Google Scholar
  65. 65.
    Vaughan GM, Reiter RJ: Pineal dependence of the Syrian hamster's nocturnal serum melatonin surge. J Pineal Res 3:9–14, 1986Google Scholar
  66. 66.
    Yaga H, Reiter RJ, Richardson BA: Tryptophan loading increases day time serum melatonin in intact and pinealectomized rats. Life Sci 52:1231–1238, 1993Google Scholar
  67. 67.
    Kezuka H, Iigo I, Furukawa K, Aida, K, Hanyu I: Effects of photoperiod, pinealectomy and ophtalmectomy on circulating melatonin rhythms in the goldfish (Carassius auratus). Zool Sci 9:1147–1153, 1992Google Scholar
  68. 68.
    Pardridge WM, Mietus LJ: Transport of albumin-bound melatonin through the blood- brain barrier. J Neurochem 34:1761–1763, 1980Google Scholar
  69. 69.
    Steindl PE, Finn B, Bendok B, Rothke S, Zee PC, Blei AT: Disruption of the diurnal rhythm of plasma melatonin in cirrhosis. Ann Intern Med 123:274–277, 1995Google Scholar
  70. 70.
    Steindl PE, Ferenci P, Marktl W: Impaired hepatic catabolism of melatonin in cirrhosis. Ann Intern Med 127:494, 1997Google Scholar
  71. 71.
    Ozaki Y, Lynch HJ: Presence of melatonin in plasma and urine of pinealectomized rats. Endocrinology 99:641–644, 1976Google Scholar
  72. 72.
    Chik C, Ho AK, Brown GM: Effect of food restriction on 24-h serum and pineal melatonin content in male rats. Acta Endocrinol 115:507–513, 1987Google Scholar
  73. 73.
    Mattison JA, Roth GS, Ingram DK, Lane MA: Endocrine effects of dietary restriction and aging: the national institute of aging study. J Anti-Aging Med 4:215–223, 2001Google Scholar
  74. 74.
    Bubenik GA, Ball RO, Pang SF: The effect of food deprivation on brain and gastrointestinal tissue levels of tryptophan, serotonin, 5-hydroxyindoleacetic acid, and melatonin. J Pineal Res 12:7–16, 1992Google Scholar
  75. 75.
    Dubbels R, Reiter RJ, Klenke E, Goebel A, Schankenberg E, Ehlers C, Schiwara HW, Schoot W: Melatonin in edible plants identified by radioimmunoassay and by high performance liquid chromatography-mass spectrometry. J Pineal Res 18:28–31, 1995Google Scholar
  76. 76.
    Murch S, Simmons C, Saxena P: Melatonin in feverfew and other medicinal plants. Lancet 350:1958–1959, 1958Google Scholar
  77. 77.
    Murch S, Krishnaraj S, Saxena P: Tryptophan is a precursor for melatonin and serotonin biosynthesis in in vitro regenerated St. John's wort plants. Plants Cell Rep 19:698–704, 2000Google Scholar
  78. 78.
    Reiter R: Melatonin in plants. Nut Rev 59:286–290, 2001Google Scholar
  79. 79.
    Tassel DL Van, Roberts N, Lewy A, O'Neill SD: Melatonin in plant organs. J Pineal Res 31:8–16, 2001Google Scholar
  80. 80.
    Hattori A, Migitaka H, Iigo M, Itoh M, Yamamoto K, Ohtaneki-Kaneko R, Tara M, Suzuki T, Reiter RJ: Identification of melatonin in plants and its effect on plasma melatonin levels and binding to melatonin receptors in vertebrates. Biochem Mol Biol Ont 35:627–634, 1995Google Scholar
  81. 81.
    Hardeland R, Fuhrberg B: Ubiquitous melatonin–presence and effects in unicells, plants and animals. Trends Comp Biochem Physiol 2:25–45, 1996Google Scholar
  82. 82.
    Messner M, Huether G, Lorf T, Ramdori G, Schwoerrer H: Presence of melatonin in the human hepatobiliary tract. Life Sci 69:543–551, 2001Google Scholar
  83. 83.
    Lee PP, Pang SF: Melatonin and its receptors in the gastrointestinal tract. Biol Signals 2:181–193, 1993Google Scholar
  84. 84.
    Lee PPN, Shiu SYU, Chow PH, Pang SF: Regional and diurnal studies on melatonin binding sites in the duck gastrointestinal tract. Biol Signals 4:212–224, 1995Google Scholar
  85. 85.
    Bogoeva M, Mileva M, Aljakov M: Regional and diurnal variations of 3H-melatonin binding sites in mouse alimentary tract. C R Acad Bulgare Sci 47:107–109, 1994Google Scholar
  86. 86.
    Menendez-Pelaez A, Poeggeler B, Reiter RJ, Barlow-Walden L, Pablos MI, Tan D-X: Nuclear localization of melationin in the different mammalian tissues: Immunocytochemical and radioimmunoassay evidence. J Cell Biol 53:373–382, 1993Google Scholar
  87. 87.
    Lucchelli A, Santagostino-Barbone MG, Tonini M: Investigation into the contractile response of melatonin in the guineapig isolated proximal colon: the role of 5-HT4 and melatonin receptors. Br J Pharmacol 121:1775–1781, 1997Google Scholar
  88. 88.
    Dubocovich ML, Yun K, Al-Ghoul WM, Benloucif S, Masana MI: SelectiveM2 melatonin receptor antagonists block melantonin-mediated phase advances of circadian rhythms. FASEB J 12:1211–1220, 1998Google Scholar
  89. 89.
    Barajas-Lopez C, Peres AL, Espinosa-Luna R, Reyes-Vazquez C, Prieto-Gomez B: Melatonin modulates cholinergic transmission by blocking nicotinic channels in the guinea-pig submucous plexus. Eur J Pharmacol 312:319–325, 1996Google Scholar
  90. 90.
    Benouali-Pellissier S: Melatonin is involved in cholecystokinin-induced changes of ileal motility in rats. J Pineal Res 17:79–85, 1994Google Scholar
  91. 91.
    Legris GJ, Will PC, Hopfer U: Inhibition of amiloridesensitive sodium conductance by indoleamines. Proc Natl Acad Sci USA 79:2040–2050, 1982Google Scholar
  92. 92.
    Chan H, Lui K, Wong W, Poon A: Effect of melatonin on chloride secretion by human colonic T84 cells. Life Sci 23:2151–2158, 1998Google Scholar
  93. 93.
    Quastel R, Rahamimoff R: Effect of melatonin on spontaneous contraction and response to 5-hydroxytryptramine of rat isolated duodenum. Br J Pharmacol 24:455–461, 1965Google Scholar
  94. 94.
    Fioretti MC, Menconi E, Ricardi C: Mechanism of the in vitro 5-hydroxytryptamine (5-HT) antagonism exerted by pineal indole derivatives. Riv Farmacol Ter 5:43–49, 1974Google Scholar
  95. 95.
    Fioretti MC, Menconi V, Ricardi C: Study on the type of antiserotonergic antagonism exerted in vitro on rat's stomach by pineal indole derivatives. Farmaco Ed Prat 29:401–412 (in Italian)Google Scholar
  96. 96.
    Bubenik GA: The effect of serotonin N-acetylserotonin, and melatonin on spontaneous contraction of isolated rat intestine. J Pineal Res 3:41–54, 1986Google Scholar
  97. 97.
    Harlow HJ, Weekly BL: Effect of melatonin on the force of spontaneous contractions of in vitro rat small and large intestines. J Pineal Res 3:277–284, 1986Google Scholar
  98. 98.
    Merle A, Delagrange Ph, Renard P, Lesieur D, Cuber JC, Roche M, Pellissier S: Effect of melatonin on motility pattern of small intestine in rats and its inhibition by melatonin receptor antagonist S 221152. J Pineal Res 29:116–124, 2000Google Scholar
  99. 99.
    Reyes-Vasquez C, Naranjo-Rodriguez EB, Garcia-Segoviano JA, Trujillo-Santana J, Prieto-Gomez B: Apamin blocks the direct relaxant effect of melatonin on rat ileal smooth muscles. J Pineal Res 22:1–8, 1997Google Scholar
  100. 100.
    Storr M, Schudziarra V, Allescher H-D: Inhibition of small conductance K+ channels attenuated melatonin-induced relaxation of serotonin-contracted rat gastric fundus. Can J Pharmacol Physiol 78:799–806, 2000Google Scholar
  101. 101.
    Bubenik GA, Dhanvantari S: Influence of serotonin and melatonin on some parameters of gastrointestinal activity. J Pineal Res 7:333–344, 1989Google Scholar
  102. 102.
    Bogoeva MV, Mileva MS, Tsanova KS, Gabev EE: Study on the circadian rhythm of duodenum mitotic activity after a single melatonin treatment of mice at the points of dark-light and light-dark transition. CR Acad Bulgare Sci 51:12–16, 1998Google Scholar
  103. 103.
    Bogoeva MV, Mileva MS, Gabev EE: Changes of the circadian rhythm of colonic mitotic activity after single melatonin application CR Acad Bulgare Sci 51:6–8, 1998Google Scholar
  104. 104.
    Bogoeva M, Mileva MS, Tsanova KS: Effect of exogenous melatonin on the twenty-four-hour mitotic activity of some normal mouse tissues. C R Acad Bulgare Sci 46:107–110, 1993Google Scholar
  105. 105.
    Bindoni M: Relationship between the pineal gland and the mitotic activity of some tissues. Arch Sci Biol 55:3–21, 1971Google Scholar
  106. 106.
    Callaghan BD: The effect of pinealectomy and autonomic denervation on crypt cell proliferation in the rat small intestine. J Pineal Res 10:180–185, 1991Google Scholar
  107. 107.
    Callaghan BD: The long-term effect of pinealectomy on the crypts of the rat gastrointestinal tract. J Pineal Res 18:191–196, 1995Google Scholar
  108. 108.
    Wajs E, Lewinski A: Melatonin and N-acetylserotonin–two pineal indoles inhibiting the proliferation of jejunal epithelial cells in rats. Med Sci Res 16:1125–1227, 1988Google Scholar
  109. 109.
    Lewinski A, Rybicka I, Wajs M, Szkundlinski M, Pawlikowski M: Influence of pineal indoleamines on the mitotic activity of gastric mucosa epithelial cells in the rat: Interaction with omeprazole. J Pineal Res 10:104–108, 1991Google Scholar
  110. 110.
    Pawlikowski M: The pineal gland and cell proliferation. Adv Pineal Res 1:27–30, 1986Google Scholar
  111. 111.
    Pentney P, Bubenik GA: Melatonin reduces the severity of dextran-induced colitis in mice. J Pineal Res 19:31–39, 1995Google Scholar
  112. 112.
    Zerek-Melen G, Lewinski A, Kulak J: The opposing effect of high and low doses of melatonin upon mitotic activity of the mouse intestinal epithelium. Endokrynol Pol 38:317–323, 1987Google Scholar
  113. 113.
    Kachi T, Suzuki T, Yanagisawa M, Kimura N, Irie T: Pinealgut relations. Hirosaki Med J 51(suppl):S209–S213, 1999Google Scholar
  114. 114.
    Huether G: Melatonin as an antiaging drug: Between facts and fantasy. Gerontology 42:87–96, 1996Google Scholar
  115. 115.
    Rice J, Mayor J, Tucker HA, Bielski RJ: Effect of light therapy on salivary melatonin in seasonal affective disorder. Psychiatry Res 56:221–226, 1995Google Scholar
  116. 116.
    Zafar NP, Morgan E: Feeding entrains an endogenous rhythm of swimming activity in the blind Mexican cave fish. Proceedings, 8th Meeting of European Society on Chronobiology 1992, pp. 165–166Google Scholar
  117. 117.
    Roky R, Kapas L, Taishi P, Fang J, Krueger JM: Food distribution alters the diurnal distribution of sleep in rats. Physiol Behav 67:697–703, 1999Google Scholar
  118. 118.
    Krieger DT, Hauser H, Krey LC: Suprachiasmatic nucleus lesions do not abolish food-shifted circadian rhythmicity and temperature rhythmicity. Science 197:398–402, 1977Google Scholar
  119. 119.
    Dollins A, Zhdanova I, Wurtman R, Lynch H, Deng M: Effect of inducing nocturnal serum melatonin concentrations in daytime on sleep, mood, body temperature, and performance. Proc Natl Acad Sci USA 91:1824–1828, 1995Google Scholar
  120. 120.
    Dawson D, Gibbon S, Singh P: The hypothermic effect of melatonin on core body temperature: is more better? J Pineal Res 20:192–197, 1996Google Scholar
  121. 121.
    Aizawa S, Tokura H, Morita T: The administration of exogenous melatonin during the day time lowers the thermoregulatory setpoint in humans. J Thermal Biol 27:115–119, 2002Google Scholar
  122. 122.
    Pierpaoli W, Dall’ Ara A, Pedrino E, Regelson W: The pineal control of aging. the effects of melatonin and pineal grafting on the survival of older mice. Ann NY Acad Sci 621:291–313, 1991Google Scholar
  123. 123.
    Trentini GP, De Gaetani AR, Criscuolo M: Pineal gland and aging. Aging 3:103–106, 1991Google Scholar
  124. 124.
    Anisimov VN, Bondarenko LA, Khavinson KM: Effect of pineal peptide preparation (epithalamin) on life span and pineal and serum melatonin levels in old rats. Ann NY Acad Sci 673:53–57, 1992Google Scholar
  125. 125.
    Kopin IJ, Pare CMB, Axelrod J, Weissbach: 6-Hydroxylation, the major metabolic pathway for melatonin. Biochem Biophys Acta 40:370–377, 1960Google Scholar
  126. 126.
    Zee PC, Mehta R, Turek FW, Blei AT: Portocaval anastomosis disrupts circadian locomotor activity and pineal melatonin rhythms in rats. Brain Res 560:17–22, 1991Google Scholar
  127. 127.
    Cordoba J, Cabrera J, Lataif L, Penev P, Zee P, Blei A: High prevalence of sleep disturbance in cirrhosis. Hepatology 27:339–345, 1998Google Scholar
  128. 128.
    Cho CH, Pang SF, Chen BW, Pfeiffer CJ: Modulating action of melatonin on serotonin-induced aggravation of ethanol ulceration and changes of mucosal blood flow in rat stomach. J Pineal Res 6:89–97, 1989Google Scholar
  129. 129.
    Khan R, Daya S, Potgieter B: Evidence for the modulation of the stress response by the pineal gland. Experientia 46:860–862, 1990Google Scholar
  130. 130.
    Otsuka M, Kato K, Murai I, Asai S, Iwasaki A, Arakawa Y: Roles of nocturnal melatonin and the pineal gland in modulation of water-immersion restraint stress-induced gastric mucosal lesions in rats. J Pineal Res 30:82–86, 2001Google Scholar
  131. 131.
    Melchiorri DE, Sewerynek E, Reiter RJ, Ortiz GG, Poegeller B, Nistico G: Suppressive effect of melatonin administration on ethanol-induced gastroduodenal injury in rats in vivo. Br J Pharmacol 121:264–270, 1997Google Scholar
  132. 132.
    Brzozowski T, Konturek PCh, Konturek SG, Pajdo R, Bielanski W, Brzozowska I, Stachura J, Hahn EG: The role of melatonin and L-tryptophan in prevention of acute gastric lesions induced by stress, ethanol, ischemia and aspirin. J Pineal Res 23:79–89, 1997Google Scholar
  133. 133.
    Alarcon De La Lastra CA, Cabeza J, Motilva V, Martin MJ: Melatonin protects against gastric ischemia-reperfusion injury in rats. J Pineal Res 23:47–52, 1997Google Scholar
  134. 134.
    Sener-Muratoglu G, Paskaloglu K, Arbak S, Hurdag C, Ayanoglu-Dulger G: Protective effect of famotidine, omeprazole, and melatonin against acetylsalicylic acid-induced gastric damage in rats. Dig Dis Sci 46:318–330, 2001Google Scholar
  135. 135.
    Ustundag B, Kazez A, Demirgab M, Canatan H, Halifeoglu I, Ozercan I: Protective effect of melatonin in experimental ischemia-reperfusion of rat small intestine. Cell Physiol Biochem 10:229–236, 2000Google Scholar
  136. 136.
    Kazez A, Demirbag M, Ustundag B, Ozercan H, Saglam M: The role of melatonin in the prevention of intestinal ischemiareperfusion injury in rats. J Pediatric Surg 35:1444–1448, 2000Google Scholar
  137. 137.
    Konturek PC, Konturek SJ, Brzozowski T, Dembinski A, Zembala M, Mytar B, Hahn EG: Gastroprotective activity of melatonin and its precursor, L-tryptophan, against stressinduced and ischemia-induced lesions is mediated by scavenge of oxygen radicals. Scand J Gastroenterol 32:433–438, 1997Google Scholar
  138. 138.
    Konturek PCh, Konturek SJ, Majka J, Zembala H, Hahn EG: Melatonin affords protection against gastric lesions induced ishemia-reperfusion possibly due to its antioxidant and mucosal microcirculatory effect. Eur J Pharmacol 122:73–77, 1997Google Scholar
  139. 139.
    Gruszka A, Kunert-Radek J, Pawlikowski M, Karasek M: Melatonin, Dehydroepiandrosterone and RZR/ROR-ligand CGP 52608 attenuate the stress-induced gastric lesion formation in rats. Neuroendocrinol Lett 18:221–229, 1997Google Scholar
  140. 140.
    Kato K, Murai I, Satoshi A, Matsuno Y, Komuro S, Kaneda N, Iwasaki A, Ishikawa Y, Kuwayama H: Protective role of melatonin and the pineal gland in modulating water immersion restraint stress ulcer in rats. J Clin Gastroenterol 27(suppl 1):S110–S115, 1998Google Scholar
  141. 141.
    Bandyopadhyay D, Biswas K, Bandyopadhyay U, Reiter RJ, Banerjee R: Melatonin protects against stress-induced lesions by scavenging the hydroxyl radical. J Pineal Res 29:143–151, 2000Google Scholar
  142. 142.
    Pertsov SS, Sosnowski AS, Progova GV: Melatonin and ulceration in rat stomach in acute emotional stress. Bull Exp Biol Med 125:7–9, 1998Google Scholar
  143. 143.
    Kato K, Asai S, Murai I, Nagata T, Takahashi Y, Komuro S, Iwasaki A, Ishikawa K, Arakawa Y: Melatonin's gastroprotective and antistress roles involve both central and peripheral effects. J Gastroenterol 36:91–95, 2001Google Scholar
  144. 144.
    Cabeza J, Motilva V, Alarcon de la Lastra CA: Mechanism involved in the gastric protection of melatonin on ischemiareperfusion-induced oxidative damage in rats. Life Sci 68:1405–1415, 2001Google Scholar
  145. 145.
    Akbulut H, Akbulut KG, Gonul B: Malodialdehyde and gluathione in rat gastric mucosa and effects of exogenous melatonin. Dig Dis Sci 42:1381–1388, 1997Google Scholar
  146. 146.
    Sjoblom M, Jedstedt G, Flemstrom G: Peripheral melatonin mediates neural stimulation of duodenal mucosal bicarbonate secretion. J Clin Invest 108:625–633, 2001Google Scholar
  147. 147.
    Malinovskaja N, Komarov F, Rapoport S, Voznesenskaya, Sharov A, Wetterberg L: Melatonin production in patients with duodenal ulcer. Neuroendocrinol Lett 22:109–117, 2001Google Scholar
  148. 148.
    Cuzzocrea S, Mazzon E, Serraino I, Lepore V, Terranova M, Ciccolo A, Caputi A: Melatonin reduces dinitrobenzene sulfonic acid-induced colitis. J Pineal Res 30:1–12, 2001Google Scholar
  149. 149.
    Maestroni GJM: The immunoneuroendocrine role of melatonin. J Pineal Res 4:1–10, 1991Google Scholar
  150. 150.
    Fraschini F, Demartini G, Esposti D, Scaglione F: Melatonin involvement in immunity and cancer. Biol Signals Recept 7:61–72, 1998Google Scholar
  151. 151.
    Yanagisawa M, Kachi T: Effects of the pineal hormone on Payer's patches in the small intestine. Acta Anat Nippon 69:522–527, 1994Google Scholar
  152. 152.
    Lissoni P, Bolis S, Brivio F, Fumagalli L: A phase II study of neuroimmunotherapy with subcutaneous low-dose IL-2 plus the pineal hormone melatonin in untreatable advanced hematologic malignancies. Anticancer Res 20:2103–2106, 2000Google Scholar
  153. 153.
    Pentney P: An investigation of melatonin in the gastrointestinal tract. Chap.4. In vitro inhibition of CaCo-2 human colorectal cancer cells by melatonin, melatonin analoques and benzodiazepines. M Sc thesis. University of Guelph, Guelph, Ontario, pp. 114–169Google Scholar
  154. 154.
    Farriol M, Venerco Y, Orta X, Castellanos J, Segovia-Silvestre T: In vitro effects of melatonin on cell proliferation in colon adenocarcinoma line. J Applied Toxicol 21:21–24, 2000Google Scholar
  155. 155.
    Wynczyk K, Pawlikowski M, Karasek M: Melatonin and RZR/ROR receptor ligand CGP 52608 induce apoptosis in the murine colonic cancer. J Pineal Res 31:179–182, 2000Google Scholar
  156. 156.
    Melen-Mucha G, Wynczyk K, Pawlikowski M: Somatostatin analogue octreotide and melatonin inhibit bromodeoxyuridine incorporation into cell nuclei and enhance apoptosis in the transplantable murine colon 38 cancer. Anticancer Res 18:3615–3620, 1998Google Scholar
  157. 157.
    Kvetnoy IM, Levin OM: Diurnal melatonin excretion in gastric and rectal cancer. Voprosi onkologii 33:29–32, 1987 (in Russian)Google Scholar
  158. 158.
    Cardinali D, Brusco L, Cutrera R, Esquifino A: Melatonin as a time-meaningful signal in organization of immuno response. Biol Signals Recept 8:41–48, 1999Google Scholar
  159. 159.
    Waldhauser F, Weiszenbacher G, Tatzer E, Gisinger B, Waldhauser M, Schemper M, Frisch H: Alternations in nocturnal serum melatonin levels in humans with growth and aging. J Clin Endocrinol Metab 66:648–652, 1988Google Scholar
  160. 160.
    Weissbluth L, Weissbluth M: Infant colic: the effect of serotonin and melatonin circadian rhythms on the intestinal smooth muscles. Med Hypoth 39:164–169, 1992Google Scholar
  161. 161.
    Weissbluth L, Weissbluth M: The photo-biochemical basis of infant colic: Pineal intracellular calcium concentrations controlled by light, melatonin and serotonin. Med Hypoth 40:158–164, 1993Google Scholar
  162. 162.
    Turek F: Melatonin hype hard to swallow. Nature 379:295–296, 1996Google Scholar
  163. 163.
    Arendt J: Safety of melatonin in long-term use(?): J Biol Rhythms 12:673–681, 1997Google Scholar
  164. 164.
    Laforce R, Rigozzi K, Paganetti M, Mossi W, Guainazzi P, Calderari G: Aspects of melatonin manufacturing and requirements for a reliable active component. Biol Signals Recept 8:143–146, 1999Google Scholar
  165. 165.
    Guardiola-Lamaitre B: Toxicology of melatonin. J Biol Rhythms 12:697–706, 1997Google Scholar
  166. 166.
    Nordlund JJ, Lerner AB: The effects of exogenous melatonin on endocrine function in man. Clin Endocrinol 24:375–382, 1986Google Scholar
  167. 167.
    Zhdanova I, Wurtman R, Regan R, Taylor M, Shi J, Leclair O: Melatonin treatment for age-related insomnia. J Clin Endocrinol Metab 86:4727–4730, 2001Google Scholar
  168. 168.
    Arendt J, Czeisler C, Dawson D, Dijk D-J, Haimor I, Lavie P, Lewy A, Parkes D, Skene D, Stone BM, Wirz-Justice, Zhdanova I: In what circumstances is melatonin a useful sleep therapy? Concensus statement, WFSRS focus group, Dresden, November 1999. J Sleep Res 9:397–398, 2000Google Scholar
  169. 169.
    Rose DA, Kahan T.L: Melatonin and sleep qualities in healthy adults: Pharmacological and expectancy effects. J Gen Psychol 128:401–421, 2001Google Scholar
  170. 170.
    Seabra M, Bignotto M, Pinto L, Tufik S: Randomized, double-blind clinical trial, controlled with placebo, of the toxicology of chronic melatonin treatment. J Pineal Res 29:193–200, 2000Google Scholar
  171. 171.
    Reiter R, Robinson J: Melatonin: Your body's natural wonder drug. New York, Bantam Books, 1995Google Scholar
  172. 172.
    Turek F: Melatonin: pathway from obscure molecule to international fame. Perspect Biol Med 41:8–20, 1997Google Scholar
  173. 173.
    Reiter R: Pineal gland: Interface between the photoperiodic environment and the endocrine system. Trends Endocrinol Metab 2:13–19, 1991Google Scholar
  174. 174.
    Brown GM, Ho AK, Chik CL: Effects of feeding on pineal indoleamines. Adv Pineal Res 2:67–80, 1987Google Scholar
  175. 175.
    Ho TK, Burns TG, Grota LJ, Brown GM: Scheduled feeding and 24-hour rhythms of N-acetylserotonin and melatonin in rats. Endocrinology 116:1858–1862, 1985Google Scholar

Copyright information

© Plenum Publishing Corporation 2002

Authors and Affiliations

  • George A. Bubenik
    • 1
  1. 1.Department of ZoologyUniversity of GuelphGuelphCanada

Personalised recommendations