Ghrelin is a 28-amino-acid peptide, with an essential n-octanoyl modification at Ser3, that elicits growth-hormone (GH) secretion in rats and humans. At present, the mechanisms of ghrelin action and its interactions with other systems controlling GH secretion remain poorly characterized. In this context, the present study was undertaken to obtain information about ontogeny and possible gender differences in the GH-releasing activity of ghrelin, and to delineate its primary site(s) of action at the hypothalamus and/or pituitary. In addition, the interactions between ghrelin and other relevant signals in the control of GH secretion, such as excitatory amino acids (EAAs), nitric oxide (NO) and serotonin, were assessed. Experiments were carried out in infantile-prepubertal animals, when GH pulsatility is not yet established. Systemic administration of ghrelin (25 nmol/rat, i.p.) to 5-, 10- and 23-day-old male and female rats increased plasma GH levels from day 10 onwards. This action was NO dependent, since it disappeared in 23-day-old males after pretreatment with an inhibitor of NO synthase (NAME). Similarly, central infusion of ghrelin (3 nmol/rat, i.c.v.) elicited GH responses in 10- and 23-day-old animals significantly higher than after systemic administration. By contrast, in vitro challenge of pituitary tissue with increasing doses of ghrelin (10–9–10–7M) failed to enhance GH release into the incubation medium, whereas stimulation with GH-releasing hormone (GHRH; 10–7M) or GHRP-6 (10–7M) was effective. Finally, effects of ghrelin were blocked by pretreatment with MK-801 and NBQX antagonists of EAA ionotropic receptors and after manipulation of endogenous serotoninergic tone. In addition, the potent releasing activity of EAA agonists NMDA and AMPA was blunted by pretreatment with D-Lys3-GHRP-6, a selective antagonist of the cognate ghrelin receptor, i.e. the GH-secretagogue receptor. In conclusion, our results demonstrate that GH-releasing activity of ghrelin appears early in the infantile period, is NO dependent and involves a primary hypothalamic site of action. The data also demonstrate for the first time the existence of a cross-talk between ghrelin and other neurotransmitter systems, such as EAAs and serotonin, in precise control of GH secretion.

Bertherat J, Bluet-Pajot MT, Epelbaum J: Neuroendocrine regulation of growth hormone. Eur J Endocrinol 1995;132:12–24.
Kojima M, Hosda H, Date Y, Nakazato M, Matsuo H, Kangawa K: Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999;402:656–660.
Kojima M, Hosoda H, Matsuo H, Kangawa K: Ghrelin: Discovery of the natural endogenous ligand for the growth hormone secretagogue receptor. Trends Endocrinol Metab 2001;12:118–122.
Seoane LM, Tovar S, Baldelli R, Arvat E, Ghigo F, Casanueva FF, Dieguez C: Ghrelin elicits a marked stimulatory effect on GH secretion in freely-moving rats. Eur J Endocrinol 2000;143:R7–R9.
Wren AM, Small CJ, Ward HL, Murphy KG, Dakin CL, Taheri S, Kennedy AR, Roberts GH, Morfgan DG, Ghatei MA, Bloom SR: The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. Endocrinology 2000;141:4325–4328.
Ahnfelt-Ronne I, Nowak J, Olsen UB: Do growth hormone-releasing peptides act as ghrelin secretagogues? Endocrine 2001;14:133–135.
Takaya K, Ariyasu H, Kanamoto N, Iwakura H, Yoshimoto A, Harada M, Mori K, Komatsu Y, Usui T, Shimatsu A, Ogawa Y, Hosoda K, Akamizu T, Kojima M, Kangawa K, Nakao K: Ghrelin strongly stimulates growth hormone release in humans. J Clin Endocrinol Metab 2001;86:1464–1469.
Hataya Y, Akamizu T, Takaya K, Kanamoto N, Ariyasu H, Saijo M, Moriyama K, Shimatsu A, Kojima M, Kangawa K, Nakao K: A low dose of ghrelin stimulates growth hormone (GH) release synergistically with GH-releasing hormone in humans. J Clin Endocrinol Metab 2001;86:4552.
Garcia A, Alvarez CV, Smith RG, Dieguez C: Regulation of pit-1 expression by ghrelin and GHRP-6 through the GH secretagogue receptor. Mol Endocrinol 2001;15:1484–1495.
Yamazaki M, Nakamura K, Kobayashi H, Matsubara M, Hayashi Y, Kangawa K, Sakai T: Regulational effect of ghrelin on growth hormone secretion from perifused rat anterior pituitary cells. J Neuroendocrinol 2002;14:156–162.
Wren AAM, Small CJ, Kennedy AR, Ghatei MA, Bloom SR: Investigation of the hypothalamic mechanism mediating pituitary hormone release by ghrelin. Fifth European Congress of Endocrinology, Turin 2001.
Tannenbaum GS, Bowers CY: Interactions of growth hormone secretagogues and growth hormone-releasing hormone/somatostatin. Endocrine 2001;14:21–27.
Kamegai J, Tamura H, Shimizu T, Ishii S, Sugihara H, Wakabayashi I: Central effect of ghrelin, an endogenous growth hormone secretagogue, on hypothalamic peptide gene expression. Endocrinology 2000;141:4797–4800.
Pinilla L, Gonzalez LC, Tena-Sempere M, Dieguez C, Aguilar E: Gonadal and age-related influences on NMDA-induced growth hormone secretion in male rats. Neuroendocrinology 1999;69:11–19.
Pinilla L, Tena-Sempere M, Gonzalez D, Aguilar E: Positive role of non-N-methyl-D-aspartate receptors in the control of growth hormone secretion in male rats. J Endocrinol Invest 1996;19:353–358.
Gonzalez LC, Pinilla L, Tena-Sempere M, Aguilar E: Regulation of growth hormone secretion by α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors in infantile, prepubertal, and adult male rats. Endocrinology 1999;140:1279–1284.
Pinilla L, Gonzalez L.C, Tena-Sempere M, Aguilar E: 5-HT1 and 5-HT2 receptor agonists blunt (±)-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-stimulated GH secretion in prepubertal male rats. Eur J Endocrinol 2001;144:535–541.
Tena-Sempere M, Pinilla L, Gonzalez LC, Aguilar E: Involvement of endogenous nitric oxide in the control of pituitary responsiveness to different elicitors of growth hormone release in prepubertal rats. Neuroendocrinology 1996;64:146–152.
Tena-Sempere M, Pinilla L, Aguilar E: A possible role for endogenous nitric oxide (NO) in kainic acid (KA)-induced growth hormone release in prepubertal rats. Neuroendocrinol Letters 1995;17:251–257.
Gabriel SM; Rocancio JR, Ruiz NS: Growth hormone pulsatility and the endocrine milieu during sexual maturation in male and female rats. Neuroendocrinology 1992;56:619–628.
Chen K, Chan WW, Barreto A, Convey EM, Smith RG: The synergistic effects of His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 on growth hormone (GH) release and intracellular adenosine 3′-5′-monophosphate accumulation in rat primary pituitary cell culture. Endocrinology 1989;124:2791–2798.
Acs Z, Lónart G, Makara G: Role of hypothalamic factors (growth hormone-releasing hormone and γ-aminobutyric acid) in the regulation of growth hormone secretion in the neonatal and adult rat. Neuroendocrinology 1990;52:156–160.
Pinilla L, Gonzalez LC, Tena-Sempere M, Aguilar E: Cross-talk between excitatory and inhibitory amino acids in the regulation of growth hormone secretion in neonatal rats. Neuroendocrinology 2001;73:62–67.
Kamegai J, Wakabayashi I, Kineman RD, Frohman LA: Growth hormone-releasing hormone receptor (GHRH-R) and growth hormone secretagogue receptor (GHS-R) mRNA levels during postnatal development in male and female rats. J Neuroendocrinol 1999;11:299–306.
Jansson JO, Eden S, Isaksson O: Sexual dimorphism in the control of growth hormone secretion. Endocr Rev 1985;6:128–150.
Gatford KL, Egan AR, Clarke IJ, Owens PC: Sexual dimorphism in the somatotropic axis. J Endocrinol 1998;157:373–389.
Sartor O, Bowers CY, Reynolds GA, Momany FA: Variables determining the growth hormonal response of His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 in the rat. Endocrinology 1985;117:1441–1447.
Gnanapavan S, Kola B, Bustin SA, Morris DG, McGee P, Fairclough P, Bhattacharya S, Carpenter R, Grossman AB, Korbonits M: The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. J Clin Endocrinol Metab 2002;87:2988–2991
Bodart V, Febbraio M, Demers A, McNicoll N, Pohankova P, Perreault A, Sejlitz T, Escher E, Silverstein RL, Lamontagne D, Ong H: CD36 mediates the cardiovascular action of growth hormone-releasing peptides in the heart. Circ Res 2002;90:844–849.
Müller EE, Locatelli V, Cocchi D: Neuroendocrine control of growth hormone secretion. Physiol Rev 1999;79:511–607.
Carro E, Señaris L, Considine RV, Casanueva FF, Dieguez C: Regulation of in vivo growth hormone secretion by leptin. Endocrinology 1997;138:2203–2206.
Bagnasco M, Kalra PS, Kalra SP: Ghrelin and leptin pulse discharge in fed and fasted rats. Neuroendocrinology 2002;143:726–729.
Gualillo O, Caminos JE, Nogueiras R, Seoane LM, Arvat E, Ghigo E, Casanueva FF, Dieguez C: Effect of food restriction on ghrelin in normal-cycling female rats in pregnancy. Obes Res 2002;10:682–687.
Cella SG, Locatelli V, De Gennaro V, Puggioni R, Pintor C, Muller EE: Human pancreatic growth hormone (GH)-releasing hormone stimulates GH synthesis and release in infant rats. An in vivo study. Endocrinology 1985;116:574–577.
Pinilla L, Tena-Sempere M, Aguilar E: Nitric oxide stimulates growth hormone secretion in vitro through a calcium-and cyclic guanosine monophosphate-independent mechanism. Horm Res 1999;51:242–247.
Valverde I, Peñalva A, Ghigo E, Casanueva FF, Dieguez C: Involvement of nitric oxide in the regulation of growth hormone secretion in dogs. Neuroendocrinology 2001;74:213–219.
Broglio F, van Koetsveld P, Benso A, Gottero C, Prodam F, Hofland L, Deghenghi R, van der Lely AJ, Ghigo E: Ghrelin secretion is inhibited by either somatostatin and cortistatin in humans (OC.3.2). J Clin Endocrinol Metab 2002;87:4829–4832.
Bero LA, Kuhn CM: Differential ontogeny of opioid, dopaminergic and serotoninergic regulation of prolactin secretion. J Pharmacol Exp Ther 1987;240:825–830.
Stuart M, Lazarus L, Smythe GA, Moore S, Sara V: Biogenic amine control of growth hormone secretion in the fetal and neonatal rat. Neuroendocrinology 1976;22:337–342.
Collu R, Fraschini F, Visconti P, Martini L: Adrenergic and serotoninergic control of growth hormone secretion in adult male rats. Endocrinology 1972;90:1231–1237.
Mota A, Bento A, Peñalva A, Pombo M, Dieguez C: Role of serotonin receptor subtype 5-HT1D on basal and stimulated growth hormone secretion. J Clin Endocrinol Metab 1995;80:1973–1977.
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