Growth hormone secretagogues (GHS) are small, synthetic compounds which have the potential of releasing growth hormone (GH) from the pituitary. The mechanism of action of GHS has not been fully elucidated. A specific GHS receptor (GHS-R) is expressed in the pituitary gland and in several areas of the brain including the hypothalamus. We have characterized the GHS-R-mRNA-expressing neurons with respect to co-expression of selected neurotransmitters in the hypothalamus. This was done by dual chromogenic and autoradiographic in situ hybridization with riboprobes for GHS-R mRNA and neuropeptide Y (NPY), pro-opiomelanocortin (POMC), somatostatin (SRIH) or GH-releasing hormone (GHRH) mRNA. In the arcuate nucleus, GHS-R mRNA was expressed in 94 ± 1% of the neurons expressing NPY, 8 ± 2% of those expressing POMC and 30 ± 6% expressing SRIH mRNA. 20–25% of the GHRH- mRNA-expressing neurons contained GHS-R mRNA, whereas the vast majority of the arcuate GHS-R-mRNA-containing cells did not contain GHRH mRNA. The finding of a significant co-expression of GHS-R and NPY mRNA in the arcuate nucleus is in accordance with the previous demonstration by Dickson et al. that c-Fos is induced in NPY neurons following GHS administration. These results indicate that GHS have other effects on neuroendocrine regulation than GH release via GHRH neurons. Stimulation of the arcuate NPY neurons via GHS-R may explain the increased appetite and the cortisol release seen after administration of some GHS compounds.

1.
Bowers CY, Sartor AO, Reynolds GA, Badger TM: On the actions of the growth hormone-releasing hexapeptide, GHRP. Endocrinology 1991;128:2027–2035.
2.
Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA, Rosenblum CI, Hamelin M, Hreniuk DL, Palyha OC, Anderson J, Paress PS, Diaz C, Chou M, Liu KK, McKee KK, Pong S-S, Chaung L-Y, Elbrecht A, Dashkevicz M, Heavens R, Rigby M, Sirinathsingshji DJS, Dean DC, Melillo DG, Patchett AA, Nargund R, Griffin PR, DeMartino JA, Gupta SK, Schaeffer JM, Smith RG, Van der Ploeg LHT: A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 1996;273:974–978.
3.
McKee KK, Palya OC, Feighner SD, Hrenhiuk DL, Tan CP, Philip MS, Smith RG, Van der Ploeg LHT, Howard AD: Molecular analysis of rat pituitary and hypothalamic growth hormone secretagogue receptors. Mol Endocrinol 1997;11:415–423.
4.
Guan X-M, Yu H, Palyha OC, McKee KK, Feighner SD, Sirinathsinghji DJS, Smith RG, Van der Ploeg LHT, Howard AD: Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues. Mol Brain Res 1997;48:23–29.
5.
Tannenbaum GS, Lapointe M, Beaudet A, Howard AD: Expression of growth hormone secretagogue-receptors by growth hormone-releasing hormone neurons in the mediobasal hypothalamus. Endocrinology 1998;139:4420–4423.
6.
Robinson ICAF: Hypothalamic targets for growth hormone secretagogues. Acta Paediatr 1997;423:88–91.
7.
Guillaume V, Magnan E, Cataldi M, Dutour A, Asuze N, Renard M, Razafindraibe H, Conte-Devolx B, Deghengi R, Lenaerts V, Oliver C: Growth hormone (GH)-releasing hormone secretion is stimulated by a new GH-releasing hexapeptide in sheep. Endocrinology 1994;135:1073–1076.
8.
Arvat E, Di Vito L, Gianotti L, Ramunni J, Bandhen MF, Deghengi R, Camanni F, Ghigo E: Mechanisms underlying the negative growth hormone (GH) autofeedback on the GH-releasing effect of hexarelin in man. Metabolism 1997;46:83–88.
9.
Robinson BM, Friberg RD, Bowers CY, Barkan AL: Acute growth hormone (GH) response to GH-releasing hexapeptide in humans is independent of endogenous GH-releasing hormone. J Clin Endocrinol Metab 1992;75:1121–1124.
10.
Loche S, Cambiaso P, Merola B, Colao A, Faedda A, Imbimbo BP, Deghengi R, Lombardi G, Cappa M: The effect of hexarelin on growth hormone (GH) secretion in patients with GH deficiency. J Clin Endocrinol Metab 1995;80:2692–2696.
11.
Popovic V, Damjanovic S, Micic D, Djurovic M, Dieguez C, Casanueva FF: Blocked growth hormone-releasing peptide (GHRP-6)-induced GH secretion and absence of the synergic action of GHRP-6 plus GH-releasing hormone in patients with hypothalamopituitary disconnection: Evidence that GHRP-6 main action is exerted at the hypothalamic level. J Clin Endocrinol Metab 1995;80:942–947.
12.
Dickson SL, Leng G, Robinson ICAF: Systemic administration of growth hormone-releasing peptide activates hypothalamic arcuate neurons. Neuroscience 1993;53:303–306.
13.
Kamegai J, Hasegawa O, Minami S, Sugihara H, Wakabayashi I: The growth hormone-releasing peptide KP-102 induces c-fos expression in the arcuate nucleus. Mol Brain Res 1996;39:153–159.
14.
Bennett PA, Thomas GB, Howard AD, Feighner SD, Van der Ploeg LHT, Smith RG, Robinson ICAF: Hypothalamic growth hormone secretagogue receptor (GHS-R) expression is regulated by growth hormone in the rat. Endocrinology 1997;138:4552–4557.
15.
Dickson SL, Luckman SL: Induction of c-fos messenger ribonucleic acid in neuropeptide Y and growth hormone (GH)-releasing factor neurons in the arcuate nucleus following systemic injection of the GH secretagogue, GH-releasing peptide-6. Endocrinology 1997;138:771–778.
16.
Paxinos G, Watson C: The Rat Brain in Stereotactic Coordinates, ed 2. San Diego, Academic Press, 1986.
17.
Kristensen P, Eriksen J, Danø K: Localization of urokinase-type plasminogen activator messenger RNA in the normal mouse by in situ hybridization. J Histochem Cytochem 1991;39:341–349.
18.
Marks DL, Wiemann JN, Burton KA, Lent KL, Clifton DK, Steiner RA: Simultaneous visualization of two cellular mRNA species in individual neurons by use of a new double in situ hybridization method. Mol Cell Neurosci 1992;3:395–405.
19.
Morris BJ: Neuronal localization of neuropeptide Y gene expression in rat brain. J Comp Neurol 1989;290:358–368.
20.
Gee CE, Chen C-LC, Roberts JL, Thompson R, Watson SJ: Identification of proopiomelanocortin neurones in rat hypothalamus by in situ cDNA-mRNA hybridization. Nature 1983;306:374–376.
21.
Baubet V, Fèvre-Montange M, Gay N, Debilly G, Bobillier P, Cespuglio R: Effects of an acute immobilization stress upon proopiomelanocortin (POMC) mRNA levels in the mediobasal hypothalamus: A quantitative in situ hybridization study. Mol Brain Res 1994;26:163–168.
22.
Fitzpatrick-McElligott S, Card JP, Lewis ME, Baldino F Jr: Neuronal localization of prosomatostatin mRNA in the rat brain with in situ hybridization histochemistry. J Comp Neurol 1988;273:558–572.
23.
Bailey ART, Smith RG, Leng G: The non-peptide growth hormone secretagogue, MK-0677, activates hypothalamic arcuate nucleus neurons in vivo. J Neuroendocrinol 1998;10:111–118.
24.
Minami S, Kamegai J, Sugihara H, Suzuki N, Wakabayashi I: Growth hormone inhibits its own secretion by acting on the hypothalamus through its receptors on neuropeptide Y neurons in the arcuate nucleus and somatostatin neurons in the periventricular nucleus. Endocr J 1998;45:S19–26.
25.
Dickson SL, Doutrelant-Vilart O, Leng G: GH-deficient dw/dw rats and lit/lit mice show increased Fos expression in the hypothalamic arcuate nucleus following systemic injection of GH-releasing peptide-6. J Endocrinol 1995;164:519–526.
26.
Locke W, Kirgis HD, Bowers CY, Abdoh AA: Intracerebroventricular growth-hormone-releasing peptide-6 stimulates eating without affecting plasma growth hormone response in rats. Life Sci 1995;56:1347–1352.
27.
Torsello A, Luoni M, Schweiger F, Grilli R, Guidi M, Bresciani E, Deghenghi R, Müller EE, Locatelli V: Novel hexarelin analogs stimulate feeding in the rat through a mechanism not involving growth hormone release. Eur J Pharmacol 1998;360:123–129.
28.
Thomas GB, Fairhall KM, Robinson ICAF: Activation of the hypothalamo-pituitary-adrenal axis by the growth hormone (GH) secretagogue, GH-releasing peptide-6, in rats. Endocrinology 1997;138:1585–1591.
29.
Clark JT, Kalra PS, Crowley WR, Kalra SP: Neuropeptide Y and human pancreatic polypeptide stimulate feeding behavior in rats. Endocrinology 1984;115:427–429.
30.
Håkansson ML, Brown H, Ghilardi N, Skoda RC, Meister B: Leptin receptor immunoreactivity in chemically defined target neurons of the hypothalamus. J Neurosci 1998;18:559–572.
31.
Wang B, Al-Barazanji M, Wang M, Neville T, Pickavance D, Dryden S, Thomas MEA, McHale MT, Gloyer IS, Wilsen S, Buckingham R, Arch JRS, Trayhurn P, Williams G: Interactions between leptin and hypothalamic neuropeptide Y neurons in the control of food intake and energy homeostasis in the rat. Diabetes 1997;46:335–341.
32.
Dickson SL, Leng G, Dyball RE, Smith RG: Central actions of peptide and nonpeptide growth hormone secretagogues in the rat. Neuroendocrinology 1995;61:36–43.
33.
Raun K, Hansen BS, Johansen NL, Thogersen H, Madsen K, Ankersen M, Andersen PH: Ipamorelin, the first selective growth hormone secretagogue. Eur J Endocrinol 1998;139:552–561.
34.
Clark RR, Thomas GB, Mortensen DL, Won WB, Ma YH, Tomlinson EE, Fairhall KM, Robinson ICAF: Growth hormone secretagogues stimulate the hypothalamic-pituitary-adrenal axis and are diabetogenic in the Zucker diabetic fatty rat. Endocrinology 1997;138:4316–4323.
35.
Murphy MG, Plunkett LM, Gertz BJ, He W, Wittreich J, Polvino WM, Clemmons DR: MK-677, an orally active growth hormone secretagogue, reverses diet-induced catabolism. J Clin Endocrinol Metab 1998;83:320–325.
36.
Bai FL, Yamano M, Shiotani Y, Emson PC, Smith AD, Powell JF, Tohyama M: An arcuato-paraventricular and -dorsomedial hypothalamic neuropeptide Y-containing system which lacks noradrenaline in the rat. Brain Res 1985;331:172–175.
37.
Honda K, Bailey ART, Bull PM, MacDonald LP, Dickson SL, Leng G: An electrophysiological and morphological investigation of the projections of growth hormone-releasing peptide-6-responsive neurons in the rat arcuate nucleus to the median eminence and to the paraventricular nucleus. Neuroscience 1999;90:875–883.
38.
Elmquist JK, Ahima RS, Elias CF, Flier JS, Saper CB: Leptin activates distinct projections from the dorsomedial and ventromedial hypothalamic nuclei. PNAS 1998;95:741–746.
39.
Willoughby JO, Kapoor R, MacKenzie L: Intrahypothalamic mu-, not delta- or kappa-opioid receptor activation causes growth hormone secretion. J Neuroendocrinol 1991;3:149–154.
40.
Bertherat J, Dournaud P, Bérod A, Normand E, Bloch B, Rostène W, Kordon C, Epelbaum J: Growth hormone-releasing hormone-synthesizing neurons are a subpopulation of somatostatin receptor-labelled cells in the rat arcuate nucleus: A combined in situ hybridization and receptor light-microscopic radioautographic study. Neuroendocrinology 1992;56:25–31.
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