Abstract
Studies were performed in healthy subjects to ascertain the neurotransmitter systems involved in the growth hormone (GH)-releasing effect of the potent enkephalin analog FK 33-824. Concomitant evaluation of prolactin (PRL) secretion was also performed in the same subjects. FK 33-824 at a dose of 0.5 mg IV elicited a clear-cut rise in plasma GH and PRL concentrations with peak levels at 45 min. Blockade of muscarinic cholinergic receptors by atropine (0.5 mg SC) or histaminergic H1 receptors by diphenhydramine (50 mg IV bolus plus 50 mg infusion) completely suppressed the GH release induced by FK 33-824, without significantly altering the PRL rise induced by the peptide. Pretreatment with the alpha-adrenergic antagonist phentolamine (0.5 mg IV/min for 120 min) or the dopamine receptor blocker metoclopramide (10 mg IV) did not alter the GH-releasing effect of FK 33-824. Phentolamine failed to alter the PRL rise induced by FK 33-824, while combined FK 33-824-metoclopramide administration induced a greater PRL increase than FK 33-824 alone. These results indicate that cholinergic and histaminergic H1 receptors play an important role in the GH-release induced by FK 33-824 in man, whereas this action seems to occur independently of catecholaminergic mediation. The same receptors are not involved in the PRL-releasing effect of the peptide.
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References
Allolio B, Winkelmann W, Hipp FX, Kaulen D, Mies R (1982) Effect of a met-enkephalin analog on adrenocorticotropin (ACTH), growth hormone and prolactin in patients with ACTH hypersecretion. J Clin Endocrinol Metab 55:1–7
Blackard WG, Heidingsfelder SA (1968) Adrenergic receptor control mechanism for growth hormone secretion. J Clin Invest 47:1407–1414
Blackard WG, Waddel CC (1969) Cholinergic blockade and growth hormone responsiveness to insulin hypoglycemia. Proc Soc Exp Biol Med 131:192–196
Brambilla F, Casanueva F, Lovati C, Peñalva A, Madeddu A, Martinez-Campos A, Müller EE (1981) Lack of tolerance in heroin-addicts to the neuroendocrine effects of an enkephalin analogue. Life Sci 29:493–501
Brownstein MJ, Palkovits M, Tappaz ML, Saavedra JM, Kizer JS (1976) Effect of surgical isolation of hypothalamus on its neurotransmitter content. Brain Res 117:287–295
Bruni JF, Meites J (1978) Effects of cholinergic drugs on growth hormone release. Life Sci 23:1351–1357
Casanueva F, Betti R, Frigerio C, Cocchi D, Ferri S, Müller EE (1980) Growth hormone releasing effect of an enkephalin analog in the dog: Evidence for cholinergic mediation. Endocrinology 106:1239–1245
Casanueva F, Spampinato S, Locatelli V, Betti R, Cocchi D, Ferri S, Müller EE (1981a) Prolactin and growth hormone releasing effects of enkephalins. In: Stark E, Makara GB, Halasz B, Rappay GY (eds) Endocrinology, neuroendocrinology, neuropeptides. Adv Physiol Sci, vol 14, Pergamon, New York, pp 303–314
Casanueva F, Spampinato S, Locatelli V, Betti R, Cocchi D, Ferri S, Müller EE (1981b) Proof for histaminergic but not for adrenegic involvement in the growth hormone-releasing effect of an enkephalin analog in the dog. Endocrinology 108:157–163
Casanueva F, Betti R, Cocchi D, Zanardi P, Motta T, Müller EE (1981c) A role for dopamine in growth hormone regulation in the dog. Endocrinology 108:1469–1473
Casanucva F, Betti R, Cella S, Müller EE, Mantegazza P (1983) Effect of agonists and antagonists of cholinergic neurotransmission on growth hormone release in the dog. Acta Endocrinol (Kbh) (in press)
Cocola F, Udeschini G, Secchi G, Penerai AE, Neri P, Müller EE (1976) A rapid radioimmunoassay method of growth hormone in dog plasma. Proc Soc Exp Biol Med 151:140–145
Cohen HN, Hay ID, Beastall GH, Thomson JA (1979) Metoclopramide induced growth hormone release in hypogonadal males. Clin Endocrinol (Lond) 11:95–97
Douglas WW (1980) Histamine and 5-hydroxytriptamine (serotonin) and their agonists. In: Goodman LS, Gilman A (eds) Pharmacological basis of therapeutics. McMillan, New York, pp 609–646
Eriksson E, Edigh S, Modigh K (1981) Importance of norepinephrine alpha2-receptor action for morphine-induced rat growth hormone secretion. Neuroendocrinology 33:91–96
Farris TS, Richards GE (1980) Morphine acts through alpha adrenergic and serotoninergic neurons to stimulate growth hormone secretion in the dog. Life Sci 27:1345–1349
Ferland L, Fuxe K, Eneroth P, Gustafsson JA, Skett A (1977) Effect of methionine-enkephalin on prolactin release and catecholamine levels and turnover in the median eminence. Eur J Pharmacol 43:89–90
Fuxe K, Andersson K, Eneroth P, Ferland L, Locatelli V, Agnati LF (1978) Hypothalamic catecholamine neurons systems and neuroendocrine control: Effect of ergot drugs and neuropeptides. In: Müller EE (ed) Neuroactive drugs in endocrinology: physiologic, diagnostic and therapeutic applications. Elsevier/North-Holland, Amsterdam, pp 149–166
Grandison L, Guidotti A (1977) Regulation of prolactin release by endogenous opiates. Nature 270:357–359
Grandison L, Fratta W, Guidotti A (1980) Location and characterization of opiate receptors regulating pituitary secretion. Life Sci 26:1633–1642
Gudelsky GA, Porter JC (1979) Morphine- and opioid peptide-induced inhibition of the release of DA from tuberoinfundibular neurons. Life Sci 25:1697–1702
Hökfelt T, Elde R, Johansson O, Terenius L, Stein L (1977) The distribution of enkephalin immunoreactive cell bodies in the rat central nervous system. Neurosci Lett 5:25–31
Ingrand J, Boulu R (1970) Etùde de la ripartition de metoclopramide titriè chez la souris. Thérapie 25:741–751
Katakami H, Kato Y, Matsushita N, Hiroto S, Shimatsu A, Imura H (1981) Involvement of alpha-adrenergic mechanisms in growth hormone release induced by opioid peptides in conscious rats. Neuroendocrinology 33:129–135
Kebabain JW, Calne DB (1979) Multiple receptors for dopamine. Nature 277:93–96
Koenig JI, Mayfield MA, McCann SM, Krulich L (1979) Stimulation of prolactin secretion by morphine: Role of the central serotoninergic system. Life Sci 25:853–864
Libertun C, McCann SM (1973) Blockade of the release of gonadotropins and prolactin by subcutaneous or intraventricular injection of atropine in male and female rats. Endocrinology 92:1714–1724
Libertun C, McCann SM (1976) The possible role of histamine in the control of prolactin and gonadotropin release. Neuroendocrinology 20:110–120
Locatelli V, Andersson K, Fuxe K, Eneroth P (1980) Discrete changes in dopamine and noradrenaline levels and turnover in various hypothalamic nuclei following systemic treatment with the synthetic enkephalin analogue FK 33-824 in rats and their possible relationship to FK 33-824 unduced changes in the secretion of adenohypophysial hormones. Neuroendocrinol Lett 2:7–18
Martin JB, Durand D, Gard W, Faille G, Audet J, Brazeau P (1978) Neuropharmacological regulation of episodic growth hormone and prolactin secretion in rat. Endocrinology 102:106–113
Meites J, Bruni JF, Van Vugt DA, Smith AF (1979) Relation of endogenous opioid peptides and morphine to neuroendocrine function. Life Sci 24:1325–1336
Müller EE, Nisticò G, Scapagnini U (1978) Neurotransmitters and anterior pituitary function. Academic Press, New York
Peñalva A, Cabezas-Cerrato J, Villanueva L, Sanchez-Lores J, Gomez-Pan A, Borja M, Casanueva F (1981) Actión de la fenfluramina, difenhidramina y ciproheptadina sobre la secreción de hormona de crecimiento inducida por arginina. Rev Esp Fisiol 37:83–89
Rivier C, Vale W, Ling M, Brown M, Guillemin R (1977) Stimulation in vivo of the secretion of prolactin and growth hormone by endorphin. Endocrinology 100:238–241
Roamer D, Weidmann H (1966) Pharmakologische Studien über das neue Antihistaminicum Tavegil. Med Welt 51:2791–2798
Schwartz JC (1975) Minireview: Histamine as a transmitter in brain. Life Sci 17:502–518
Spampinato S, Locatelli V, Cocchi D, Vicentini L, Bajusz S, Ferri S, Müller EE (1979) Involvement of brain serotonin in the prolactin-releasing effect of opioid peptides. Endocrinology 105:163–170
Stubbs WA, Jones A, Edwards CRW, Delitala G, Jeffcoate WJ, Rater SJ, Besser GM, Bloom SR, Alberti KGMM (1978) Hormonal and metabolic response to an enkephalin analogue in normal man. Lancet ii:1225–1227
Van Loon GR, Ho D, Kim C (1980) Beta-endorphin-induced decrease in hypothalamic dopamine turnover. Endocrinology 106:76–80
Von Graffenried B, Del Pozo E, Roubicek J, Krebs E, Poldinger W, Burmeister P, Kerp L (1978) Effect of the synthetic enkephalin analogue FK 33-824 in man. Nature 272:729–730
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Peñalva, A., Villanueva, L., Casanueva, F. et al. Cholinergic and histaminergic involvement in the growth hormone releasing effect of an enkephalin analog FK 33-824 in man. Psychopharmacology 80, 120–124 (1983). https://doi.org/10.1007/BF00427953
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DOI: https://doi.org/10.1007/BF00427953