G. Delitala

HORMONAL AND METABOLIC RESPONSES TO AN ENKEPHALIN ANALOGUE IN NORMAL MAN

An enkephalin analogue [D-Ala2, MePhe4, Met(o)-ol] enkephalin (DAMME), given intravenously to normal subjects raised serum prolactin and growth-hormone levels but lowered serum levels of luteinising hormone, follicle-stimulating hormone, cortisol, and corticotrophin. There was also a small fall in total glucagon and gastric inhibitory peptide (G.I.P.) and a rise in thyrotrophin. beta-Lipotrophin, motilin, vasoactive intestinal peptide, insulin, gastrin, and pancreatic glucagon were unchanged. Blood-glycerol increased, and blood lactate, alanine, and glucose fell. Prior administration of the opiate antagonist, naloxone, attenuated the hormonal responses to DAMME. This enkephalin analogue produces endocrine and metabolic changes in man which may be mediated through opiate-binding receptors both within and outside the brain. The enkephalins and related substances may provide an important link between perception, behaviour, and neuroendocrine regulation of hormone secretion and metabolism.

THE OPIOID CONTROL OF LH AND FSH RELEASE: EFFECTS OF A MET‐ENKEPHALIN ANALOGUE AND NALOXONE

The effect of a long‐acting analogue of met‐enkephalin (DAMME) and naloxone on gonadotrophin secretion has been investigated in man. In menopausal women DAMME induced a progressive fall in LH to approximately 60% of basal levels at 3 h, which was blocked by naloxone; there was a smaller fall in FSH that did not attain statistical significance. However, the LHRH‐induced rise in LH and FSH in young male volunteers was unaffected by pretreatment with a high‐dose DAMME infusion. Naloxone infusion in young male and female normal subjects produced a significant rise in both LH and FSH. Long‐term infusion of naloxone appeared to increase the rate, and possibly the amplitude, of LH pulsatility. These results suggest that met‐enkephalin‐like opioid peptides exert a tonic inhibitory control of LH release in both menopausal and young subjects of both sexes. This control is most likely to be at the level of the hypothalamus, and involves modulation of pulsatile LHRH release.

STUDIES OF THE OPIATE CONTROL OF PROLACTIN, GH AND TSH

Opiate peptides are known to influence the secretion of several anterior pituitary hormones under basal conditions. Further studies on prolactin, GH and TSH have therefore been performed in normal subjects, under basal and stimulated conditions, using an opiate agonist and antagonist. Sixteen mg naloxone had no effect on the basal release of prolactin or GH, but lowered TSH. An infusion of the met‐enkephalin analogue DAMME (1 mg) increased GH, and produced an exaggerated response of both prolactin and TSH to 200 μg TRH i.v. The peak responses of both prolactin and GH to hypoglycaemia were unaffected by pretreatment with either low‐dose (0·4 mg) or high‐dose (25 mg) naloxone, or DAMME (0·25 mg). These results suggest that opiate peptides are unlikely to play a major role in the tonic or hypoglycaemia‐stimulated release of prolactin and GH, although they may be of importance in the control of TSH.

GABA and Muscimol Inhibit the Release of Prolactin from Dispersed Rat Anterior Pituitary Cells

Prolactin release from columns of dispersed rat anterior pituitary cells was inhibited by GABA and the GABA agonist muscimol. The log dose-response curves for GABA and muscimol appeared to be parallel, but were not parallel to that for dopamine. Two GABA antagonists, bicuculline and picrotoxin, blocked the action of both GABA and muscimol, but the dopamine antagonists metoclopramide and perphenazine did not. The data suggest that there are specific GABA receptors on pituitary lactotrophs.

OPIATE PEPTIDES CONTROL GROWTH HORMONE THROUGH A CHOLINERGIC MECHANISM IN MAN

Opiate peptides are known to elevate circulating GH in man, and data in other animals suggest that acetylcholine may be involved. We have administered the long‐acting met‐enkephalin analogue DAMME to 6 normal males, and have shown that the resulting elevation in GH is blocked by the specific cholinergic antagonist, pirenzipine. It seems likely that a cholinergic mechanism may interact with opiate‐induced changes in GH in man.

THE ENDOCRINE AND METABOLIC EFFECTS OF CIMETIDINE

Serial blood sampling in nine patients treated with cimetidine (1 g/day) showed that PRL values were within the normal range apart from a stress‐induced initial rise. Hormonal and metabolic profiles from 08.30 to 18.30 h were performed in six patients before and after 1 months treatment with cimetidine (1 g/day). Circulating PRL, LH, FSH, GH, TSH T3, T4 and testosterone were similar before and after treatment. The mean blood glucose fell from 5·4 ± 0·3 mmol/l to 4·8 ± 0·2 mmol/l on cimetidine (P<0·02). Small changes were also observed in blood pyruvate, lactate, 3‐hydroxybutyrate and the (lactate)/(pyruvate) ratio. The effects of oral or i.v. cimetidine on the circulating concentrations of insulin, glucose and intermediary metabolites were investigated in normal subjects. Intravenous cimetidine (100 mg/h for 4 h) given to fasting subjects decreased blood glucose and serum insulin by 15 and 34% respectively at 150 min. During an oral GTT, i.v. cimetidine caused a striking decline in blood glucose, lactate and pyruvate responses compared with control studies, although the serum insulin was similar to control values. When given for 48 h before the study, oral cimetidine did not alter basal serum insulin and blood glucose, lactate, pyruvate, alanine, glycerol and 3‐hydroxybutyrate levels. However, 150 min after an oral GTT the serum insulin was increased by 47% by oral cimetidine although the blood glucose was not significantly changed compared with the control day. Oral cimetidine had no effect on the blood glucose or serum insulin during an i.v. GTT. These results show that oral cimetidine given at therapeutic doses to patients with peptic ulcers does not produce consistent changes in circulating anterior pituitary hormones. Oral cimetidine given to patients for 1 month and i.v. cimetidine given to normal subjects have mild hypoglycaemic effects. Oral cimetidine administered over 48 h to normal subjects has little effect on blood glucose concentration.

THE PARTICIPATION OF HYPOTHALAMIC DOPAMINE IN MORPHINE‐INDUCED PROLACTIN RELEASE IN MAN

In order to assess the role of dopamine in opiate‐induced prolactin secretion, morphine alone or in combination with the dopamine blocker metoclopramide, or the L‐aromatic aminoacid decarboxylase inhibitor benserazide, was administered to a group of normal adult men. Morphine (10 mg) stimulated prolactin release in all subjects; however, the effect was totally abolished when 10 mg metoclopramide or 200 mg benserazide were given before the opiate agonist. The prolactin releasing effect of a sub‐maximal metoclopramide dose (1 mg) was potentiated by morphine. In vitro, benserazide was totally inactive in stimulating prolactin release by isolated anterior pituitary cells. Moreover, benserazide failed to alter the inhibiting action of dopamine on prolactin release.

THE EFFECT OF LISURIDE HYDROGEN MALEATE, AN ERGOT DERIVATIVE ON ANTERIOR PITUITARY HORMONE SECRETION IN MAN

The effects of single oral doses of 0.2 mg of lisuride hydrogen maleate, a semisynthetic ergot derivative, on serum levels of prolactin (PRL), growth hormone (GH), thyroid stimulating hormone (TSH), luteinizing hormone (LH), follicle stimulating hormone (FSH), cortisol and blood glucose were studied in six normal males. Lisuride effectively inhibited basal PRL secretion as well as the PRL response to TRH given 3 h later. In addition, the drug raised basal GH levels and decreased basal and TRH stimulated TSH secretion. No significant differences between lisuride and control were observed in basal LH and FSH, LHRH stimulated gonadotrophins or in cortisol. Drowsiness was noted by all subjects, one became nauseated and another vomited, 60 and 90 min respectively after administration of lisuride. No changes were seen in pulse rate and blood pressure. The endocrine effects of lisuride were attenuated by the prior administration of the dopamine antagonist metoclo‐pramide. These results suggest that lisuride acts as a long‐acting dopamine agonist and that therefore this drug could be of therapeutic use in hyperprolactinaemic states and acromegaly.

CHLORPROMAZINE, HALOPERIDOL, METOCLOPRAMIDE AND DOMPERIDONE RELEASE PROLACTIN THROUGH DOPAMINE ANTAGONISM AT LOW CONCENTRATIONS BUT PARADOXICALLY INHIBIT PROLACTIN RELEASE AT HIGH CONCENTRATIONS

1 The effects of chlorpromazine, haloperidol, metoclopramide and domperidone on the release of prolactin from perfused columns of dispersed rat anterior pituitary cells were studied. 2 Chlorpromazine, haloperidol, metoclopramide and domperidone antagonized the dopamine‐mediated inhibition of prolactin release at low concentrations. 3 Each dopamine antagonist displaced the dose‐response curve for dopamine‐induced suppression of prolactin release to the right in a parallel manner. 4 At higher concentrations, the four drugs became less effective as dopamine antagonists. 5 At high concentrations in the absence of dopamine, chlorpromazine, haloperidol, metoclopramide and domperidone paradoxically suppressed prolactin secretion by an unknown mechanism.

EFFECTS OF THE H2 RECEPTOR ANTAGONIST CIMETIDINE ON PITUITARY HORMONES IN MAN

The effects of the histamine (H2) receptor antagonist cimetidine on serum levels of prolactin (PRL), growth hormone (GH), thyroid stimulating hormone (TSH), luteinizing hormone (LH), follicle stimulating hormone (FSH) and cortisol were studied in five normal males. Cimetidine, when given by infusion at the dose of 100 mg/h for 5 h, did not alter adenohypophyseal secretion either basally or after pituitary stimulation with LHRH and TRH. However, 400 mg cimetidine given intravenously as a bolus injection significantly stimulated PRL release in all subjects, without affecting any other measured hormone. A dose‐response relationship existed, and 200 mg cimetidine seems to be the minimum PRL‐releasing dose when given as an intravenous bolus injection. These results suggest that cimetidine releases PRL and that this effect is dose‐related, but only when large intravenous injections are given.