Julia C. Buckingham

Differences in Hypothalamo-Pituitary-Adrenocortical Activity in the Rat after Acute and Prolonged Treatment with Morphine

The influence of opioid substances on the secretion in vivo and in vitro of corticosterone, corticotrophin (ACTH) and corticotrophin releasing factor (CRF) in the rat was studied. Rats given a single injection of morphine exhibited a marked hypersecretion of ACTH and an exaggeration of the hypothalamo-pituitary-adrenocortical (HPA) response to stress. In contrast, animals rendered tolerant to morphine failed to release ACTH or corticosterone in response either to a subsequent injection of the opiate or to stress. The development of the inhibitory effect paralleled the development of tolerance to the analgesic actions of the drug. The production of ACTH by pituitary segments removed from control animals was not affected by the addition of opioid substances to the incubation medium. However, morphine, met-enkephalin and leu-enkephalin stimulated the secretion of CRF by hypothalami and their effects were competitively antagonized by naloxone. The secretory activity of hypothalami removed from rats treated acutely with morphine was enhanced. In contrast hypothalami from morphine-tolerant rats failed to secrete CRF in response to morphine, met-enkephalin, acetylcholine or 5-hydroxytryptamine. Neither the density nor the affinity of 3H-naloxone binding sites in the hypothalamus was influenced by the morphine treatment. The results suggest the opioid peptides and their receptors play a major role in the regulation of HPA function.

Secretion of Corticotrophin and Its Hypothalamic Releasing Factor in Response to Morphine and Opioid Peptides

The influence of morphine and enkephalins on the functional activity of the hypothalamo-pituitary-adrenocortical system in the rat was studied by investigating their effects on the secretion in vivo and in vitro of corticotrophin (ACTH) by the pituitary gland and corticotrophin-releasing factor (CRF) by the hypothalamus. A single injection of morphine caused a rise followed by a fall in hypothalamic CRF content and increases in the concentrations of ACTH in the plasma and adenohypophysis. In addition, the stress-induced increments in hypothalamic CRF and pituitary and plasma ACTH were exaggerated in morphine-treated rats. The production of ACTH by pituitary segments in vitro was not affected by the addition to the incubation medium of morphine, met-enkephalin, leu-enkephalin or naloxone. However, morphine and the enkephalins stimulated the secretion of CRF by isolated hypothalami and their effects were antagonized by naloxone. The results indicate that morphine and the enkephalins evoke hypothalamo-pituitary-adrenocortical activity by stimulating specific receptors in the hypothalamus and raise the possibility that opioid peptides and their receptors are physiologically important in the control of the secretion of CRF.

Hypothalamic receptors influencing the secretion of corticotrophin releasing hormone in the rat

1. The production of corticotrophin releasing hormone (CRH) by the rat hypothalamus in vitro was studied in the presence and absence of various neurotransmitter substances and drugs which mimic or antagonize their actions.

Pharmacological characterization of opioid receptors influencing the secretion of corticotrophin releasing factor in the rat.

The effects of selective agonists and antagonists of opioid receptors on the secretion of corticotrophin releasing factor (CRF) by isolated rat hypothalami in vitro were studied. Morphine (10(-8)-10(-6) M) and the mu-opioid receptor agonists, FK33-824CH (10(-8)-10(-6) M) and Tyr-D-Ala-Gly-MePhe-NH(CH2)2OH (10(-8)-10(-6) M), caused dose-related increases in the release of CRF from isolated hypothalami. The kappa-opioid receptor agonist, U50,488 (10(-8)-10(-6) M), was also weakly active in this respect but the delta-opioid receptor agonist, (D-Pen2,D-Pen5)-enkephalin (2 X 10(-10)-2 X 10(-7) M), was not. The stimulatory actions of morphine and Tyr-D-Ala-Gly-MePhe-NH(CH2)2OH on CRF release were antagonized by naloxone (10(-8) M) and by the mu/delta-opioid receptor antagonist, beta-funaltrexamine (beta-FNA, 10(-9) M), but not by the delta-opioid receptor antagonist, ICI-154129 (5 X 10(-6) M). The effects of U50,488 on CRF release were unaffected by either beta-FNA or ICI-154129 but were antagonized by high doses of naloxone (10(-6) M). The results suggest that both mu- and kappa-opioid receptors are involved in the stimulation of CRF secretion but that delta-opioid receptors are not important in this respect.

Effects of chronic administration of melanin-concentrating hormone on corticotrophin, melanotrophin, and pigmentation in the trout

This paper reports the effects of salmonid melanin-concentrating hormone (MCH), administered via an Alzet minipump, on pigmentation and secretion of pituitary melanotrophin (MSH) and corticotrophin (ACTH) by black-adapted, adult rainbow trout. The drug induced melanin concentration in the skin melanophores and prevented melanogenesis. Both the cytological appearance of the pituitary pars intermedia and determinations of plasma alpha-MSH suggest that MCH prevented the increase in secretory activity of the melanotrophic cells seen normally in black-adapted trout. Resting plasma cortisol titres were similar in all groups of fish but anterior pituitary glands taken from stressed, MCH-treated fish released less ACTH in vitro than those from corresponding saline-treated fish.

Stimulation and Inhibition of Corticotrophin Releasing Factor Secretion by Beta Endorphin

The influence of beta-endorphin on the secretion of corticotrophin releasing factor (CRF) by isolated rat hypothalami in vitro was studied. beta-Endorphin (10(-11)-10(-10) M) caused dose-related increases in the CRF contents of the hypothalami and of the medium in which they were incubated. Its effects were antagonized by naloxone (10(-8)-10(-7) M). In contrast, in higher concentrations (10(-7) - 10(-5) M), it reduced, in a dose-dependent manner, both the spontaneous release of CRF from the hypothalami and the release which normally occurred in response to acetylcholine, 5-hydroxytryptamine, morphine, met-enkephalin and leu-enkephalin. The inhibition of CRF release was associated with a rise in the tissue content of the hormone and was not blocked readily by naloxone. The results support the concept that opioid substances may be involved in the control of hypothalamo-pituitary-adrenocortical function.

The influence of corticosteroids on the secretion of corticotrophin and its hypothalamic releasing hormone

1. The effects of stress, adrenalectomy and corticosterone treatment on the functional activity of the hypothalamo‐pituitary‐adrenocortical system have been studied using highly sensitive and precise bio‐assay methods for the determination of ACTH and CRH.

Interrelationships of Opioidergic and Adrenergic Mechanisms Controlling the Secretion of Corticotrophin Releasing Factor in the Rat

The effects of morphine and naloxone on hypothalamo-pituitary-adrenocortical (HPA) activity and blood pressure were studied in rats in which adrenergic transmission had been impaired pharmacologically. The alpha 1-adrenoceptor antagonist, prazosin and the tyrosine hydroxylase inhibitor, alpha-methyl-para-tyrosine (alpha-MPT), increased the hypothalamic corticotrophin releasing factor (CRF) content and the plasma corticotrophin (ACTH) concentration and exaggerated the HPA response to stress. In addition, the spontaneous secretion of CRF by hypothalami in vitro was increased by alpha-MPT-treatment. Morphine enhanced the basal and stress-induced activity of the HPA system in vivo. It also stimulated the secretion of CRF by hypothalami in vitro. Naloxone did not affect resting HPA activity but reduced markedly the stress-induced release of corticotrophin. The effects of morphine and naloxone on the HPA axis, in vivo, were reduced by pretreatment with alpha-MPT and prazosin, respectively. The HPA responses could not be correlated with the changes in blood pressure which the drugs caused. The results suggest that opioid substances stimulate HPA activity by depressing the activity of the adrenergic pathways which inhibit the secretion of CRF.

Effects of naloxone on hypothalamo-pituitary-adrenocortical activity in the rat.

The influences of morphine and naloxone on hypothalamo-pituitary-adrenocortical (HPA) function were studied in the rat to investigate further the role of opioidergic mechanisms in the control of the secretion of corticotrophin and its hypothalamic releasing factor (CRF). Morphine not only caused rises in hypothalamic CRF content and plasma ACTH concentration but also potentiated the HPA response to stress. Its effects were antagonized by naloxone which, when given alone, did not influence basal plasma concentrations of ACTH and corticosterone but which inhibited, in a dose-dependent manner, the release of both of these hormones which normally occurs in response to stress. Naloxone also attenuated the exaggeration in stress-induced HPA activity but did not affect the increases in plasma ACTH concentration which followed adrenalectomy. The findings suggest that opioidergic mechanisms may be involved in the regulation of the HPA response to stress.

SUPPRESSION OF PLASMA ACTH CONCENTRATION BY ANGIOTENSIN II INFUSION IN NORMAL HUMANS AND IN A SUBJECT WITH A STEROID 17α‐HYDROXYLASE DEFECT

Six healthy subjects were infused with angiotensin II and plasma concentrations of angiotensin, ACTH and cortisol were measured before, during and after the infusion. In all cases the plasma ACTH concentration fell as plasma angiotensin increased and rose again, sometimes to higher than basal levels, when the angiotensin infusion was terminated. These effects were most marked at the highest rate of infusion (8 pmol/kg/min) and, at the lower rates (2 and 4 pmol/kg/min), there was some recovery of ACTH levels during the infusion period in some subjects. Plasma ACTH concentrations also fell when angiotensin was infused into a patient with high ACTH levels due to a steroid 17α‐hydroxylation defect. The inhibition of ACTH secretion is not due to a rise in plasma cortisol operating a negative feedback inhibition. It could be a direct effect of the infused angiotensin on the brain‐hypothalamus‐pituitary complex or an effect on the metabolism of ACTH.