Hypothalamo-pituitary-adrenocortical System Research Articles

L-type Ca 2+ channel ligands modulate morphine effects on the hypothalamus-pituitary-adrenocortical axis in rats

The role of the L-type Ca 2+ channel in the acute effects of morphine on the hypothalamo-pituitary-adrenocortical (HPA) system was studied by administration of the Ca 2+ channel agonist, BAY K 8644, and the antagonists, verapamil and nimodipine, to rats. Morphine (30 mg/kg i.p.) induced an increase in corticosterone secretion 30 min after injection, which was correlated with a simultaneous change in hypothalamic noradrenaline (NA) and dopamine DA) contents. Pretreatment with verapamil (10 or 20 mg/kg i.p.) or nimodipine (5 mg/kg i.p.) antagonized the HPA activation induced by morphine, blocking both the decrease in hypothalamic NA levels and the elevation in plasma corticosterone induced by the opioid. BAY K 8644 (2 mg/kg i.p.) potentiated the effects of morphine, decreasing the hypothalamic NA content and increasing the release of corticosterone. The Ca 2+ channel antagonist, nimodipine, given alone induced a slight reduction in hypothalamic NA content but did not modify plasma corticosterone levels. Verapamil given alone did not alter HPA activity. Instead, the Ca 2+ agonist decreased the hypothalamic catecholamine content and increased plasma corticosterone levels. These results indicate that Ca 2+ influx is necessary for the expression of opioid actions on the HPA system, and suggest that the Ca 2+ flux in hypothalamic neurons is functionally linked to activation of opioid receptors.

Effects of selective opioid-receptor blockade on the hypothalamo-pituitary-adrenocortical responses to surgical trauma in the rat

Opioid substances have been shown to stimulate and depress the secretion of ACTH in the rat. Their opposing actions appear to be mediated in part by specific receptors in the hypothalamus which influence the secretion of corticotrophin-releasing factor (CRF). In an attempt to determine the physiological role of these receptor systems, experiments were carried out in which the plasma ACTH and serum corticosterone concentrations were determined before and after stress in rats treated s.c. with selective antagonists of mu-(naloxone, naltrexone), delta-(ICI 174864) and kappa-(MR2266) opioid receptors. Neither naloxone (25-100 micrograms/100 g) nor naltrexone (50 micrograms/100 g) influenced the resting plasma ACTH or serum corticosterone concentrations. However, both inhibited (P less than 0.01) the secretion of the two hormones elicited normally by surgical stress (laparotomy under ether anaesthesia). ICI 174864 (30-100 micrograms/100 g) also had little effect on resting hypothalamo-pituitary-adrenocortical (HPA) activity but, at the highest dose, it caused a small (P less than 0.05) potentiation of the response to surgery. In contrast, MR2266 (150-300 micrograms/100 g) produced marked activation of the HPA system and not only stimulated the resting secretion of ACTH and corticosterone but also potentiated and prolonged the HPA response to stress. The results suggest that mu- and kappa-opioid receptors mediate opposing actions of endogenous opioid peptides, both of which may be physiologically important in the regulation of CRF release.

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.

Treatment with massive doses of synthetic corticoids and hypothalamopituitary adrenocortical function with reference to acute leukemia

The effect of massive doses of synthetic corticoids, with an initial dose equivalent to 200 mg/day prednisolone, on the hypothalamo-pituitary adrenocortical function and its reserve in the acute leukemic patients was studied. On the basis of results obtained, the adequacy of massive administration of corticoids was discussed.The cases employed in the study were a total of 26 patients (31 therapeutic courses). They were determined for the daily urinary excretion of Porter-Silber chromogens, Zimmermann chromogens and 17-KGS and then for their consequent response to i. m. injection of 25 unit ACTH-Z or to oral administration of 3 gm SU 4885, before and after treatment. In postmedication follow-ups the 7th day of discontinuance of treatment was taken as Day 1.i) Both the daily urinary excretion of corticosteroids and the response to ACTH-Z & SU 4885 of the patients with acute leukemia before treatment showed no significant difference from those of the control group, though varied considerably. This means that there generally is no demonstrable dysfunction of the hypothalamo-pituitary adrenocortical system in acute leukemia.ii) Since, however, there was evidence of dysfunction of the hypothalamo-pituitary adrenocortical system and of reduction in its reserve in some cases, the possible influences of clinical factors on them were studied. The clinical factors examined included age, sex, bleeding tendency, high fever, hepatic enlargement, hepatic insufficiency, A/G ratio, hematocrit, platelet count, WBC & NCC. On each of these factors, the patients were divided into 2 groups as in Fig. 5 to determine whether there is statistically any significant difference in urinary excretion of corticosteroids and response to ACTH-Z between both groups. None of these factors were found to have any conspicuous effect on them.iii) The 24 hours' urinary excretion of corticosteroids following treatment with massive doses of corticoids in the acute leukemic patients showed no significant difference from that before treatment or of the control group. This is presumably due to our careful reduction of dosage with subsequent tapering at 5 mg daily for two weeks.iv) The response to ACTH-Z after treatment, as compared to that before treatment or of the control group, was reduced with a significant difference (P<0.05), indicating a reduced adrenocortical reserve following treatment with massive doses of corticoids. Similarly, the response to SU 4885 was found significantly reduced (P<0.05) after treatment as compared to that before treatment or of the control group. But it is impossible to determine whether this change is of hypothalamo-pituitary or of adrenocortical origin.v) Throughout the therapeutic courses, no clinical and laboratory findings suggestive of hypothalamo-pituitary adrenocortical insufficiency were obtained in any instance.vi) There was no inverse correlation between the 24 hours' excretion as well as response to ACTH-Z or SU-4885 of urinary corticosteroids after treatment and the sum of administered doses of corticoids as prednisolone or duration (days) of corticoid therapy. It is unlikely, therefore, that the hypothalamo-pituitary adrenocortical function and its reserve reduce with increasing doses and with a longer duration of administration, which is given within the dosage range employed in the present study.vii) The recovery of the adrenocortical reserve appears to be somewhat retarded after treatment with “massive” doses than with “ordinary” ones. However, the reduction in the adrenocortical reserve produced by treatment with massive doses is by no means irreversible, the reserve being found normalized after 8 months in all instances.It has been generally accepted that corticoids, when used not as a replacement therapy but for their pharmacologic effects, produce the suppression of the hypothalamo-pituitary adrenocortical system. These results, however,

Stress and Uropepsin

The changes of uropepsin levels were estimated after the method of West et al. in the administrations of adrenocorticotropic or adrenal hormone, in various kinds of stress and in insulin response test. 1) The average value of uropepsin in 24-hour urine of Addison's disease was significantly lower than that in healthy controls.2) The therapeutic minimal dosis of cortisone in Addison's disease caused only a slight increase of uropepsin excretion, while the larger amounts of cortisone induced a significant rise of uropepsin. The therapeutic dosis of cortisone administered in lymphatic leukemia caused a significant elevation of uropepsin.3) The therapeutic administration of ACTH-gel in nephrotic syndrome caused a significant elevation of uropepsin excretion with the evidences of activation of adrenal cortex, followed by the clinical improvements. Succesive administration of ACTH-gel in the secondary adrenocortical insufficiency complicated in acromegaly induced a gradual increase of uropepsin and urinary total 17-hydroxy-corticods.4) Eight hour intravenous ACTH infusion test were made with nine subjects and uropepsin changes were observed. The cases of normal adrenal response showed a significant increase of uropepsin, while the cases of insufficient response showed no significant increase.5) The levels of uropepsin were estimated with 10 cases of primary thoracoplasty, 8 cases of secondary thoracoplasty and 3 cases of laparotomy. The uropepsin levels were definitely elevated after operations in all cases of primary thoracoplasty and laparotomy, and in 6 cases of secondary thoracoplasty. In five cases of surgical operations, parallel estimations of the level of urinary total 17-hydroxycorticoids were made. The levels of urinary total 17-hydroxycorticoids were significantly elevated simultaneously or prior to the increase of uropepsin.6) In the cases under the other stressors, such as muscular exercise, trauma, exercise in Coni-Island show (rapid shaking of body and psychic tension for fear), and infection of tetanus, the uropepsin significantly increased in the course of stress.7) The changes of uropepsin levels and circulating eosinophil counts were observed after subcutaneous injection of insulin 0.15 units per kg of body weight. The cases of normal eosinopenic response showed a significant increase of uropepsin after 2 and 4 hours of insulin injection, while the cases of abnormal eosinopenic response showed a definite decrease after 4 hours of insulin injection. The saline injected controls showed no significant increase or decrease of uropepsin.8) In conclusion, the change of the excretion level of uropepsin has an intimate relationship to the adrenocortical function, which is likely representing one of clinical indexes for stress. Although the increase of adrenocortical hormone in blood may cause the elavation of uropepsin levels, it can not be always concluded that the adrenocortical function to be accentiated in the actual stress with the increase of uropepsin. These uropepsin change is applicable for a useful index in insulin response test, which may afford an available information concerning the activity of hypothalamo-pituitary adrenocortical system.