Effects of sodium valproate and diazepam on beta-endorphin, beta-lipotropin and cortisol secretion induced by hypoglycemic stress in humans

Evidence that gamma-aminobutyric acid (GABA) and benzodiazepine receptors play a role in the inhibition of ACTH-cortisol secretion in humans has until now been drawn only from data indicating that sodium valproate, a GABA mimetic, and diazepam, a benzodiazepine, decrease hypothalamus-pituitary-adrenal (HPA) axis secretion in patients affected by pathological hypersecretion of the axis. Therefore, the present study investigated the effects, in the same healthy subjects, of sodium valproate or diazepam, on both basal and stress-stimulated concentrations of beta-endorphin (beta-EP), beta-lipotropin (beta-LPH) and cortisol. A single maximal dose of sodium valproate (400 mg) or diazepam (10 mg) did not significantly modify basal concentrations of beta-EP, beta-LPH and cortisol. On the other hand, in the same subjects, pretreatment with sodium valproate (20 mg X 3) or diazepam (10 mg X 2) blocked the increases in these hormones produced by hypoglycemic stress in all patients tested (p less than 0.01 vs. placebo at 45, 60 and 90 min after insulin injection), without affecting the decrease in blood glucose levels. The present data show that sodium valproate and diazepam inhibit stress-induced beta-EP, beta-LPH and cortisol secretion in humans, suggesting that endogenous GABA and benzodiazepine receptors participate in physiological mechanisms regulating the activity of the HPA axis.     

Serotoninergic agonists increase plasma levels of beta-endorphin and beta-lipotropin in humans

A pharmacological approach was used to investigate the serotoninergic control of plasma levels on beta-endorphin (beta-EP) and beta-lipotropin (beta-LPH) in humans. Acute administration of L5-OH-triptophan, the physiologic precursor of serotonin (SE), induced a significant rise in plasma beta-EP and beta-LPH levels both when injected iv (20 and 40 mg) (four normal men) and when administered orally (200 and 400 mg) (seven normal men) (P less than 0.01 vs. placebo). The iv route of administration induced a prompt (mean peak values after 150 min) dose-dependent increase in beta-EP and beta-LPH levels. The responses evoked by oral administration (mean peak values after 130 and 240 min) were not dose dependent. Fluoxetine (15 and 30 mg orally) a blocker of SE reuptake, induced a significant dose-related rise in plasma beta-EP and beta-LPH levels in a group of seven normal men (P less than 0.01) (mean peak values after 150 min). Pretreatment with methysergide, a SE receptor antagonist (3 X 2.8 mg orally, five men), did not induce any significant changes in plasma beta-EP and beta-LPH levels, but blocked the increase in the two hormones evoked by L5-OH-triptophan (40 mg iv). Plasma cortisol levels changed similarly to those of beta-EP and beta-LPH in all the experiments, indicating that putative serotoninergic drugs exert a positive role on the various corticotropin-releasing hormone-mediated secretions.     

PLASMA IMMUNOREACTIVE β-ENDORPHIN IS ELEVATED IN URAEMIA

Plasma immunoreactive-(IR) beta-endorphin (beta-EP) and beta-lipotrophin (beta-LPH) levels were measured in 15 adult uraemic patients on chronic haemodialysis. The presence of immunoreactivity eluting in the position of beta-EP was demonstrated following submission of pooled extracts of uraemic plasma to gel permeation chromatography on Sephadex G-50. To separate beta-EP from beta-LPH, pre-dialysis plasma extracts from six individual patients, and three pools of three patients each, were submitted to sequential immune-affinity chromatography and levels were measured by radioimmunoassay. In all cases, plasma IR beta-EP concentrations were markedly increased compared with normal subjects (m +/- SEM fmol/ml; 64.4 +/- 13.7 vs. 2.3 +/- 0.2). IR beta-LPH concentrations were also increased (m +/- SEM fmol/ml; 55.7 +/- 13.2 vs. normal 6.1 +/- 0.8). In addition, post-dialysis concentrations of plasma IR beta-EP and beta-LPH were lower than pre-dialysis levels (n = 4).     

Plasma beta-endorphin and beta-lipotropin levels increase in well trained athletes after competition and non competitive exercise

Plasma beta-endorphin (beta-EP) and beta-lipotropin (beta-LPH) levels were measured in 15 healthy trained marathon runners. These hormones were evaluated in two different conditions: 1-before (1h) and after a marathon race (n = 10); 2-before, during and after a prolonged (90 min) submaximal exercise (bicycle ergometer at 50% VO2 max) (n = 5). In these latter group plasma beta-EP and beta-LPH levels were measured every 15 min for 165 min. In all the athletes, both plasma beta-EP and beta-LPH levels were significantly higher after the end of the marathon race than in basal conditions (p less than 0.01). The prolonged exercise with bicycle ergometer significantly stimulated plasma beta-EP and beta-LPH levels. Starting 60 min after the beginning of the exercise, plasma beta-EP and beta-LPH levels resulted significantly higher than basal values until the end of the exercise (p less than 0.01 at 60, 75 and 90 min). These data confirming that marathon running is a potent stress stimulus, showed that the duration and related factors but not the work load may be considered critical in stimulating beta-EP and beta-LPH release during physical exercise.     

Modulation of arginine-induced insulin and glucagon secretion by the hepatic vagus nerve in the rat: effects of celiac vagotomy and administration of atropine

We hypothesized the existence of vagal arginine sensors in the liver which modulate arginine-induced pancreatic hormone secretion. The present study was carried out to examine the efferent pathways and receptor mechanisms from arginine sensors using selective vagotomies and autonomic drugs on the secretion of insulin and glucagon after ip injection of L-arginine (1 g/kg BW) in rats in an unanesthetized and unrestrained state. Hepatic vagotomy (sectioning of the hepatic branch of the vagus nerve) enhanced both plasma insulin and glucagon concentrations after ip arginine more than those in sham-vagotomized (control) rats. The effect of hepatic vagotomy was blocked by adding celiac vagotomy (sectioning of the celiac branches of the vagus nerve) or by previous administration of atropine methyl nitrate (10 mg/kg BW), but not by phentolamine (1 mg/kg BW) or propranolol (2 mg/kg BW). Celiac vagotomy alone did not affect the plasma insulin concentration; however, it reduced the plasma glucagon concentration after ip arginine compared to that in sham-vagotomized rats. Administration of atropine alone did not affect plasma insulin or glucagon concentrations after ip arginine. These results suggest that celiac branches of the vagus nerve act as efferent pathways to the pancreas through a muscarinic receptor mechanism in the hepatic arginine sensor-mediated pancreatic neuroendocrine system. The physiological role of these hepatic sensors may be to prevent arginine-induced exaggerated pancreatic hormone secretion and maintain blood glucose homeostasis.     

Impaired circadian rhythmicity of beta-lipotrophin, beta-endorphin and ACTH in heroin addicts

The circadian rhythm of plasma proopiocortin-related peptides was studied in 15 heroin addicts and in 6 sex- and age-matched controls. ACTH, beta-lipotrophin, (beta-LPH), beta-endorphin (beta-EP) and cortisol were measured by RIA either directly (cortisol), or after plasma extraction (ACTH) and Sephadex G-75 gel chromatography (beta-LPH and beta-EP) every 4 h from 8 a.m. to 8 p.m. and again at 8 a.m. the next morning. The means of the two 8 a.m. measurements of beta-LPH (2.67 +/- 0.34 fmol/ml, mean +/- SE), ACTH (2.74 +/- 0.71) and cortisol (218 +/- 31 pmol/ml) levels in heroin addicts were significantly lower than those in controls (6.28 +/- 0.61, 10.1 +/- 0.74 and 364 +/- 27, respectively, P less than 0.01) while beta-EP concentrations in heroin addicts (5.1 +/- 0.6) were similar to those of healthy volunteers (6.44 +/- 0.56). In controls, all three peptides and cortisol show a circadian rhythm of secretion, the lowest values being in the evening and the highest ones in the morning. Heroin addicts partially lack this phenomenon showing constant levels of the three proopiocortin-related peptides throughout the day, with a slight but significant decrease of plasma cortisol. In the 7 subjects who took heroin throughout the study, no systematic changes were observed in the three proopiocortin-related peptides, while it seems that this group of addicts shows a cortisol decrease in the evening to a lesser extent than subjects receiving methadone maintenance only.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacological manipulations of alpha-adrenoceptors in the infant rat and effects on growth hormone secretion. Study of the underlying mechanisms of action

The aim of this study was to evaluate whether in infant rats, as in adult rats, the brain adrenergic mechanisms regulate plasma GH levels and, if so, to determine the contribution of GH-releasing hormone (GHRH) and/or somatostatin (SS) pathways. In 10-day-old rats, activation of alpha 2-adrenoceptors by clonidine (CLO) was effective to stimulate GH release starting from 50 micrograms/kg ip and up to 450 micrograms/kg ip, though no dose-related effect was evident. Conversely, alpha 2-adrenoceptor blockade by yohimbine (YOH, 10 mg/kg, ip) decreased baseline GH levels. Administration of methoxamine (METHOX, 10 micrograms/rat, ip), a alpha 1-adrenoceptor agonist, significantly reduced plasma GH concentrations, while prazosin (5 mg/kg BW, ip), a specific alpha 1-adrenoceptor antagonist, stimulated plasma GH secretion. Administration of an anti-SS serum (SS-ab, 300 microliters, ip) induced a significant rise in plasma GH levels, while administration of an anti-GHRH serum (GHRH-ab, 100 microliters, ip) was associated with a striking fall in GH levels. In rats pretreated with SS-ab, administration of CLO induced a further rise in plasma GH levels. GHRH-ab significantly reduced plasma GH levels, and this effect was not altered by subsequent CLO administration. Administration of SS-ab and YOH resulted in plasma GH levels intermediate between those of rats treated with SS-ab alone or YOH alone, while pretreatment with GHRH-ab induced a lowering of plasma GH greater than when YOH was given alone. in rats pretreated with SS-ab, the GH-lowering effect of METHOX was completely lacking, while GHRH-ab and METHOX induced a lowering of plasma GH similar to that ensuing after METHOX alone or GHRH-ab alone. Administration of prazosin in rats pretreated with SS-ab did not elicit any further rise in plasma GH, while combined administration with GHRH-ab elicited a GH-lowering effect comparable to that elicited by GHRH-ab alone. These data demonstrate that in the infant rat: brain adrenergic mechanisms involved in the neural regulation of GH secretion are operative; different neuropeptide mechanisms mediate the effect of activation or inhibition of alpha 1- and alpha 2-adrenoceptors. In particular, activation of alpha 2-adrenoceptors stimulates GH secretion via endogenous GHRH release, although a mechanism operating to inhibit hypothalamic SS release cannot be excluded; stimulation of alpha 1-adrenoceptors is inhibitory to GH secretion exclusively via an increased release of hypothalamic SS.     

Serotonin and dopamine independently regulate pituitary beta-endorphin release in vivo

Serotonin and dopamine neurons have been shown to exert a stimulatory and inhibitory control, respectively, over pituitary release of beta-endorphin-like immunoreactivity (beta-END-LI). In the present study we sought to determine whether an interaction exists between these two reciprocal mechanisms regulating beta-END-LI in the rat. The intraperitoneal (i.p.) administration of 5 mg/kg quipazine, a serotonin receptor agonist, or 2.5 mg/kg haloperidol, a dopamine receptor antagonist, each elevated circulating levels by beta-END-LI 5-fold over control levels by 30 min post-injection. Pretreatment (1 h) with 5 mg/kg, i.p., cinanserin, a serotonin receptor antagonist, completely blocked the quipazine-induced rise in beta-END-LI without affecting the elevated levels of beta-END-LI in haloperidol-treated animals. Conversely, pretreatment (2 h) with 1 mg/kg, i.p., bromocriptine, a dopamine receptor agonist, had no effect on quipazine-induced release of beta-END-LI but did completely prevent the rise in plasma beta-END-LI due to haloperidol treatment. Gel filtration chromatography revealed that quipazine and haloperidol treatments elevated plasma levels of both beta-END-size immunoreactivity and beta-lipotropin (beta-LPH)-sized immunoreactivity though to different relative degrees. However, since circulating levels of beta-LPH serve as a marker for anterior lobe (AL) beta-END-LI secretion, serotonin and dopamine appear to exert stimulatory and inhibitory control, respectively, over AL beta-END-LI release. Further, the quipazine-induced rise in total plasma beta-END-LI primarily resembled beta-LPH in size and was blocked by cinanserin but not bromocriptine pretreatment. And conversely, bromocriptine but not cinanserin prevented the haloperidol-induced rise in circulating beta-END-LI.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prolactin release after 5-hydroxytryptophan treatment requires an intact neurointermediate pituitary lobe

The present study was designed to evaluate the role of the neurointermediate pituitary lobe (NIL) in the 5-hydroxytryptophan (5-HTP)-induced increase in plasma PRL levels. The neurochemical mechanisms involved in this neuroendocrine regulation were also analyzed by examining the concentrations of serotonin (5-HT), norepinephrine, and dopamine as well as their primary metabolites in the median eminence (ME), NIL, and anterior pituitary (AP) after different treatments. Removal of the NIL (NIL-X) did not significantly affect basal plasma PRL concentrations or amine metabolism in the ME or AP. 5-HTP administration resulted in a 5-fold increase in plasma PRL in sham-operated (SHAM) animals, but NIL-X completely abolished this PRL response. 5-HTP injection elicited large increases in 5-HT and 5-hydroxyindole-3-acetic acid concentrations in ME, NIL, and AP in SHAM animals, and similar changes within the ME and AP in NIL-X animals, but did not significantly affect norepinephrine or dopamine metabolism in the ME, NIL, or AP of NIL-X or SHAM animals. Moreover, tissue concentrations of 5-HTP after 5-HTP injection increased similarly in SHAM and NIL-X animals. Inhibition of peripheral decarboxylase activity with MK486 prevented the 5-HTP-induced increase in PRL in SHAM animals and the increase in 5-HT metabolism in both SHAM and NIL-X groups. These data indicate that an intact NIL is required for the 5-HTP-induced increase in plasma PRL, but does not seem to be essential for the regulation of basal PRL release. They also demonstrate that the 5-HTP-induced activation of 5-HT metabolism in both ME and AP is not sufficient, by itself, to enhance PRL release.     

Beta-lipotropin and beta-endorphin in physiological and surgical menopause

Beta-lipotropin (beta-LPH) and beta-endorphin (beta-EP) plasma levels were characterized by a significant decrease in postmenopausal females (22 subjects aged from 56 to 70 yr) when compared to fertile women (22 subjects from 31 to 45 yr). On the contrary, ACTH plasma levels determined in 10 of the premenopausal and 13 of the postmenopausal subjects reported above showed constant levels in both groups. A significant increase in the beta-LPH/beta-EP molar ratio was observed in postmenopausal females. The plasma beta-LPH and beta-EP levels studied before and 6 months after ovariectomy, showed a significant decrease in 8 out of 10 patients, while they remained constant in the other 2. Two subjects, in whom postsurgical samples were taken during a flushing episode, showed beta-LPH and beta EP plasma levels which were both higher than the corresponding preovariectomy values. The results suggest that these changes may be important in explaining modifications in behavior and mood frequently found in postmenopausal females and in patients undergoing surgical castration in the fertile age.     

Impairment of adrenergic-induced proopiomelanocortin-related peptide release in heroin addicts

The effects of iv stimulation with clonidine on plasma levels of beta-lipotropin (beta-LPH), beta-endorphin (beta-EP), cortisol, growth hormone (GH) and adrenocorticotrophic hormone (ACTH) were tested in a group of 10 healthy volunteers and in 8 heroin abusers. Hormones were measured either by direct radioimmunoassay (RIA) (GH, cortisol) or after plasma extraction and Sephadex G-75 column chromatography (beta-LPH and beta-EP) or by immunoradiometric assay (IRMA) (ACTH). Plasma levels of GH increased in a similar fashion in the two groups. In the controls, clonidine induced release of beta-LPH and beta-EP after 30 min (from 8.9 +/- 1.0 to 19.1 +/- 4.6 fmol/ml, P less than 0.01 and from 8.1 +/- 0.6 to 17.9 +/- 4.6, P less than 0.01) and of ACTH after 60 min (from 12.1 +/- 1.8 to 18.1 +/- 1.8, P less than 0.05) while in addicts beta-EP but not beta-LPH showed a significant increase (from 8.5 +/- 0.7 to 19.8 +/- 4.2, P less than 0.05), 90 min after the injection. In heroin addicts, plasma cortisol levels decreased continuously after clonidine stimulation while in controls they showed a biphasic pattern, decreasing until the 60th min (from 135.2 +/- 30.4 ng/ml to 74.0 +/- 13.3, P less than 0.05) and regaining basal levels 1 h later (122.0 +/- 24.8, P less than 0.05 vs 60th min value). These data demonstrate the existence in human beings of noradrenergic control of proopiomelanocortin (POMC)-related peptides and indicate that chronic opiate abuse greatly interferes with this control. Clonidine-induced release of plasma beta-EP may be of importance with regard to its therapeutic effects in detoxification.     

Hyperprolactinemia decreases the luteinizing hormone-releasing hormone concentration in pituitary portal plasma: a possible role for beta-endorphin as a mediator

Hyperprolactinemia can reduce the LH secretion in rats, but the mechanism of the effect of PRL is not clear. We have investigated the actions of PRL on the secretion of LHRH and LH and the interaction among PRL, beta-endorphin (beta-EP), and LHRH. The effects of PRL on LHRH and LH secretion were studied in ovariectomized female rats after transplanting four anterior pituitaries to the right kidney capsule of each ovariectomized rat for 2-3 weeks. The level of PRL in rats with pituitary transplants was approximately 5 times higher than that in control rats. The concentration of LHRH in pituitary portal plasma of hyperprolactinemic rats was approximately 4 times lower than that in control rats. Hyperprolactinemic animals also showed lower plasma LH levels than the controls. Since beta-EP inhibits the secretion of LHRH, we have tested whether the reduced secretion of LHRH in hyperprolactinemic ovariectomized rats is associated with an increase in beta-EP activity. This was studied by measuring the concentration of beta-EP in pituitary portal plasma and the response of LHRH and LH to the opiate antagonist naloxone. The level of beta-EP-like immunoreactivity in pituitary portal plasma was significantly higher in hyperprolactinemic rats than in control animals. Naloxone (10 mg/kg, sc) increased both LHRH and LH concentrations in hyperprolactinemic rats, but not in control rats. The present results demonstrate that hyperprolactinemia can reduce LHRH release and suggest a possible involvement of beta-EP in the PRL inhibitory action on LHRH.     

Insulin and glucagon secretion in swimming mice: effects of autonomic receptor antagonism

To study the regulation of islet hormone secretion in exercise-stress, we developed a swimming mouse model. Mice swam for 2, 6, or 10 minutes whereafter blood was sampled for analysis of plasma levels of insulin, glucagon, and glucose. Plasma insulin levels, which were not different from resting controls after 2 or 6 minutes of swimming, were slightly lower after 10 minutes of swimming (P less than .05). Plasma glucagon levels were increased after 2, 6, and 10 minutes of swimming (P less than .001), and plasma glucose levels were lower after 6 and 10 minutes of swimming (P less than .05). Glucose (5.6 mmol/kg)-stimulated insulin secretion was inhibited by 52% +/- 9% by the swimming (P less than .001). The mechanisms behind this inhibition of glucose-stimulated insulin secretion and the increase in basal plasma glucagon levels induced during 2 minutes of swimming were investigated by the use of autonomic receptor antagonists, administered intraperitoneally 20 minutes before the swimming period. The ganglionic antagonist hexamethonium (56 mumols/kg) prevented the swimming-induced inhibition of glucose-stimulated insulin secretion, indicating involvement of nerves in the inhibition. Also the nonselective alpha-adrenoceptor antagonist phentolamine (6.0 mumols/kg) and the alpha 2-adrenoceptor antagonist yohimbine (3.6 mumols/kg) prevented the inhibition of glucose-stimulated insulin secretion induced by swimming, whereas the beta-adrenoceptor antagonist L-propranolol (9.6 mumols/kg) had no effect. The swimming-induced increase in plasma glucagon levels was partially inhibited by hexamethonium by (58% +/- 24%, P less than .05). Phentolamine and yohimbine totally prevented the increase in plasma glucagon levels, whereas L-propranolol had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)     

DL-2-amino-5-phosphonopentanoic acid, a specific N-methyl-D-aspartic acid receptor antagonist, suppresses pulsatile LH release in the rat

To determine whether neuroexcitatory amino acids may play a role in generating intermittent hypothalamic GnRH release, the effect of N-methyl-D-aspartate (NMDA) receptor blockade on pulsatile LH secretion was examined in male rats. The ability of the NMDA receptor antagonist, DL-2-amino-5-phosphonopentanoic acid (AP5), to inhibit activation of the hypothalamic-pituitary gonadotroph axis that follows peripheral administration of NMDA, was first established in intact rats. Subsequently, acutely castrated rats (n = 12) bearing venous catheters received four consecutive intravenous injections of AP5 (3.75 mg/injection/rat; approx. 13.6 mg/kg BW/injection) at 15-min intervals. Blood samples were collected at 10-min intervals for 1 h before and 2 h after initiation of AP5 treatment, and plasma LH concentrations were determined by RIA. For control purposes, norvaline, and amino acid structurally related to AP5, was administered to a second group of animals (n = 7) in a quantity (2.25 mg/injection/rat; approx. 8.2 mg/kg BW/injection) equimolar to that of the NMDA receptor antagonist. A third group of animals (n = 8) received only saline, the vehicle employed to inject AP5 and norvaline. AP5, but not norvaline, resulted in a marked suppression of pulsatile LH secretion. These findings suggest that neuroexcitatory amino acids acting at the NMDA receptor may play a physiological role in generating the intermittent mode of hypothalamic GnRH release.     

Ontogeny of opioid inhibition of vasopressin and oxytocin release in response to osmotic stimulation

We have shown, using the opiate receptor antagonist naltrexone, that endogenous opioid peptides inhibit the release of oxytocin (OT), but not of vasopressin (AVP), from the hypothalamo-neurohypophysial system during dehydration. The stimulus for the release of neurohypophysial hormones during dehydration is both hypovolemia and increased plasma osmolality. The aims of this study were to determine whether opioid peptides inhibit OT secretion during an osmotic stimulus alone and, if so, to study the ontogeny of opiate inhibition of OT and AVP release during osmotic stimulation. Effects of endogenous opioid peptides were evaluated by injecting naloxone into immature and adult rats. Hypertonic saline was used as the osmotic stimulus. Adult male rats were injected sc with normal saline (0.85%; 1 ml/kg BW) or naloxone (5 mg/kg BW), followed 5 min later by normal or hypertonic (1 M) saline (15 ml/kg BW). After 170 min, a second injection of saline or naloxone was given; animals were decapitated 10 min later. Immature male and female rats at 2, 8, 21, and 30 days of age received 0.85% saline (1 ml/kg BW) or naloxone (5 mg/kg BW) ip 5 min before normal or hypertonic (2.5%) saline (20 ml/kg BW, ip). Pups were decapitated 15 min later. AVP and OT were measured by RIA in extracts of plasma, pituitaries, and hypothalami. In control rats, the contents of AVP and OT increased with age in both the pituitary and hypothalamus, attaining adult levels by day 21 for AVP and by day 30 for OT. In contrast, plasma concentrations of both AVP and OT were highest in 8-day-old rats and decreased thereafter to adult levels by 30 days of age. Hypertonic saline raised plasma osmolality 9-16 mosmol/kg H2O, increased AVP and OT concentrations in plasma of adults and immature rats at 2, 8, 21, and 30 days of age, and reduced pituitary stores of OT in adult animals. Blocking the action of opioid peptides with naloxone during osmotic stimulation augmented the rise in plasma OT in rats of all ages but further elevated plasma AVP only in immature rats. In adult animals, blocking opiate receptors with naloxone enhanced the depletion of OT stores from the pituitary, but did not affect the AVP content. We conclude that in the adult rat, endogenous opioid peptides inhibit OT release during osmotic stimulation, thereby allowing preferential release of AVP.(ABSTRACT TRUNCATED AT 400 WORDS)     

Opioid peptides of the pituitary and hypothalamus: changes in pregnant and lactating rats

Immunoreactive (Ir) beta-endorphin concentrations were determined in plasma, anterior pituitary (AP), neurointermediate pituitary lobe (NIL) and mediobasal hypothalamus (MBH) of pregnant (12-14 and 18-20 days) and fertile control rats, during labour and lactation. Immunoreactive Met-enkephalin concentrations were also evaluated in the MBH. Concentrations of Ir beta-endorphin in plasma, AP and NIL of rats during early and late pregnancy were significantly higher than in controls, the plasma and AP contents showing an increasing pattern in the second half of gestation. During labour, Ir beta-endorphin concentrations in plasma and AP reached the highest values, whereas those in NIl remained unchanged. Lactating rats showed Ir beta-endorphin concentrations in NIL and plasma in a range similar to that found in pregnant rats, resulting in concentrations in the AP not significantly different from those of nonpregnant controls. Immunoreactive beta-endorphin and Ir Met-enkephalin concentrations in MBH of pregnant rats were almost twice as high as in controls, rising markedly during labour; during lactation levels were in the same range as in non-pregnant controls. These results indicate that pregnancy and labour are characterized by high plasma, pituitary and hypothalamic concentrations of Ir-beta-endorphin as well as by high hypothalamic Ir Met-enkephalin levels, and that Ir beta-endorphin concentrations vary differently during pregnancy, lactation and labour in the two pituitary lobes, supporting the existence of different control mechanisms in the AP and NIL.     

Hyperprolactinemia exerts a negative effect on the beta-endorphin content of the rat neurointermediate pituitary lobe

Implantation of the PRL, ACTH, beta-endorphin (beta-EP), and beta-lipotropin (beta-LPH)-secreting transplantable rat pituitary tumor 7315a resulted in a suppression of the PRL and the ACTH content of the anterior pituitary gland and also of the beta-EP/beta-LPH content of the neurointermediate (NI) lobe. Treatment with bromocriptine further diminished the anterior lobe PRL content, whereas haloperidol partially inhibited this tumor-mediated diminution. The administration of these drugs did not influence the suppressed ACTH content of the anterior pituitary lobe. The diminished beta-EP/beta-LPH content of the NI lobe of tumor-bearing rats became completely normal after treatment with haloperidol, whereas bromocriptine administration further diminished the NI lobe beta-EP/beta-LPH content. There was a close correlation between the anterior pituitary lobe PRL content and the beta-EP/beta-LPH content of the NI lobe in all four groups of rats taken together (including nontumor-bearing controls, control tumor rats, and tumor rats treated with bromocriptine or haloperidol; P less than 0.01). Implantation of the pure PRL-secreting pituitary tumor 7315b resulted in hyperprolactinemia and a suppression of the PRL content of the anterior lobe and the beta-EP/beta-LPH content of the NI lobe, without affecting the ACTH content of the anterior pituitary lobe. There was a negative correlation between the level of the circulating PRL concentration and the beta-EP/beta-LPH content of the NI lobe. These results suggest a possible relationship between the synthesis of PRL by the anterior pituitary lactotroph and of the hormones of the NI lobe. The level of the circulating PRL concentration may play, directly or indirectly, a role in the regulation of both systems.     

Specific radioimmunoassay of human beta-endorphin in unextracted plasma.

With an antiserum against human beta-endorphin (beta-EP) crossreacting less than 2% with human beta-lipotropin (beta-LPH) by weight we have developed a radioimmunoassay that can detect 1 pg beta-EP in diluted raw plasma. In a.m. fasting plasma of 14 normal subjects beta-EP ranged from less than 5 to 45 pg/ml. beta-EP was elevated in untreated, but normal in successfully treated Cushing's disease; undetectable in a patient with adrenal adenoma; extremely high in Nelson's syndrome; and elevated in a patient with bronchogenic carcinoma before, but undetectable after tumor resection. In subjects with intact hypothalamic-pituitary-adrenal axis, beta-EP was undetectable after dexamethasone and increased after metyrapone administration and insulin-induced hypoglycemia. beta-EP concentration was considerably lower in serum than in simultaneously collected plasma, but increased in serum left unfrozen for several hours after clot removal. Thus, beta-EP behaves like a hormone responding to the same stimuli as ACTH and beta-LPH and blood appears to contain enzymes both generating and destroying immunoreactive beta-EP.     

Role of alpha-adrenergic mechanism in effects of morphine on the hypothalamo-pituitary-adrenocortical and cardiovascular systems in the rat

The role of alpha-adrenergic mechanism in the acute effects of morphine in the hypothalamo-pituitary-adrenocortical (HPA) and cardiovascular (CV) systems, and the interrelationship between the HPA and CV responses to alpha-adrenoceptor antagonists and/or morphine were studied by peripheral administration of prazosin, a selective alpha 1-adrenoceptor antagonist, and yohimbine, a selective alpha 2-adrenoceptor antagonist, in conscious, unstressed or ether-stressed rats. The test substances were administered intravenously or intraperitoneally in chronically cannulated or noncannulated rats. In the i.v. experiment, morphine (1 mg/100 g BW) rapidly induced a pronounced bradycardia and a short-lasting fall in blood pressure (BP), followed by a rise in BP, and increased plasma corticosterone concentration. Prazosin (0.5 mg/kg BW) induced a rapid fall in BP and tachycardia, and increased plasma corticosterone concentration. Pretreatment with prazosin did not block the effect of morphine on the CV system, but abolished the morphine-induced increment in plasma corticosterone concentration. Yohimbine (0.5 mg/kg BW) induced a rapid and a subsequent slowly developing rise in BP and tachycardia, and increased plasma corticosterone concentration. Pretreatment with yohimbine did not block the effect of morphine on the CV system nor alter the stimulatory effect of morphine on the secretion of corticosterone. In the intraperitoneal experiment, morphine (2 mg/100 g BW) stimulated the secretion of adrenocorticotropic hormone (ACTH) and corticosterone and prazosin (1 mg/kg BW) stimulated the secretion of corticosterone, but pretreatment with prazosin reduced the morphine-induced increment in plasma corticosterone concentration in unstressed rats. In stressed rats, morphine reduced the stress-induced increment in plasma ACTH and corticosterone concentrations and prazosin also reduced the stress-induced increment in plasma corticosterone concentration. Pretreatment with prazosin did not alter the inhibitory effect of morphine...     

Stress-induced suppression of luteinizing hormone concentrations in wild baboons: role of opiates

Numerous stressors disrupt male reproductive physiology; previous studies of a population of wild baboons, living freely in a national park in East Africa, indicated that the stress of anesthetization by phencyclidine darting decreased both LH secretion and testicular sensitivity to LH. This study was undertaken to determine the mechanism(s) of the decreased LH secretion in these animals. Neither stress-induced glucocorticoid nor catecholamine release was responsible, since neither blockade of glucocorticoid secretion with the adrenal steroidogenesis inhibitor metyrapone nor blockade of catecholamine secretion with the sympathetic ganglionic blocking drug chlorisondamine prevented the stress-induced decline in serum LH concentrations. Administration of the opiate receptor antagonist naloxone (0.5 mg/kg BW), however, not only prevented the decline, but also transiently elevated serum LH concentrations, suggesting that opiates play a role in tonic as well as stress-induced decreases in LH secretion. Administration of a small dose of naloxone (0.03 mg/kg BW) commensurate with occupancy of only mu-opiate receptors slowed the stress-induced decline in LH concentrations, as did administration of the kappa-receptor antagonist MR 1452. These data suggest that opiates inhibit LH release via the combined occupancy of both mu- and kappa-receptors.