Beta-endorphin Secretion Research Articles

Liraglutide Activates Glucagon-Like Peptide 1 Receptor to Attenuate Hyperglycemia through Endogenous Beta-Endorphin in Diabetic Rats.

Liraglutide, an acylated analog of glucagon-like peptide 1 (GLP-1), could improve glycemic control in diabetes. Moreover, endogenous opioid peptides play a role in blood sugar regulation. Since GLP-1 receptors are also expressed in extra-pancreatic tissues, this study investigates the effect of liraglutide on endogenous opioid secretion in type 1-like diabetes. The endogenous opioid level was determined by enzyme-linked immunosorbent assay. The direct effect of liraglutide on endogenous opioid secretion was determined in the isolated adrenal medulla. Acute treatment with liraglutide dose-dependently attenuated hyperglycemia, and increased the plasma opioid neuropeptide, beta-endorphin (BER) levels in diabetic rats. These effects have been blocked by GLP-1 receptor antagonist, naloxone. Additionally, the effects of liraglutide were markedly reduced in adrenalectomized diabetic rats. In the isolated adrenal medulla, liraglutide induced BER secretion and increased the BER mRNA levels. Subcellular effects of liraglutide on the adrenal gland were further identified to mediate through the exchange proteins directly activated by cAMP, mainly using the pharmacological blockade. After repeatedly administering liraglutide, metabolic changes in diabetic rats were investigated, and genes associated with gluconeogenesis in the liver were downregulated. Naloxone pretreatment inhibited these effects of liraglutide, indicating the involvement of endogenous opioids. The present study indicated that liraglutide had an acute effect of reducing hyperglycemia by regulating endogenous opioid BER and modifying the glucose homeostasis.

Molecular Basis for Hormone Recognition and Activation of Corticotropin-Releasing Factor Receptors.

Corticotropin-releasing factor (CRF) and the three related peptides urocortins 1-3 (UCN1-UCN3) are endocrine hormones that control the stress responses by activating CRF1R and CRF2R, two members of class B G-protein-coupled receptors (GPCRs). Here, we present two cryoelectron microscopy (cryo-EM) structures of UCN1-bound CRF1R and CRF2R with the stimulatory G protein. In both structures, UCN1 adopts a single straight helix with its N terminus dipped into the receptor transmembrane bundle. Although the peptide-binding residues in CRF1R and CRF2R are different from other members of class B GPCRs, the residues involved in receptor activation and G protein coupling are conserved. In addition, both structures reveal bound cholesterol molecules to the receptor transmembrane helices. Our structures define the basis of ligand-binding specificity in the CRF receptor-hormone system, establish a common mechanism of class B GPCR activation and G protein coupling, and provide a paradigm for studying membrane protein-lipid interactions for class B GPCRs.

296 Minerals skin effects, new discoveries and proposed mechanism as demonstrated via Dead Sea water

This study suggests possible bio-mechanisms of Dead Sea (DS) minerals, in which epidermal structure and skin barrier functioning could be affected. Various skin biomarkers were measured on skin tissue models following topical application of DS water. Therapeutic effects of DS minerals are well established, and their unique combination was analyzed and reported. Clinical studies had demonstrated alleviation in health parameters related to skin manifestations derived from psoriasis, atopic dermatitis and premature photo-aging, as well as enhancing moisturizing level and decrease roughness. Yet, skin biological mechanisms, beyond all reported bioactivities, are not fully understood. In this study the effects of topical application of DS water were analyzed using reconstructed skin and human skin organ culture models. DNA/RNA micro-array techniques, protein quantification and enzymatic activity assays were performed to explore possible modes of action on healthy and stressed skin. The reported results present new findings of DS minerals, revealing unexpected activation of pivotal pathways linked to beta endorphin secretion, Keap1-Nrf2 system upregulation, attenuation of stress-induced cytokines (IL-1 alpha, IL-1 beta, TNF alpha), ion pumps activation and barrier function recovery. These new findings, including the new discovery of DS water bioactivity via beta-endorphin secretion, may provide a new explanation for established DS minerals contribution in alleviating skin symptoms (e.g. psoriasis, atopic dermatitis and pre-mature photo aging) and pave the way for new strategies in future therapies.

Ancient Chinese medicine and mechanistic evidence of acupuncture physiology

Acupuncture has been widely used in China for three millennia as an art of healing. Yet, its physiology is not yet understood. The current interest in acupuncture started in 1971. Soon afterward, extensive research led to the concept of neural signaling with possible involvement of opioid peptides, glutamate, adenosine and identifying responsive parts in the central nervous system. In the last decade scientists began investigating the subject with anatomical and molecular imaging. It was found that mechanical movements of the needle, ignored in the past, appear to be central to the method and intracellular calcium ions may play a pivotal role. In this review, we trace the technique of clinical treatment from the first written record about 2,200 years ago to the modern time. The ancient texts have been used to introduce the concepts of yin, yang, qi, de qi, and meridians, the traditional foundation of acupuncture. We explore the sequence of the physiological process, from the turning of the needle, the mechanical wave activation of calcium ion channel to beta-endorphin secretion. By using modern terminology to re-interpret the ancient texts, we have found that the 2nd century b.c. physiologists were meticulous investigators and their explanation fits well with the mechanistic model derived from magnetic resonance imaging (MRI) and confocal microscopy. In conclusion, the ancient model appears to have withstood the test of time surprisingly well confirming the popular axiom that the old wine is better than the new.

Salivary stress markers and psychological stress in simulated microgravity: 21 days in 6° head-down tilt

Spaceflight occurs in an environment of temperature extremes, microgravity, solar and galactic cosmic radiation, lack of atmospheric pressure, and high-speed micrometeorites. Exposure to microgravity and the space environment during space missions of short and long duration has important medical and health implications for astronauts. Psychological well-being is of increasing importance in planned spaceflights and interplanetary missions of long duration. The 6° head-down tilt (HDT) is an established method of mimicking low gravity on earth. The aim of the present study was to determine the effects of 21 days of HDT on psychological stress in 12 healthy male volunteers. Psychological state was assessed by the current stress test, and chromogranin-A (CgA), cortisol, alpha-amylase, and beta-endorphin were measured in saliva. After one week of HDT, all volunteers developed psychological stress, and secretion of CgA, cortisol, alpha-amylase, and beta-endorphin were all significantly higher. Thus, 6° HDT appears to be a valid model to induce psychological stress changes in the immune system, changes that might also be encountered by astronauts and cosmonauts during both a short stay in space, such as that required while orbiting a space station, and in longer spaceflights.

Endothelin-A Receptor Antagonism Attenuates Carcinoma-Induced Pain Through Opioids in Mice

We previously reported that endothelin A (ET-A) receptor antagonism attenuates carcinoma-induced pain in a cancer pain mouse model. In this study, we investigated the mechanism of ET-A receptor-mediated antinociception and evaluated the role of endogenous opioid analgesia. Squamous cell carcinoma (SCC) cell culture treated with the ET-A receptor antagonist (BQ-123) at 10(-6) M and 10(-5) M significantly increased production and secretion of beta-endorphin and leu-enkephalin, respectively. Behavioral studies were performed by inducing tumors in the hind paw of female nude mice with local injection of cells derived from a human oral SCC. Significant pain, as indicated by reduction in withdrawal thresholds in response to mechanical stimulation, began at 4 days after SCC inoculation and lasted to 18 days, the last day of measurement. Local administration of either naloxone methiodide (500 microg/kg), selective antagonists for mu-opioid receptor (CTOP, 500 microg/kg), or delta-opioid receptor (naltrindole, 11 mg/kg) but not kappa-opioid receptor (nor-BNI, 2.5 mg/kg) significantly reversed antinociception observed from ET-A receptor antagonism (BQ-123, 92 mg/kg) in cancer animals. These results demonstrate that antagonism of peripheral ET-A receptor attenuates carcinoma pain by modulating release of endogenous opioids to act on opioid receptors in the cancer microenvironment. This article proposes a novel mechanism for ET-A receptor antagonist drugs in managing cancer-induced pain. An improved understanding of the role of innate opioid analgesia in ET-A receptor-mediated antinociception might provide novel alternatives to morphine therapy for the treatment of cancer pain.

The dynamics of beta-endorphin release by the hypothalamic nuclei and pituitary gland in sheep under physiological and stress condition.

The secretion of beta-endorphin (beta-End) by the infundibular nuclei--median eminence (IN-ME) and paraventricular nuclei (PVN) of the hypothalamus and the anterior lobe (AL) of the pituitary gland was determined in 18 anestrous ewes by RIA assay of this opioid in perfusates collected from these formations. Perfusion with Ringer-Locke solution was carried out on the animals under resting and stress-full conditions, using a pushpull cannula method. Electrical footshocks were used as stress stimuli. Two series of perfusion experiments were performed. In the first, the perfusions were carried out over two hours and perfusates were collected before and during stress for 1 h. In the second series of experiments the dynamics of the release of the opioid by the IN-ME and the pituitary gland were followed by collecting five or six perfusates in 20 min fractions before and during stress, respectively. The first series of experiments showed that the concentrations of beta-End in perfusates from the pituitary gland were much higher than those from the hypothalamic nuclei and that the concentrations of this opioid during stressing rose significantly only in perfusates from the IN-ME nuclei. In the second series of experiments the release of beta-End from the IN-ME and pituitary gland was altered by stress. The shift was very characteristic in that the concentrations of the opioid during stimulation initially significantly rose and then gradually declined. The concentration of the opioid in the peripheral blood also rose at the beginning of stimulation and declined as stimulation continued.(ABSTRACT TRUNCATED AT 250 WORDS)

Mediation of β-endorphin in andrographolide-induced plasma glucose-lowering action in type I diabetes-like animals

In the present study, we investigated the mechanism(s) for glucose-lowering action of andrographolide in streptozotocin-induced diabetic rats (STZ-diabetic rats). Andrographolide lowered plasma glucose concentrations in a dose-dependent manner and increased plasma beta-endorphin-like immunoreactivity (BER) dose-dependently in diabetic rats. Both of these responses to andrographolide were abolished by the pretreatment of animals with prazosin or N-(2-(2-cyclopropylmethoxy) ethyl) 5-choro-alpha-dimethyl-1H-indole-3-thylamine (RS17053) at doses sufficient to block alpha1-adrenoceptors (ARs). Also, andrographolide enhanced BER release from isolated rat adrenal medulla in a concentration-related manner that could be abolished by alpha1-ARs antagonists. Bilateral adrenalectomy in STZ-diabetic rats eliminated the activities of andrographolide, including the plasma glucose-lowering effect and the plasma BER-elevating effect. Andrographolide failed to lower plasma glucose in the presence of opioid micro-receptor antagonists and in the opioid micro-receptor knockout diabetic mice. Treatment of STZ-diabetic rats with andrographolide resulted in the reduced expression of phosphoenolpyruvate carboxykinase (PEPCK) in liver and an increased expression of the glucose transporter subtype 4 (GLUT 4) in soleus muscle. These effects were also blocked by opioid micro-receptor antagonists. In conclusion, our results suggest that andrographolide may activate alpha1-ARs to enhance the secretion of beta-endorphin which can stimulate the opioid micro-receptors to reduce hepatic gluconeogenesis and to enhance the glucose uptake in soleus muscle, resulting in a decrease of plasma glucose in STZ-diabetic rats. However, the roles of other endogenous opioid peptides or the mixture of several opioid peptides in the activation of opioid micro-receptors associated with the plasma glucose-lowering action of andrographolide, should be considered and need more investigation in the future.

Increase of β-Endorphin Secretion by Syringin, an Active Principle of Eleutherococcus senticosus, to Produce Antihyperglycemic Action in Type 1-like Diabetic Rats

We employed streptozotocin-induced diabetic rats (STZ-diabetic rats) as type 1 diabetes-like animal models to investigate the mechanism(s) of antihyperglycemic action produced by syringin, an active principle purified from the rhizome and root part S of ELEUTHEROCOCCUS SENTICOSUS (Araliaceae). Bolus intravenous (i. v.) injection of syringin dose-dependently decreased the plasma glucose of STZ-diabetic rats in 30 minutes in a way parallel to the increase of plasma beta-endorphin-like immunoreactivity (BER). Syringin enhanced BER release from the isolated adrenal medulla of STZ-diabetic rats in a concentration-dependent manner from 0.001 to 10 micromol/l. Bilateral adrenalectomy in STZ-diabetic rats eliminated the activities of syringin (1 mg/kg, i. v.) including the plasma glucose-lowering effect and the plasma BER-elevating effect. Also, syringin failed to lower plasma glucose in the presence of micro-opioid receptor antagonists and/or in the micro-opioid receptor knockout diabetic mice. In conclusion, the obtained results suggest that syringin can enhance the secretion of beta-endorphin from adrenal medulla to stimulate peripheral micro-opioid receptors resulting in a decrease of plasma glucose in diabetic rats lacking insulin.

Dopamine-2 receptors in the arcuate nucleus modulate cocaine-seeking behavior

Beta-endorphin is an endogenous opioid peptide, implicated in the behavioral effects of drugs of abuse. It is synthesized in the arcuate nucleus and secreted into the nucleus accumbens. In the present study, we examined the interaction between arcuate nucleus dopaminergic cells and accumbal beta-endorphin, during cocaine exposure. Using microdialysis, we found that blockade of arcuate dopamine-2 receptors with a selective antagonist significantly attenuated cocaine-induced increases of beta-endorphin levels in the nucleus accumbens. Moreover, rats chronically exposed to cocaine using the self-administration paradigm displayed extinction-like behavior following blockade of dopamine-2 receptors. These findings indicate that dopaminergic neurons in the arcuate nucleus may induce the secretion of beta-endorphin in the nucleus accumbens, and that they are implicated in the cocaine reward pathway.

Mediation of β-Endorphin by Ginsenoside Rh2 to Lower Plasma Glucose in Streptozotocin-Induced Diabetic Rats

We investigated the plasma glucose-lowering mechanism(s) of Rh2, a ginsenoside derived from Panax ginseng, in rats with streptozotocin-induced diabetes (STZ-diabetic rats). After intravenous injection over 120 min into fasting STZ-diabetic rats, Rh2 decreased plasma glucose in a dose-dependent manner. In parallel to the lowering of plasma glucose, an increase of plasma beta-endorphin-like immunoreactivity was observed. In addition, naloxone and naloxonazine at doses sufficient to block opioid mu-receptors inhibited the plasma glucose-lowering action of Rh2 in genetically wild-type, diabetic mice. In contrast, Rh2 failed to lower plasma glucose in opioid mu-receptor knockout diabetic mice. An increase in gene expression at both the mRNA and protein levels of glucose transporter subtype 4 (GLUT 4) was observed in soleus muscle obtained from STZ-diabetic rats treated with Rh2 three times daily for one day; this increase in expression was absent when opioid mu-receptors were blocked. In conclusion, our results suggest that ginsenoside Rh2 may lower plasma glucose in STZ-diabetic rats based on an increase in beta-endorphin secretion that activates opioid mu-receptors thereby resulting in an increased expression of GLUT 4.

Repeated stress alters the ability of nicotine to activate the hypothalamic–pituitary–adrenal axis

Acute nicotine administration has been shown to activate the hypothalamic-pituitary-adrenal (HPA) axis and stimulate secretion of adrenocorticotrophic hormone (ACTH), corticosterone/cortisol and beta-endorphin (beta-END) in both rodents and humans, raising the possibility that activation of the HPA axis by nicotine may mediate some of the effects of nicotine. Since stress can increase the risk of drug use and abuse, we hypothesized that repeated stress would increase the ability of nicotine to stimulate the secretion of HPA hormones. To test our hypothesis, mice were exposed to repeated stress (swimming in 15 degrees C water for 3 min/day for 5 days) and killed 15 min after injection of saline or nicotine (0.1 mg/kg, s.c.). Repeated exposure to stress increased the ability of nicotine to stimulate plasma ACTH (p<0.05) and beta-END (p<0.05), but not corticosterone secretion. In contrast, repeated exposure to stress increased the post-saline injection levels of corticosterone (p<0.05), but not ACTH and beta-END. The present results suggest that chronic stress leads to an enhanced sensitivity of some components of the HPA axis to a subsequent nicotine challenge.

Mechanism for blockade of angiotensin subtype 1 receptors to lower plasma glucose in streptozotocin‐induced diabetic rats

We investigated the mechanism(s) by which valsartan, a selective antagonist of angiotensin subtype 1 (AT(1)) receptor, decreased plasma glucose in streptozotocin (STZ)-induced diabetic rats. The plasma glucose concentration was assessed by the glucose oxidase method. The concentration of beta-endorphin in plasma or medium incubating adrenal medulla was measured using an enzyme-linked immunosorbent assay. The mRNA levels of the subtype 4 form of glucose transporter (GLUT4) in soleus muscle and phosphoenolpyruvate carboxykinase (PEPCK) in the liver were detected by Northern blotting analysis, while the protein levels of GLUT4 in isolated soleus muscle and hepatic PEPCK were investigated using Western blotting analysis. A single intravenous injection of valsartan dose-dependently increased plasma beta-endorphin-like immunoreactivity (BER) in parallel with the lowering of plasma glucose concentration in STZ-induced diabetic rats. Naloxone and naloxonazine inhibited the plasma glucose-lowering action of valsartan at doses sufficient to block opioid micro-receptors. In contrast to its action in wild-type diabetic mice, valsartan failed to modify plasma glucose in opioid micro-receptor knockout diabetic mice. Bilateral adrenalectomy in STZ-induced diabetic rats eliminated both the plasma glucose-lowering action and the plasma BER-elevating action of valsartan. In the isolated adrenal medulla of STZ-induced diabetic rats, angiotensin II (Ang II) or valsartan did not affect spontaneous BER secretion. Activation of cholinergic receptors by 1.0 micromol/l acetylcholine (ACh) enhanced BER secretion from the isolated adrenal medulla of STZ-induced diabetic rats, but not in the presence of 1.0 nmol/l Ang II, while valsartan reversed this inhibition by Ang II in a concentration-dependent manner. Treatment of STZ-induced diabetic rats with valsartan (0.2 mg/kg) three times daily for 3 days resulted in an increase in gene expression of GLUT4 in soleus muscle and impeded the reduction of elevated mRNA or protein level of hepatic PEPCK. Both of these effects were blocked by opioid micro-receptor antagonist. The results suggest that blockade of AT(1) receptor by valsartan may enhance the adrenal beta-endorphin secretion induced by ACh, activating the opioid micro-receptors to increase glucose utilization and/or to decrease hepatic gluconeogenesis, resulting in the reduction of plasma glucose in STZ-induced diabetic rats.

Activation of imidazoline receptors in adrenal gland to lower plasma glucose in streptozotocin-induced diabetic rats

The present study investigated the effect of agmatine, an endogenous ligand of imidazoline receptors, on plasma glucose in streptozotocin-induced diabetic rats (STZ-diabetic rats). Plasma glucose was assessed by the glucose oxidase method. Plasma insulin and beta-endorphin-like immunoreactivity in plasma or adrenal medulla were measured by enzyme-linked immunosorbent assay. Systolic blood pressure was determined by the tail-cuff method. The mRNA levels of glucose transporter subtype 4 (GLUT4) in soleus muscle and phosphoenolpyruvate carboxykinase (PEPCK) in liver were detected by northern blotting. Protein levels of GLUT4 in soleus muscle and hepatic PEPCK were estimated using western blotting analysis. After intravenous injection into fasting STZ-diabetic rats for 30 min, agmatine decreased plasma glucose in a dose-dependent manner without changing systolic blood pressure. At the same time, plasma beta-endorphin-like immunoreactivity also increased in STZ-diabetic rats receiving the same treatment. Plasma glucose was significantly elevated in STZ-diabetic rats by an intravenous injection of clonidine at a dose sufficient to decrease systolic blood pressure. Involvement of I(1)-imidazoline receptors and/or alpha2-adrenoceptors in this effect of agmatine was thus unlikely. The lowering of plasma glucose and increase of plasma beta-endorphin-like immunoreactivity by agmatine were abolished by pretreating the rats with BU-224 at a dose sufficient to block I(2)-imidazoline receptors. Both effects of agmatine were also abolished in adrenalectomised STZ-diabetic rats. Moreover, agmatine enhanced beta-endorphin-like immunoreactivity release from the isolated adrenal medulla of STZ-diabetic rats, an effect also blocked by BU-224. Release of beta-endorphin from the adrenal glands by I(2)-imidazoline receptor activation seems responsible for the plasma glucose-lowering action of agmatine. This was supported by the fact that intravenous injection of naloxone or naloxonazine at doses sufficient to block opioid mu-receptors inhibited the action of agmatine. In addition to lowering plasma glucose, repeated intravenous injection of agmatine into STZ-diabetic rats for 4 days also increased mRNA and protein levels of GLUT4 in soleus muscle. The same treatment also reversed the higher mRNA and protein levels of PEPCK in liver of STZ-diabetic rats. Our results suggest that agmatine may activate I(2)-imidazoline receptors in the adrenal gland. This enhances secretion of beta-endorphin, which can activate opioid mu-receptors to increase GLUT4 gene expression and/or suppress hepatic PEPCK gene expression, resulting in a lowering of plasma glucose in diabetic rats lacking insulin. The results provide a potential new target for intervention in type 1 diabetes.

Mediation of beta-endorphin by the isoflavone puerarin to lower plasma glucose in streptozotocin-induced diabetic rats.

We investigate the mechanism(s) of plasma glucose lowering action of puerarin in streptozotocin-induced diabetic rats (STZ-diabetic rats). Puerarin at the effective dosage to lower higher plasma glucose increased plasma beta-endorphin-like immunoreactivity (BER) in STZ-diabetic rats. Both effects of puerarin were abolished by the pretreatment with prazosin. Also, puerarin enhanced BER release from isolated rat adrenal medulla in a concentration-dependent manner that can be abolished by prazosin. Moreover, bilateral adrenalectomy in STZ-diabetic rats eliminated the actions of puerarin including the plasma glucose lowering effect and plasma BER elevating effect. In addition, naloxone and naloxonazine inhibited the plasma glucose lowering action of puerarin. Unlike in wild-type diabetic mice, puerarin failed to lower the plasma glucose in opioid micro-receptor knockout diabetic mice. In conclusion, our results suggest that puerarin may activate alpha (1)-adrenoceptors on the adrenal gland to enhance the secretion of beta-endorphin to result in a decrease of plasma glucose in STZ-diabetic rats.

Mediation of beta-endorphin by isoferulic acid to lower plasma glucose in streptozotocin-induced diabetic rats.

We investigated the mechanism(s) by which isoferulic acid lowers plasma glucose levels in streptozotocin-induced diabetic rats (STZ-diabetic rats). In STZ-diabetic rats, isoferulic acid dose dependently lowered plasma glucose concentrations and increased plasma beta-endorphin-like immunoreactivity (BER). Both of these effects of isoferulic acid were abolished by pretreatment of rats with tamsulosin or 2-[2,6-dimethoxyphenoxyethyl]aminomethyl-1,4-benzodioxane hydrochloride (WB 4101) at doses sufficient to block alpha1-adrenoceptors. Also, isoferulic acid enhanced BER release from isolated rat adrenal medulla in a concentration-dependent manner that could be abolished by treatment with alpha1-adrenoceptor antagonists. Moreover, bilateral adrenalectomy in STZ-diabetic rats eliminated the activities of isoferulic acid, including the plasma glucose-lowering effect and the plasma BER-elevating effect. Naloxone and naloxonazine inhibited the plasma glucose-lowering activity of isoferulic acid at doses sufficient to block opioid mu-receptors. In contrast with the effect in wild-type diabetic mice, isoferulic acid failed to lower plasma glucose levels in opioid mu-receptor knockout diabetic mice. Treatment of STZ-diabetic rats with isoferulic acid three times in 1 day resulted in an increase in the expression of the glucose transporter subtype 4 form in soleus muscle. This effect was blocked by alpha1-adrenoceptor or opioid mu-receptor antagonists. The reduction of elevated mRNA or protein level of hepatic phosphoenolpyruvate carboxykinase was also impeded in the same groups of STZ-diabetic rats. In conclusion, our results suggest that isoferulic acid may activate alpha1-adrenoceptors to enhance the secretion of beta-endorphin, which can stimulate the opioid mu-receptors to increase glucose use or/and reduce hepatic gluconeogenesis, resulting in a decrease of plasma glucose in STZ-diabetic rats.

The effects of GnRH and adrenergic agents on PRL and ß-endorphin secretion by porcine pituitary cells in vitro

The direct effects of alpha- and beta-adrenergic agents on PRL and beta-endorphin (beta-END) secretion in vitro by porcine pituitary cells have been investigated. Pituitary glands were obtained from mature gilts, which were ovariectomised (OVX) one month before slaughter. Ovariectomised gilts, assigned to four groups, were primed with: (1) vehicle (OVX); (2) and (3) oestradiol benzoate (EB; 2.5 mg/100 kg b.w.) at 30-36 h (OVX+EB I) and 60-66 h (OVX+EB II) before slaughter, respectively; and (4) progesterone (P4; 120 mg/100 kg b.w.) for 5 consecutive days before slaughter (OVX+P4). Isolated anterior pituitary cells were submitted to 3.5 h incubation in the presence of GnRH, alpha- and beta-adrenergic agonists [phenylephrine (PHEN) and isoproterenol (ISOP), respectively], or alpha- and beta-adrenergic blockers [phentolamine (PHENT) and propranolol (PROP), respectively]. The culture media were assayed for PRL (exp. I) and beta-endorphin-like immunoreactivity (beta-END-LI) (experiment II). In experiment I, GnRH did not influence PRL release by pituitary cells in all experimental groups. Some of tested doses of adrenergic agonists, PHEN and ISOP, increased PRL release from pituitary cells of OVX gilts, but not from those of OVX+EB I animals. In the OVX+EB II group, PHEN alone, but ISOP with PROP, potentiated PRL secretion by the cells. In OVX+P4 animals, PHEN alone or in combination with PHENT and also ISOP alone or with PROP enhanced PRL output from the cells. In experiment II, addition of GnRH increased beta-END-LI release from pituitary cells only in the OVX+EB II group. PHEN and PHENT potentiated beta-END-LI secretion by pituitary cells in OVX+EB II and OVX+P4 groups, while ISOP and PROP increased beta-END-LI secretion by the cells of OVX and OVX+EB II animals. In turn, in the OVX+EB I group, effect of PHENT and PROP on PRL secretion by pituitary cells was inhibitory. In conclusion, our results suggest that adrenergic agents can modulate PRL and beta-END secretion by porcine pituitary cells in a manner dependent on the hormonal status of gilts.

Neuroendocrine effects of raloxifene hydrochloride in postmenopausal women

Raloxifene is a selective estrogen modulator able to exert an estrogen-like action on some target tissues and a specific antiestrogenic action on the uterus and breast. In ovariectomized rats, it has been shown to stimulate the beta-endorphin and allopregnanolone concentrations of the anterior and neurointermediate pituitary lobes, the hypothalamus and the hippocampus. The present study aimed to evaluate, in 12 healthy postmenopausal women, the effect of 60 mg/day raloxifene hydrochloride administration for 6 months on plasma beta-endorphin and allopregnanolone levels, and on the dynamic changes of both beta-endorphin and allopregnanolone secretion after the administration of: (1) clonidine, an alpha 2-presynaptic adrenergic agonist; (2) naloxone, an opioid receptor antagonist; and (3) fluoxetine, a serotonin selective reuptake inhibitor. The administration of raloxifene significantly increased both circulating beta-endorphin and allopregnanolone concentrations, at both the third and sixth months of treatment (p < 0.01). Clonidine, fluoxetine and naloxone administration before therapy was not able to stimulate the release of beta-endorphin, but the response was completely restored after raloxifene administration. Before therapy, clonidine and naloxone tests were accompanied by a significant rise in allopregnanolone secretion; the same changes were observed after raloxifene administration, but with significantly higher allopregnanolone concentrations at each time considered. While the fluoxetine test before therapy failed to increase the release of allopregnanolone, the same test after 6 months of raloxifene administration was characterized by a significant release of allopregnanolone at 60 and 90 minutes. The present data indicate that raloxifene has an estrogen-like effect on neuroendocrine pathways in postmenopausal women.

The content of beta-endorphin-like immunoreactivity in porcine corpus luteum and the potential roles of progesterone, oxytocin and prolactin in the regulation of beta-endorphin release from luteal cells in vitro.

The amount of beta-endorphin-like immunoreactivity (beta-END-LI) in porcine corpora lutea from several stages of the oestrous cycle and the effects of progesterone, oxytocin, and prolactin on beta-END-LI secretion in vitro by luteal cells were studied. Porcine corpora lutea obtained on days 1-5, 6-10, 11-13, 14-18, and 19-21 of the cycle were used to prepare extracts for beta-END-LI determination. Additionally, corpora lutea from days 11-13 and 14-18 were enzymatically dissociated and isolated luteal cells were used for further study of beta-endorphin secretion in vitro. Cells were cultured in serum-free defined M 199 medium (106 cells/ml) at 37 degrees C under 5% CO2 in air, for 12 h. The influences of the following factors on beta-END-LI secretion by luteal cells were tested: progesterone (10-9, 10-7 and 10-5 M), oxytocin (0.01, 0.1, 1 and 10 ng/ml), and prolactin (0.1, 1, 10 and 100 ng/ml). The beta-END-LI contents in extracts and media were measured by radioimmunoassay. The tissue concentration of beta-END-LI was lowest on days 1-5 of the cycle (0.35 +/- 0.03 ng/g wet tissue). Subsequently, it constantly increased to the highest value on days 14-18 (16.58 +/- 0.52 ng/g wet tissue) and on days 19-21 it declined (11.10 +/- 0.52 ng/g wet tissue). Progesterone at a low dose (10-9 M) resulted in significant (p < 0.05) increases and decreases in beta-END-LI secretion by luteal cells from days 11-13 and 14-18, respectively. Higher doses of progesterone (10-7 and 10-5 M) had no effect on beta-END-LI release, compared with the control group. All dose-levels of oxytocin used decreased beta-END-LI secretion by luteal cells on days 11-13 and 14-18 of the cycle. Prolactin at doses of 0.1 and 1 ng/ml on days 11-13, and all doses tested on days 14-18 resulted in decreases in beta-END-LI release from luteal cells. These results document evident changes in beta-END-LI content in the pig corpus luteum during its development and indicate the potential roles of progesterone, oxytocin, and prolactin in luteal cell secretion of beta-END-LI.

The mood cycle hypothesis: possible involvement of steroid hormones in mood regulation by means of Na+, K+-ATPase inhibition.

The mood cycle hypothesis attempts to propose a model for mood regulation based on current data. The hypothesis contends that steroid hormones inhibit sodium-potassium adenosine triphosphatase (Na+, K+-ATPase; Na+ pump) in the hypothalamus, either directly or by converting into digitalis-like compounds. This inhibition stimulates beta-endorphin (beta-E) secretion, which is normally construed as elevated mood. In turn, beta-E inhibits steroid secretion, thus completing negative feedback loops. These loops are collectively termed the mood cycle.