Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The nucleus tractus solitarius (NTS) receives dense terminations from cranial visceral afferents, including those from the gastrointestinal (GI) system. Although the NTS integrates peripheral satiety signals and relays this signal to central feeding centers, little is known about which NTS neurons are involved or what mechanisms are responsible. Proopiomelanocortin (POMC) neurons are good candidates for GI integration, because disruption of the POMC gene leads to severe obesity and hyperphagia. Here, we used POMC-enhanced green fluorescent protein (EGFP) transgenic mice to identify NTS POMC neurons. Intraperitoneal administration of cholecystokinin (CCK) induced c-fos gene expression in NTS POMC-EGFP neurons, suggesting that they are activated by afferents stimulated by the satiety hormone. We tested the synaptic relationship of these neurons to visceral afferents and their modulation by CCK and opioids using patch recordings in horizontal brain slices. Electrical activation of the solitary tract (ST) evoked EPSCs in NTS POMC-EGFP neurons. The invariant latencies, low failure rates, and substantial paired-pulse depression of the ST-evoked EPSCs indicate that NTS POMC-EGFP neurons are second-order neurons directly contacted by afferent terminals. The EPSCs were blocked by the glutamate antagonist 2,3-dihydroxy-6-nitro-7-sulfonyl-benzo[f]quinoxaline. CCK increased the amplitude of the ST-stimulated EPSCs and the frequency of miniature EPSCs, effects attenuated by the CCK1 receptor antagonist lorglumide. In contrast, the orexigenic opioid agonists [D-Ala(2), N-Me-Phe(4), Gly-ol(5)]-enkephalin and met-enkephalin inhibited both ST-stimulated EPSCs and the frequency of miniature EPSCs. These findings identify a potential satiety pathway in which visceral afferents directly activate NTS POMC-EGFP neurons with excitatory inputs that are appropriately modulated by appetite regulators.
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PMID:Proopiomelanocortin neurons in nucleus tractus solitarius are activated by visceral afferents: regulation by cholecystokinin and opioids. 1581 88

The present studies were undertaken to help determine the putative neural circuits mediating activation of the hypothalamo-pituitary-adrenocortical (HPA) axis and the release of adrenocorticotropin hormone (ACTH) and corticosterone in response to the perceived threat of loud noise. This experiment involved placing rats in acoustic chambers overnight to avoid any handling and context changes prior to noise exposure, which was done for 30 min (between 9:00 and 10:00 am) at intensities of 80, 85, 90, 95, 100, 105, and 110 dBA in different groups (n = 8), and included a background condition (60 dBA ambient noise). This manipulation produced a noise-intensity-related increase in plasma ACTH and corticosterone levels, with levels beginning to rise at approximately 85 dBA. c-fos mRNA induction was very low in the brains of the control and 80 dBA groups, but several brain regions displayed a noise-intensity-related induction. Of these, several forebrain regions displayed c-fos mRNA induction highly correlated (r > 0.70) with that observed in the paraventricular hypothalamic nucleus and plasma ACTH levels. These regions included the ventrolateral septum, the anteroventral subiculum, several preoptic nuclei, the anterior bed nucleus of the stria terminalis (BNST), the anterior paraventricular nucleus of the thalamus, and the medial subdivision of the medial geniculate body. Together with prior findings with audiogenic stress, the present results suggest that either or both the anterior BNST or the lateral septum is ideally situated to trigger HPA axis activation by stimuli that are potentially threatening.
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PMID:A detailed characterization of loud noise stress: Intensity analysis of hypothalamo-pituitary-adrenocortical axis and brain activation. 1625 84

This study examined the effects of the glucocorticoid receptor (GR) agonist RU28362 on stress-induced gene expression in the pituitary of rats to investigate mechanisms of glucocorticoid negative feedback in vivo. In an initial experiment, acute restraint stress produced rapid (within 15 min) induction of c-fos mRNA, zif268 mRNA and pro-opiomelanocortin (POMC) hnRNA within the anterior and intermediate/posterior pituitary as determined by quantitative real-time polymerase chain reaction. Treatment with RU28362 (150 microg/kg, i.p.) 60 min before restraint inhibited adrenocorticotrophic hormone (ACTH) and corticosterone secretion and selectively suppressed the stress-induced increase in POMC hnRNA in the anterior pituitary gland. The failure of RU28362 to surpress the stress-induced rise in c-fos and expression of zif268 mRNA suggests that the central release of ACTH secretagogues was not affected at this time point by treatment with the GR agonist. Rather, the inhibition of ACTH release appeared to be due to a direct effect of RU28362 within the pituitary. A follow-up time-course study varied the interval (10, 60 or 180 min) between RU28362 pretreatment and the onset of restraint. The stress-induced increase in POMC hnRNA was completely blunted by RU28362 treatment within 10 min of treatment, although the stress induced hormone secretion, c-fos mRNA and zif268 mRNA were unaffected. The rapid inhibition of the stress-induced rise in POMC hnRNA in the anterior pituitary appears to reflect direct, GR-mediated suppression of POMC gene expression. RU28362 pretreatment 180 min before restraint onset was sufficient to suppress the stress-induced expression in the anterior pituitary gland of all three genes examined. Thus, the delayed negative feedback effects on hypothalamic-pituitary-adrenal axis activity that emerged after 180 min after glucocorticoid treatment were not evident at 60 min. Taken together, the data suggest that the inhibition of the stress-induced release of ACTH apparent within the first hour of glucocorticoid exposure is effected at the level of the pituitary gland. The delayed glucocorticoid effects evident 180 min after RU28362 treatment may include glucocorticoid actions in the brain and additional actions within the pituitary.
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PMID:Specific and time-dependent effects of glucocorticoid receptor agonist RU28362 on stress-induced pro-opiomelanocortin hnRNA, c-fos mRNA and zif268 mRNA in the pituitary. 1642 Feb 82

Estrogen receptor beta (ERbeta) and androgen receptor (AR) are found in high levels within populations of neurons in the hypothalamus. To determine whether AR or ERbeta plays a role in regulating hypothalamo-pituitary-adrenal (HPA) axis function by direct action on these neurons, we examined the effects of central implants of 17beta-estradiol (E2), 5alpha-dihydrotestosterone (DHT), the DHT metabolite 5alpha-androstan-3beta, 17beta-diol (3beta-diol), and several ER subtype-selective agonists on the corticosterone and adrenocorticotropin (ACTH) response to immobilization stress. In addition, activation of neurons in the paraventricular nucleus (PVN) was monitored by examining c-fos mRNA expression. Pellets containing these compounds were stereotaxically implanted near the PVN of gonadectomized male rats. Seven days later, animals were killed directly from their home cage (nonstressed) or were restrained for 30 min (stressed) before they were killed. Compared with controls, E2 and the ERalpha-selective agonists moxestrol and propyl-pyrazole-triol significantly increased the stress induced release of corticosterone and ACTH. In contrast, central administration of DHT, 3beta-diol, and the ERbeta-selective compound diarylpropionitrile significantly decreased the corticosterone and ACTH response to immobilization. Cotreatment with the ER antagonist tamoxifen completely blocked the effects of 3beta-diol and partially blocked the effect of DHT, whereas the AR antagonist flutamide had no effect. Moreover, DHT, 3beta-diol, and diarylpropionitrile treatment significantly decreased restraint-induced c-fos mRNA expression in the PVN. Together, these studies indicate that the inhibitory effects of DHT on HPA axis activity may be in part mediated via its conversion to 3beta-diol and subsequent binding to ERbeta.
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PMID:The androgen 5alpha-dihydrotestosterone and its metabolite 5alpha-androstan-3beta, 17beta-diol inhibit the hypothalamo-pituitary-adrenal response to stress by acting through estrogen receptor beta-expressing neurons in the hypothalamus. 1645 68

Nitric oxide (NO) generated by inducible NO synthase (iNOS) may be implicated in the biological responses of the central nervous system to immune stimuli. To elucidate the role of iNOS in the hypothalamo-pituitary axis in responses to endotoxemia, using iNOS knockout (KO) mice, we examined the levels of c-fos, a neural activational marker, and corticotropin-releasing hormone (CRH) gene transcription in the paraventricular nucleus (PVN) and central amygdala (CeAMY) during lipopolysaccharide (LPS)-induced endotoxemia. In addition, the serum adrenocorticotropic hormone (ACTH) levels were also examined during endotoxemia. Following the intraperitoneal administration of LPS (1 mg/kg), the levels of the c-fos gene expression significantly increased in the PVN and the CeAMY regardless of the genotype. However, the disruption of the iNOS gene resulted in a significant decrease in the c-fos gene induction in the PVN in comparison to that observed in control mice. LPS administration caused a significant increase in CRH mRNA levels in the PVN and CeAMY regardless of genotype. However, the LPS-induced upregulation of CRH mRNA was significantly attenuated in the PVN of iNOS KO mice in comparison to that in the control mice. In contrast, no such genotype differences in the neural activity or CRH gene transcription were observed in the CeAMY. The serum ACTH responses to LPS were also significantly blunted in the iNOS KO mice in comparison to the control mice. These results suggest that iNOS-derived NO may therefore play a stimulatory role in the activity of the hypothalamo-pituitary axis during endotoxemia.
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PMID:The hypothalamo-pituitary axis responses to lipopolysaccharide-induced endotoxemia in mice lacking inducible nitric oxide synthase. 1663 Nov 35

The effects of i.c.v. administration of prolactin-releasing peptide on neurons in the paraventricular nucleus of rats and plasma corticosterone levels were examined by measuring changes in Fos-like immunoreactivity, c-fos mRNA using in situ hybridization histochemistry, and plasma corticosterone using a specific radioimmunoassay. Approximately 80% of corticotropin-releasing hormone immunoreactive cells exhibited Fos-like immunoreactivity in the parvocellular division of the paraventricular nucleus 90 min after i.c.v. administration of prolactin-releasing peptide. The greatest induction of the c-fos mRNA expression in the paraventricular nucleus was observed 30 min after administration of prolactin-releasing peptide, and occurred in a dose-related manner. Plasma corticosterone levels were also significantly increased 30 min after administration of prolactin-releasing peptide. Next, the effects of restraint stress, nociceptive stimulus and acute inflammatory stress on the expression of the prolactin-releasing peptide mRNA in the dorsomedial hypothalamic nucleus, nucleus of the solitary tract and ventrolateral medulla were examined using in situ hybridization histochemistry for prolactin-releasing peptide mRNA. Restraint stress and acute inflammatory stress upregulated the prolactin-releasing peptide mRNA expression in the nucleus of the solitary tract and ventrolateral medulla. Nociceptive stimulus upregulated the prolactin-releasing peptide mRNA expression in the ventrolateral medulla. Finally, we observed that pretreatment (i.c.v. administration) with an anti-prolactin-releasing peptide antibody significantly attenuated nociceptive stimulus-induced c-fos mRNA expression in the paraventricular nucleus. These results suggest that prolactin-releasing peptide is a potent and important mediator of the stress response in the brain through the hypothalamic paraventricular nucleus.
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PMID:Prolactin-releasing peptide is a potent mediator of stress responses in the brain through the hypothalamic paraventricular nucleus. 1673 Apr 16

The effects of stress, including their putative contribution to pathological psychiatric conditions, are crucially governed by the age at which the stress takes place. However, the cellular and molecular foundations for the impact of stress on neuronal function, and their change with age, are unknown. For example, it is not known whether 'psychological' stress signals are perceived by similar neuronal populations at different ages, and whether they activate similar or age-specific signaling pathways that might then mediate the spectrum of stress-evoked neuronal changes. We employed restraint and restraint/noise stress to address these issues in juvenile (postnatal day 18, [P18]) and adult rats, and used phosphorylation of the transcription factor CREB (pCREB) and induction of c-fos as markers of hippocampal neuronal responses. Stress-activated neuronal populations were identified both anatomically and biochemically, and selective blockers of the stress-activated hippocampal peptide, corticotropin-releasing hormone (CRH) were used to probe the role of this molecule in stress-induced hippocampal cell activation. Stress evoked strikingly different neuronal response patterns in immature vs adult hippocampus. Expression of pCREB appeared within minutes in hippocampal CA3 pyramidal cells of P18 rats, followed by delayed induction of Fos protein in the same cell population. In contrast, basal pCREB levels were high in adult hippocampus and were not altered at 10-120 min by stress. Whereas Fos induction was elicited by stress in the adult, it was essentially confined to area CA1, with little induction in CA3. At both age groups, central pretreatment with either a nonselective blocker of CRH receptors (alpha-helical CRH [9-41]) or the CRF1-selective antagonist, NBI 30775, abolished stress-evoked neuronal activation. In conclusion, hippocampal neuronal responses to psychological stress are generally more rapid and robust in juvenile rats, compared to fully mature adults, and at both ages, CRH plays a key role in this process. Enhanced hippocampal response to stress during development, and particularly the activation of the transcription factor CREB, may contribute to the enduring effects of stress during this period on hippocampal function.
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PMID:Cellular and molecular mechanisms of hippocampal activation by acute stress are age-dependent. 1680 51

The experiments described herein present a method for tracking diffusion of the glucocorticoid receptor agonist RU28362 in brain following i.c.v. drug administration. A useful property of glucocorticoid receptor is that it is primarily cytoplasmic when unbound and rapidly translocates to the nucleus when bound by ligand. Thus, removal of endogenous glucocorticoids by adrenalectomy allows us to identify brain regions with activated glucocorticoid receptor after i.c.v. glucocorticoid receptor agonist treatment by examining the presence or absence of nuclear glucocorticoid receptor immunostaining. We have previously demonstrated that an i.p. injection of 150 microg/kg RU28362 1 h prior to restraint stress is sufficient to suppress stress-induced hypothalamic-pituitary-adrenal axis hormone secretion [Ginsberg AB, Campeau S, Day HE, Spencer RL (2003) Acute glucocorticoid pretreatment suppresses stress-induced hypothalamic-pituitary-adrenal axis hormone secretion and expression of corticotropin-releasing hormone hnRNA but does not affect c-fos mRNA or fos protein expression in the paraventricular nucleus of the hypothalamus. J Neuroendocrinol 15:1075-1083]. We report here, however, that in rats i.c.v. treatment with a high-dose of RU28362 (1 microg) 1 h prior to stressor onset does not suppress stress-induced hypothalamic-pituitary-adrenal axis activity. We then performed a series of experiments to examine the possible differences in glucocorticoid receptor activation patterns in brain and pituitary after i.c.v. or i.p. treatment with RU28362. In a dose-response study we found that 1 h after i.c.v. injection of RU28362 (0.001, 0.1 and 1.0 microg) glucocorticoid receptor nuclear immunoreactivity was only evident in brain tissue immediately adjacent to the lateral or third ventricle, including the medial but not more lateral portion of the medial parvocellular paraventricular nucleus of the hypothalamus. In contrast, i.p. injection of RU28362 produced a uniform predominantly nuclear glucocorticoid receptor immunostaining pattern throughout all brain tissue. I.c.v. injection of the endogenous glucocorticoid receptor agonist, corticosterone (1 microg) also had limited diffusion into brain tissue. Time-course studies indicated that there was not a greater extent of nuclear glucocorticoid receptor immunostaining present in brain after shorter (10 or 30 min) or longer (2 or 3 h) intervals of time after i.c.v. RU28362 injection. Importantly, time-course studies found that i.c.v. RU28362 produced significant increases in nuclear glucocorticoid receptor immunostaining in the anterior pituitary that were evident within 10 min after injection and maximal after 1 h. These studies support an extensive literature indicating that drugs have very limited ability to diffuse out of the ventricles into brain tissue after i.c.v. injection, while at the same time reaching peripheral tissue sites. In addition, these studies indicate that significant occupancy of some glucocorticoid receptor within the paraventricular nucleus of the hypothalamus and pituitary is not necessarily sufficient to suppress stress-induced hypothalamic-pituitary-adrenal axis activity.
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PMID:Limited brain diffusion of the glucocorticoid receptor agonist RU28362 following i.c.v. administration: implications for i.c.v. drug delivery and glucocorticoid negative feedback in the hypothalamic-pituitary-adrenal axis. 1680 20

It is well established that estrogens markedly enhance the glucocorticoid response to acute stress in females. However, the precise mechanism responsible for this regulation is poorly understood. Here, we tested whether estrogens enhance the activation of the paraventricular nucleus (PVN) of the hypothalamus by measuring stress-induced c-fos mRNA expression in the PVN of restraint-stressed ovariectomized (OVX) rats treated with physiologically relevant doses of estradiol (E(2)), the major female estrogen. As expected, E(2) enhanced plasma corticosterone responses to restraint in OVX females. However, E(2) markedly attenuated the stress-induced c-fos gene expression in the PVN and inhibited plasma ACTH responses in these animals. Furthermore, E(2)-inhibitory effects were mimicked by progesterone (P) alone or in combination with E(2). Interestingly, the suppressive central effects of both E(2) and P were apparently independent of basal paraventricular corticotropin-releasing hormone (CRH) transcription, since these ovarian steroids did not significantly affect PVN CRH mRNA expression in unstressed rats. These unexpected findings suggested that E(2) promotes glucocorticoid hypersecretion in females by additional peripheral (i.e., adrenal) mechanisms. Indeed, E(2) markedly enhanced plasma corticosterone responses and adrenal corticosterone content in dexamethasone-blocked OVX rats challenged with varying doses of exogenous ACTH. These results suggest that enhanced adrenal sensitive to ACTH is an important physiological mechanism mediating E(2)-related glucocorticoid hypersecretion in stressed females.
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PMID:Estrogen potentiates adrenocortical responses to stress in female rats. 1717 93

The effects of intraperitoneal (i.p.) administration of 2-buten-4-olide (2-B4O), an endogenous sugar acid, on the hypothalamo-adenohypophysial system were examined in Lewis rats that were normal and in adjuvant-induced arthritic (AA) rats. In comparison with vehicle-treated rats, the plasma corticosterone and c-fos mRNA levels in the paraventricular nucleus (PVN) of normal rats increased significantly after i.p. administration of 2-B4O. Dual immunostaining revealed that almost all corticotrophin-releasing factor (CRF)-immunopositive neurones in the parvocellular division of the PVN exhibited Fos-like immunoreactivity (LI) 120 min after i.p. administration of 2-B4O (100 mg/kg). In the AA rats, repeated i.p. administration of 2-B4O (100 mg/kg) after immunisation significantly suppressed the expression of clinical symptoms and significantly increased plasma concentrations of corticosterone. Further, repeated i.p. administration of 2-B4O significantly increased CRF mRNA levels in the PVN and pro-opiomelanocortin mRNA levels in the anterior pituitary; however, they did not change arginine vasopressin mRNA levels in the parvocellular division of the PVN. These results suggest that i.p. administration of 2-B4O activates the hypothalamo-pituitary-adrenal (HPA) axis via the activation of CRF neurones in the PVN, and the activation of the HPA axis by i.p. administration of 2-B4O may be associated with the inhibition of AA in rats.
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PMID:Effects of the short chain sugar acid 2-buten-4-olide on the hypothalamo-pituitary-adrenal axis in normal and adjuvant-induced arthritic rats. 1718 86


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