Associated endocrine,physiological and behavioral changes in rhesus monkeys after intravenous corticotropin-releasing factor administration

The intravenous (IV) administration of synthetic ovine corticotropin-releasing factor (CRF) (10 and 125 μg/kg) to chair restrained rhesus monkeys stimulated the pituitary-adrenal axis. At these doses, increases in plasma concentrations of adrenocorticotropic hormone (ACTH) and cortisol were associated with blood pressure decreases and behavioral effects. These data demonstrate that synthetic ovine CRF (10 and 125 μg/kg) administered IV to the rhesus monkey results in associated endocrine, physiological, and behavioral changes.     

Innovative Approaches for the Treatment of Depression: Targeting the HPA Axis

Altered activity of the hypothalamic pituitary adrenal (HPA) axis is one of the most commonly observed neuroendocrine abnormalities in patients suffering from major depressive disorder (MDD). Altered cortisol secretion can be found in as many as 80% of depressed patients. This observation has led to intensive clinical and preclinical research aiming to better understand the molecular mechanisms which underlie the alteration of the HPA axis responsiveness in depressive illness. Dysfunctional glucocorticoid receptor (GR) mediated negative feedback regulation of cortisol levels and changes in arginine vasopressin (AVP)/vasopressin V_1b receptor and corticotrophin-releasing factor/CRF₁ receptor regulation of adrenocotricotrophin (ACTH) release have all been implicated in over-activity of the HPA axis. Agents that intervene with the mechanisms involved in (dys)regulation of cortisol synthesis and release are under investigation as possible therapeutic agents. The current status of some of these approaches is described in this review. Special issue article in honor of George Fink.     

FlyXCDB—A Resource for Drosophila Cell Surface and Secreted Proteins and Their Extracellular Domains

Genomes of metazoan organisms possess a large number of genes encoding cell surface and secreted (CSS) proteins that carry out crucial functions in cell adhesion and communication, signal transduction, extracellular matrix establishment, nutrient digestion and uptake, immunity, and developmental processes. We developed the FlyXCDB database (http://prodata.swmed.edu/FlyXCDB) that provides a comprehensive resource to investigate extracellular (XC) domains in CSS proteins of Drosophila melanogaster, the most studied insect model organism in various aspects of animal biology. More than 300 Drosophila XC domains were discovered in Drosophila CSS proteins encoded by over 2500 genes through analyses of computational predictions of signal peptide, transmembrane (TM) segment, and GPI-anchor signal sequence, profile-based sequence similarity searches, gene ontology, and literature. These domains were classified into six classes mainly based on their molecular functions, including protein–protein interactions (class P), signaling molecules (class S), binding of non-protein molecules or groups (class B), enzyme homologs (class E), enzyme regulation and inhibition (class R), and unknown molecular function (class U). Main cellular functions such as cell adhesion, cell signaling, and extracellular matrix composition were described for the most abundant domains in each functional class. We assigned cell membrane topology categories (E, secreted; S, type I/III single-pass TM; T, type II single-pass TM; M, multi-pass TM; and G, GPI-anchored) to the products of genes with XC domains and investigated their regulation by mechanisms such as alternative splicing and stop codon readthrough.     

柴半六合汤对慢性肾衰竭模型大鼠血清胃泌素、胃动素及生长抑素的影响(英文)

目的:观察柴半六合汤对慢性肾衰竭(CRF)模型大鼠血清胃泌素(GAS)、胃动素(MTL)、生长抑素(SS)水平的影响,探讨其作用机制。方法:采用5/6肾切除的方法复制CRF大鼠模型,设立假手术组、模型组、柴半六合汤高剂量组、低剂量组、尿毒清对照组,检测血肌酐(Scr)、尿素氮(BUN)、胃泌素(GAS)、胃动素(MTL)及生长抑素(SS),取胃粘膜行HE染色,光镜下观察其组织病理变化。结果:用药各组大鼠治疗后Scr、BUN低于模型组;柴半六合汤高剂量组大鼠Scr、BUN、GAS、MTL低于低剂量组、SS高于低剂量组;柴半六合汤高、低剂量组大鼠GAS、MTL低于尿毒清对照组、SS高于尿毒清对照组。结论:柴半六合汤通过降低CRF模型大鼠GAS、MTL水平、SS升高水平,改善胃肠道症状。     

Gastric erosions induced by intracisternal thyrotropin-releasing hormone (TRH) in rats

Intracisternal injection of TRH (1 microgram) under light ether anesthesia induced within 4 hr gastric lesions in 24-hr fasted rats maintained unrestrained at room temperature. Saline, ovine corticotropin-releasing factor (oCRF, 10 micrograms), or human pancreatic growth hormone-releasing factor [hpGRF(1-40), 10 micrograms] tested under the same conditions did not modify the integrity of the gastric mucosa. TRH injected intravenously (100 micrograms/kg) proved to be ineffective. The production of gastric erosions elicited by intracisternal TRH (0.1-1 microgram) or by a stabilized TRH analog, RX 77368 [pGlu-His-(3,3'-dimethyl)-ProNH2, (0.01-0.1 microgram)] was dose-dependent. RX 77368 shows an enhanced potency over TRH. TRH action on gastric mucosa was reversed by atropine, omeprazole and cimetidine. These results demonstrate that TRH, unlike the other hypothalamic releasing factors CRF or GRF, is able to act within the brain to cause the formation of gastric erosions probably through mechanisms involving changes in gastric acid secretion. Intracisternal injection of TRH or its potent analog RX 77368 appears also as a new, simple method to produce centrally mediated experimental gastric erosions in 24 hr-fasted rats.     

Corticotropin-releasing factor inhibits gastric emptying in dogs: Studies on its mechanism of action

The effects of corticotropin-releasing factor (CRF) on gastric emptying of a saline solution was further investigated in six dogs prepared with gastric fistulas and chronic cerebroventricular guides and in four other dogs with chronic gastric fistulas and pancreatic (Herrera) cannulas. Intravenous infusion of CRF significantly inhibited gastric emptying whereas intracerebroventricular injection of CRF had no effect. Pharmacologic blockade of β-adrenergic system by propranolol did not modify intravenous CRF induced delay in gastric emptying. Intravenous CRF did not influence basal pancreatic secretion whereas secretin infused stimulated bicarbonate secretion. These results indicate that intravenous but not intracerebroventricular administration of CRF inhibited gastric emptying of a saline solution in dogs. The inhibitory effect of intravenous CRF on gastric emptying is not mediated by the β-adrenergic nervous system, and not secondary to the release of other peptides that affect both pancreatic secretion and gastric emptying such as cholecystokinin and peptide YY.     

CRF R1受体拮抗剂对幼年大鼠快眼动睡眠的影响

目的：观察腹腔注射CRFR1受体拮抗剂NBI27914对幼年大鼠睡眠/觉醒周期的影响。方法：生后13d的大鼠行电极安装术,术后12h开始多导睡眠描记,描记的第6h分别给予腹腔注射不同剂量的NBI27914、阿托品和等量生理盐水。结果：与基础水平相比,腹腔注射任何剂量NBI27914使幼年大鼠快眼动（REM）睡眠均显著减少,同时伴随着非快眼动（NREM）睡眠的增加,而生理盐水组无显著变化;阿托品组的大鼠REM睡眠也显著减少,伴随的是觉醒的增加。结论：阻断CRFR1受体可以剥夺幼鼠的REM睡眠。     

Anxiogenic and antinociceptive effects induced by corticotropin-releasing factor (CRF) injections into the periaqueductal gray are modulated by CRF1 receptor in mice

Chemical or electrical stimulation of the dorsal portion of the midbrain periaqueductal gray (dPAG) produces anxiogenic and antinociceptive effects. In rats, chemical stimulation of dPAG by local infusion of the neuropeptide corticotropin-releasing factor (CRF) provokes anxiogenic effects in the elevated plus-maze test (EPM). CRF also produces antinociception when injected intracerebroventricularly in rats, however it remains unclear whether this response is also observed following CRF injection into the dPAG in mice. Yet, given that there are CRF1 and CRF2 receptor subtypes within the PAG, it is important to show in which receptor subtypes CRF exert its anxiogenic and antinociceptive effects in the dPAG. Here, we investigated the role of these receptors in the anxiogenic (assessed in the EPM) and antinociceptive (assessed by the Formalin test: 2.5% formalin injection into the right hind paw) effects following intra-dPAG infusion of CRF in mice. The results show that intra-dPAG injections of CRF (75 pmol/0.1 μl and 150 pmol/0.2 μl) produced dose-dependent anxiogenic and antinociceptive effects. In addition, local infusion of NBI 27914 (5-chloro-4-(N-(cyclopropyl)methyl-N-propylamino)-2-methyl-6-(2,4,6-trichlorophenyl)-aminopyridine; 2 nmol/0.2 μl), a CRF1 receptor antagonist, completely blocked both the anxiogenic and antinociceptive effects induced by local infusion of CRF, while that of antisauvagine 30 (ASV30; 1 nmol/0.2 μl), a CRF2 receptor antagonist, did not alter the CRF effects. Present results are suggestive that CRF1 (but not CRF2) receptors play a crucial role in the anxiogenic and antinociceptive effects induced by CRF in the dPAG in mice.     

Modulation of gastric motility by brain-gut peptides using a novel non-invasive miniaturized pressure transducer method in anesthetized rodents

Acute in vivo measurements are often the initial, most practicable approach used to investigate the effects of novel compounds or genetic manipulations on the regulation of gastric motility. Such acute methods typically involve either surgical implantation of devices or require intragastric perfusion of solutions, which can substantially alter gastric activity and may require extended periods of time to allow stabilization or recovery of the preparation. We validated a simple, non-invasive novel method to measure acutely gastric contractility, using a solid-state catheter pressure transducer inserted orally into the gastric corpus, in fasted, anesthetized rats or mice. The area under the curve of the phasic component (pAUC) of intragastric pressure (IGP) was obtained from continuous manometric recordings of basal activity and in responses to central or peripheral activation of cholinergic pathways, or to abdominal surgery. In rats, intravenous ghrelin or intracisternal injection of the thyrotropin-releasing hormone agonist, RX-77368, significantly increased pAUC while coeliotomy and cacal palpation induced a rapid onset inhibition of phasic activity lasting for the 1-h recording period. In mice, RX-77368 injected into the lateral brain ventricle induced high-amplitude contractions, and carbachol injected intraperitoneally increased pAUC significantly, while coeliotomy and cecal palpation inhibited baseline contractile activity. In wild-type mice, cold exposure (15 min) increased gastric phasic activity and tone, while there was no gastric response in corticotropin releasing factor (CRF)-overexpressing mice, a model of chronic stress. Thus, the novel solid-state manometric approach provides a simple, reliable means for acute pharmacological studies of gastric motility effects in rodents. Using this method we established in mice that the gastric motility response to central vagal activation is impaired under chronic expression of CRF.     

Stress effects on AVT and CRF systems in two strains of rainbow trout (Oncorhynchus mykiss) divergent in stress responsiveness

The aim for this study was to examine whether the F4 generation of two strains of rainbow trout divergent in their plasma cortisol response to confinement stress (HR: high responder or LR: low responder) would also differ in stress-induced effects on forebrain concentrations of mRNA for corticotropin-releasing factor (CRF), arginine vasotocin (AVT), CRF receptor type 1 (CRF-R1), CRF receptor type 2 (CRF-R2) and AVT receptor (AVT-R). In addition, plasma cortisol concentrations, brainstem levels of monoamines and monoamine metabolites, and behaviour during confinement were monitored. The results confirm that HR and LR trout differ in their cortisol response to confinement and show that fish of these strains also differ in their behavioural response to confinement. The HR trout displayed significantly higher locomotor activity while in confinement than LR trout. Moreover, following 180 min of confinement HR fish showed significantly higher forebrain concentrations of CRF mRNA than LR fish. Also, when subjected to 30 min of confinement HR fish showed significantly lower CRF-R2 mRNA concentrations than LR fish, whereas there were no differences in CRF-R1, AVT or AVT-R mRNA expression between LR and HR fish either at 30 or 180 min of confinement. Differences in the expression of CRF and CRF-R2 mRNA may be related to the divergence in stress coping displayed by these rainbow trout strains.