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Jean Rivier - One of the best experts on this subject based on the ideXlab platform.
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anxiolytic like effects of antisauvagine 30 in mice are not mediated by crf2 receptors
PLOS ONE, 2013Co-Authors: Eric P Zorrilla, Amanda J Roberts, Jean Rivier, George F KoobAbstract:: The role of brain corticotropin-releasing factor type 2 (CRF2) receptors in behavioral stress responses remains controversial. Conflicting findings suggest pro-stress, anti-stress or no effects of impeding CRF2 signaling. Previous studies have used antisauvagine-30 as a selective CRF2 antagonist. The present study tested the hypotheses that 1) potential anxiolytic-like actions of intracerebroventricular (i.c.v.) administration of antisauvagine-30 also are present in mice lacking CRF2 receptors and 2) potential anxiolytic-like effects of antisauvagine-30 are not shared by the more selective CRF2 antagonist Astressin2-B. Cannulated, male CRF2 receptor knockout (n = 22) and wildtype littermate mice (n = 21) backcrossed onto a C57BL/6J genetic background were tested in the marble burying, elevated plus-maze, and shock-induced freezing tests following pretreatment (i.c.v.) with vehicle, antisauvagine-30 or Astressin2-B. Antisauvagine-30 reduced shock-induced freezing equally in wildtype and CRF2 knockout mice. In contrast, neither Astressin2-B nor CRF2 genotype influenced shock-induced freezing. Neither CRF antagonist nor CRF2 genotype influenced anxiety-like behavior in the plus-maze or marble burying tests. A literature review showed that the typical antisauvagine-30 concentration infused in previous intracranial studies (∼1 mM) was 3 orders greater than its IC50 to block CRF1-mediated cAMP responses and 4 orders greater than its binding constants (Kd , Ki ) for CRF1 receptors. Thus, increasing, previously used doses of antisauvagine-30 also exert non-CRF2-mediated effects, perhaps via CRF1. The results do not support the hypothesis that brain CRF2 receptors tonically promote anxiogenic-like behavior. Utilization of CRF2 antagonists, such as Astressin2-B, at doses that are more subtype-selective, can better clarify the significance of brain CRF2 systems in stress-related behavior.
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crf receptor antagonist Astressin b reverses and prevents alopecia in crf over expressing mice
PLOS ONE, 2011Co-Authors: Lixin Wang, Jean Rivier, Mulugeta Million, Catherine Rivier, Noah Craft, Mary P Stenzelpoore, Yvette TachéAbstract:Corticotropin-releasing factor (CRF) signaling pathways are involved in the stress response, and there is growing evidence supporting hair growth inhibition of murine hair follicle in vivo upon stress exposure. We investigated whether the blockade of CRF receptors influences the development of hair loss in CRF over-expressing (OE)-mice that display phenotypes of Cushing's syndrome and chronic stress, including alopecia. The non-selective CRF receptors antagonist, Astressin-B (5 µg/mouse) injected peripherally once a day for 5 days in 4–9 months old CRF-OE alopecic mice induced pigmentation and hair re-growth that was largely retained for over 4 months. In young CRF-OE mice, Astressin-B prevented the development of alopecia that occurred in saline-treated mice. Histological examination indicated that alopecic CRF-OE mice had hair follicle atrophy and that Astressin-B revived the hair follicle from the telogen to anagen phase. However, Astressin-B did not show any effect on the elevated plasma corticosterone levels and the increased weights of adrenal glands and visceral fat in CRF-OE mice. The selective CRF2 receptor antagonist, Astressin2-B had moderate effect on pigmentation, but not on hair re-growth. The commercial drug for alopecia, minoxidil only showed partial effect on hair re-growth. These data support the existence of a key molecular switching mechanism triggered by blocking peripheral CRF receptors with an antagonist to reset hair growth in a mouse model of alopecia associated with chronic stress.
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increased ghrelin sensitivity and calorie consumption in subordinate monkeys is affected by short term Astressin b administration
Endocrine, 2010Co-Authors: Vasiliki Michopoulos, Jean Rivier, Tammy L Loucks, Sarah L Berga, Mark E WilsonAbstract:Animals chronically exposed to stressors with access to diets high in fat and sugar consume and prefer these diets, a result consistent with the association between stress and comfort food ingestion in humans. As social subordination in rhesus monkeys provides an ethologically relevant translational model of psychosocial stress, we tested the hypothesis that differences in food intake between dominant and subordinate female monkeys are due to corticotropin-releasing hormone-(CRH) induced alteration in sensitivity to ghrelin, a potent orexigenic signal. We assessed food intake of animals given a choice between a low (LCD) and high calorie diet (HCD) in response to 4-day treatment with the CRH receptor antagonist, Astressin B, and to an acute treatment of ghrelin. Ghrelin stimulated intake of LCD in subordinates but did not further increase consumption of HCD, whereas ghrelin decreased LCD consumption without affecting HCD intake in dominant females. Astressin B decreased cortisol levels and increased preference for and intake of the HCD in subordinates and decreased calorie intake and HCD preference in dominant animals. These results suggest that increased caloric intake by subordinates may, in part, be explained by a greater sensitivity to postprandial increases in ghrelin and that CRH receptor antagonism leading to a decrease in cortisol has mixed effects on food choice depending on an individual’s stress background.
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central nesfatin 1 reduces dark phase food intake and gastric emptying in rats differential role of corticotropin releasing factor2 receptor
Endocrinology, 2009Co-Authors: Andreas Stengel, Peter Kobelt, Lixin Wang, Jean Rivier, Miriam Goebel, Hubert Monnikes, Nils Lambrecht, Yvette TachéAbstract:Nesfatin-1, derived from nucleobindin2, is expressed in the hypothalamus and reported in one study to reduce food intake (FI) in rats. To characterize the central anorexigenic action of nesfatin-1 and whether gastric emptying (GE) is altered, we injected nesfatin-1 into the lateral brain ventricle (intracerebroventricular, icv) or fourth ventricle (4v) in chronically cannulated rats or into the cisterna magna (intracisternal, ic) under short anesthesia and compared with ip injection. Nesfatin-1 (0.05 μg/rat, icv) decreased 2–3 h and 3–6 h dark-phase FI by 87 and 45%, respectively, whereas ip administration (2 μg/rat) had no effect. The corticotropin-releasing factor (CRF)1/CRF2 antagonist Astressin-B or the CRF2 antagonist Astressin2-B abolished icv nesfatin-1’s anorexigenic action, whereas an Astressin2-B analog, devoid of CRF-receptor binding affinity, did not. Nesfatin-1 icv induced a dose-dependent reduction of GE by 26 and 43% that was not modified by icv Astressin2-B. Nesfatin-1 into the 4v (0.05 μg/rat) or ic (0.5 μg/rat) decreased cumulative dark-phase FI by 29 and 60% at 1 h and by 41 and 37% between 3 and 5 h, respectively. This effect was neither altered by ic Astressin2-B nor associated with changes in GE. Cholecystokinin (ip) induced Fos expression in 43% of nesfatin-1 neurons in the paraventricular hypothalamic nucleus and 24% of those in the nucleus tractus solitarius. These data indicate that nesfatin-1 acts centrally to reduce dark phase FI through CRF2-receptor-dependent pathways after forebrain injection and CRF2-receptor-independent pathways after hindbrain injection. Activation of nesfatin-1 neurons by cholecystokinin at sites regulating food intake may suggest a role in gut peptide satiation effect.
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Astressin b a nonselective corticotropin releasing hormone receptor antagonist prevents the inhibitory effect of ghrelin on luteinizing hormone pulse frequency in the ovariectomized rhesus monkey
Endocrinology, 2008Co-Authors: Nicolas R Vulliemoz, Jean Rivier, Ennian Xiao, Linna Xiazhang, Michel FerinAbstract:Administration of ghrelin, a key peptide in the regulation of energy homeostasis, has been shown to decrease LH pulse frequency while concomitantly elevating cortisol levels. Because increased endogenous CRH release in stress is associated with an inhibition of reproductive function, we have tested here whether the pulsatile LH decrease after ghrelin may reflect an activated hypothalamic-pituitary-adrenal axis and be prevented by a CRH antagonist. After a 3-h baseline LH pulse frequency monitoring, five adult ovariectomized rhesus monkeys received a 5-h saline (protocol 1) or ghrelin (100-μg bolus followed by 100 μg/h, protocol 2) infusion. In protocols 3 and 4, animals were given Astressin B, a nonspecific CRH receptor antagonist (0.45 mg/kg im) 90 min before ghrelin or saline infusion. Blood samples were taken every 15 min for LH measurements, whereas cortisol and GH were measured every 45 min. Mean LH pulse frequency during the 5-h ghrelin infusion was significantly lower than in all other treatments (P < 0.05) and when compared with the baseline period (P < 0.05). Pretreatment with Astressin B prevented the decrease. Ghrelin stimulated cortisol and GH secretion, whereas Astressin B pretreatment prevented the cortisol, but not the GH, release. Our data indicate that CRH release mediates the inhibitory effect of ghrelin on LH pulse frequency and suggest that the inhibitory impact of an insufficient energy balance on reproductive function may in part be mediated by the hypothalamic-pituitary-adrenal axis.
Theoharis C Theoharides - One of the best experts on this subject based on the ideXlab platform.
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Human Mast Cells Express Corticotropin-Releasing Hormone (CRH) Receptors and CRH Leads to Selective Secretion of Vascular Endothelial
2016Co-Authors: Growth Factor, Jing Cao, Nikoletta Papadopoulou, Duraisamy Kempuraj, Koreaki Sugimoto, Curtis L Cetrulo, William S. Boucher, Theoharis C TheoharidesAbstract:Mast cells are critical for allergic reactions, but also for innate or acquired immunity and inflammatory conditions that worsen by stress. Corticotropin-releasing hormone (CRH), which activates the hypothalamic-pituitary-adrenal axis under stress, also has proinflammatory peripheral effects possibly through mast cells. We investigated the expression of CRH receptors and the effects of CRH in the human leukemic mast cell (HMC-1) line and human umbilical cord blood-derived mast cells. We detected mRNA for CRH-R1, 1, 1c, 1e, 1f isoforms, as well as CRH-R1 protein in both cell types. CRH-R2 (but not R2 or R2) mRNA and protein were present only in human cord blood-derived mast cells. CRH increased cAMP and induced secretion of vascular endothelial growth factor (VEGF) without tryptase, histamine, IL-6, IL-8, or TNF- release. The effects were blocked by the CRH-R1 antagonist antalarmin, but not the CRH-R2 antagonist Astressin 2B. CRH-stimulated VEGF production was mediated through activation of adenylate cyclase and increased cAMP, as evidenced by the fact that the effect of CRH was mimicked by the direct adenylate cyclase activator forskolin and the cell-permeable cAMP analog 8-bromo-cAMP, whereas it was abolished by the adenylate cyclase inhibitor SQ22536. This is the first evidence that mast cells express functional CRH receptors and that CRH can induce VEGF secretion selectively. CRH-induced mast cell-derived VEGF could, therefore, be involved in chronic inflammatory conditions associated with increased VEGF, such as arthritis or psoriasis, both of which worsen by stress. The Journal of Immunology, 2005, 174: 7665–7675. M ast cells are ubiquitous in the body and are critical forallergic reactions due to their secretion of numerousvasoactive molecules and cytokines (1). Increasing ev
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human mast cells express corticotropin releasing hormone crh receptors and crh leads to selective secretion of vascular endothelial growth factor
Journal of Immunology, 2005Co-Authors: Jing Cao, Nikoletta Papadopoulou, Duraisamy Kempuraj, William Boucher, Koreaki Sugimoto, Curtis L Cetrulo, Theoharis C TheoharidesAbstract:Mast cells are critical for allergic reactions, but also for innate or acquired immunity and inflammatory conditions that worsen by stress. Corticotropin-releasing hormone (CRH), which activates the hypothalamic-pituitary-adrenal axis under stress, also has proinflammatory peripheral effects possibly through mast cells. We investigated the expression of CRH receptors and the effects of CRH in the human leukemic mast cell (HMC-1) line and human umbilical cord blood-derived mast cells. We detected mRNA for CRH-R1alpha, 1beta, 1c, 1e, 1f isoforms, as well as CRH-R1 protein in both cell types. CRH-R2alpha (but not R2beta or R2gamma) mRNA and protein were present only in human cord blood-derived mast cells. CRH increased cAMP and induced secretion of vascular endothelial growth factor (VEGF) without tryptase, histamine, IL-6, IL-8, or TNF-alpha release. The effects were blocked by the CRH-R1 antagonist antalarmin, but not the CRH-R2 antagonist Astressin 2B. CRH-stimulated VEGF production was mediated through activation of adenylate cyclase and increased cAMP, as evidenced by the fact that the effect of CRH was mimicked by the direct adenylate cyclase activator forskolin and the cell-permeable cAMP analog 8-bromo-cAMP, whereas it was abolished by the adenylate cyclase inhibitor SQ22536. This is the first evidence that mast cells express functional CRH receptors and that CRH can induce VEGF secretion selectively. CRH-induced mast cell-derived VEGF could, therefore, be involved in chronic inflammatory conditions associated with increased VEGF, such as arthritis or psoriasis, both of which worsen by stress.
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human mast cells express corticotropin releasing hormone crh receptors and crh leads to selective secretion of vascular endothelial growth factor
Journal of Immunology, 2005Co-Authors: Nikoletta Papadopoulou, Duraisamy Kempuraj, William Boucher, Koreaki Sugimoto, Curtis L Cetrulo, Theoharis C TheoharidesAbstract:Mast cells are critical for allergic reactions, but also for innate or acquired immunity and inflammatory conditions that worsen by stress. Corticotropin-releasing hormone (CRH), which activates the hypothalamic-pituitary-adrenal axis under stress, also has proinflammatory peripheral effects possibly through mast cells. We investigated the expression of CRH receptors and the effects of CRH in the human leukemic mast cell (HMC-1) line and human umbilical cord blood-derived mast cells. We detected mRNA for CRH-R1α, 1β, 1c, 1e, 1f isoforms, as well as CRH-R1 protein in both cell types. CRH-R2α (but not R2β or R2γ) mRNA and protein were present only in human cord blood-derived mast cells. CRH increased cAMP and induced secretion of vascular endothelial growth factor (VEGF) without tryptase, histamine, IL-6, IL-8, or TNF-α release. The effects were blocked by the CRH-R1 antagonist antalarmin, but not the CRH-R2 antagonist Astressin 2B. CRH-stimulated VEGF production was mediated through activation of adenylate cyclase and increased cAMP, as evidenced by the fact that the effect of CRH was mimicked by the direct adenylate cyclase activator forskolin and the cell-permeable cAMP analog 8-bromo-cAMP, whereas it was abolished by the adenylate cyclase inhibitor SQ22536. This is the first evidence that mast cells express functional CRH receptors and that CRH can induce VEGF secretion selectively. CRH-induced mast cell-derived VEGF could, therefore, be involved in chronic inflammatory conditions associated with increased VEGF, such as arthritis or psoriasis, both of which worsen by stress.
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potent mast cell degranulation and vascular permeability triggered by urocortin through activation of corticotropin releasing hormone receptors
Journal of Pharmacology and Experimental Therapeutics, 1999Co-Authors: Leena K Singh, William Boucher, Xinzhu Pang, Richard Letourneau, Dimitri Seretakis, Marlon Green, Theoharis C TheoharidesAbstract:Urocortin (Ucn) is related to corticotropin-releasing hormone (CRH), and both are released in the brain under stress where they stimulate CRH 1 and 2 receptors (CRHR). Outside the brain, they may have proinflammatory actions through activation of mast cells, which are located perivascularly close to nerve endings and degranulate in response to acute psychological stress. Here, we report that a concentration of intradermal Ucn as low as 10 nM induced dose-dependent rat skin mast cell degranulation and increased vascular permeability. This effect appeared to be equipotent to that of calcitonin gene-related peptide and neurotensin. Ucn-induced skin vasodilation was inhibited by pretreatment with the mast cell stabilizer disodium cromoglycate (cromolyn) and was absent in the mast cell-deficient W/Wv mice. The selective nonpeptide CRH receptor 1 antagonist, antalarmin and the nonselective peptide antagonist Astressin both reduced vascular permeability triggered by Ucn but not that by Substance P or histamine. In contrast, the peptide antagonist α-helical CRH-(9–41) reduced the effect of all three. The vasodilatory effect of Ucn was largely inhibited by pretreatment with H1 receptor antagonists, suggesting that histamine is the major mediator involved in vitro. Neuropeptide depletion of sensory neurons, treatment with the ganglionic blocker hexamethonium, or in situ skin infiltration with the local anesthetic lidocaine did not affect Ucn-induced vascular permeability, indicating that its in situ effect was not mediated through the peripheral nervous system. These results indicate that Ucn is one of the most potent triggers of rat mast cell degranulation and skin vascular permeability. This effect of Ucn may explain stress-induced disorders, such as atopic dermatitis or psoriasis, and may lead to new forms of treatment.
Yvette Taché - One of the best experts on this subject based on the ideXlab platform.
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UROCORTIN 2 ACTS CENTRALLY TO DELAY GASTRIC EMPTYING THROUGH SYMPATHETIC PATHWAYS WHILE CRF AND UROCORTIN 1 INHIBITORY ACTIONS ARE VAGAL DEPENDENT IN RATS
2013Co-Authors: József Czimmer, Mulugeta Million, Yvette TachéAbstract:We characterized the influence of the selective corticotropin-releasing factor 2 (CRF2) receptor agonist, urocortin 2 (Ucn 2), injected intracisternally (ic), on gastric emptying and its mechanism of action compared with ic CRF or urocortin (Ucn 1) in conscious rats. The methylcellulose phenol red solution was gavaged 20 min after peptide injection and gastric emptying measured 20 min later. The ic injection of Ucn 2 (0.1 and 1 µg) and Ucn 1 (1 µg) decreased gastric emptying to 37.8 ± 6.9%, 23.1 ± 8.6 % and 21.6 ± 5.9%, respectively, compared with 58.4 ± 3.8 % in ic vehicle. At lower doses, Ucn 2 (0.03 µg) and Ucn 1 (0.1 µg) had no effect. The CRF2 antagonist, Astressin2-B (3 µg, ic), antagonized ic Ucn 2 (0.1 µg) and CRF (0.3 µg)-induced inhibition of gastric emptying. Vagotomy enhanced ic Ucn 2 (0.1 or 1 µg)-induced inhibition of gastric emptying compared to sham-operated group, while blocking ic CRF (1 µg) action (45.5 ± 8.4 % vs. 9.7 ± 9.7%). Sympathetic blockade by bretylium prevented ic and intracerebroventricular Ucn 2-induced delayed gastric emptying, while not influencing intravenous Ucn 2-, ic CRF- and ic Ucn 1-induced inhibition of gastric emptying. Prazosin abolished ic Ucn 2 inhibitory effect, while yohimbine and propranolol did not. None of th
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crf receptor antagonist Astressin b reverses and prevents alopecia in crf over expressing mice
PLOS ONE, 2011Co-Authors: Lixin Wang, Jean Rivier, Mulugeta Million, Catherine Rivier, Noah Craft, Mary P Stenzelpoore, Yvette TachéAbstract:Corticotropin-releasing factor (CRF) signaling pathways are involved in the stress response, and there is growing evidence supporting hair growth inhibition of murine hair follicle in vivo upon stress exposure. We investigated whether the blockade of CRF receptors influences the development of hair loss in CRF over-expressing (OE)-mice that display phenotypes of Cushing's syndrome and chronic stress, including alopecia. The non-selective CRF receptors antagonist, Astressin-B (5 µg/mouse) injected peripherally once a day for 5 days in 4–9 months old CRF-OE alopecic mice induced pigmentation and hair re-growth that was largely retained for over 4 months. In young CRF-OE mice, Astressin-B prevented the development of alopecia that occurred in saline-treated mice. Histological examination indicated that alopecic CRF-OE mice had hair follicle atrophy and that Astressin-B revived the hair follicle from the telogen to anagen phase. However, Astressin-B did not show any effect on the elevated plasma corticosterone levels and the increased weights of adrenal glands and visceral fat in CRF-OE mice. The selective CRF2 receptor antagonist, Astressin2-B had moderate effect on pigmentation, but not on hair re-growth. The commercial drug for alopecia, minoxidil only showed partial effect on hair re-growth. These data support the existence of a key molecular switching mechanism triggered by blocking peripheral CRF receptors with an antagonist to reset hair growth in a mouse model of alopecia associated with chronic stress.
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central nesfatin 1 reduces dark phase food intake and gastric emptying in rats differential role of corticotropin releasing factor2 receptor
Endocrinology, 2009Co-Authors: Andreas Stengel, Peter Kobelt, Lixin Wang, Jean Rivier, Miriam Goebel, Hubert Monnikes, Nils Lambrecht, Yvette TachéAbstract:Nesfatin-1, derived from nucleobindin2, is expressed in the hypothalamus and reported in one study to reduce food intake (FI) in rats. To characterize the central anorexigenic action of nesfatin-1 and whether gastric emptying (GE) is altered, we injected nesfatin-1 into the lateral brain ventricle (intracerebroventricular, icv) or fourth ventricle (4v) in chronically cannulated rats or into the cisterna magna (intracisternal, ic) under short anesthesia and compared with ip injection. Nesfatin-1 (0.05 μg/rat, icv) decreased 2–3 h and 3–6 h dark-phase FI by 87 and 45%, respectively, whereas ip administration (2 μg/rat) had no effect. The corticotropin-releasing factor (CRF)1/CRF2 antagonist Astressin-B or the CRF2 antagonist Astressin2-B abolished icv nesfatin-1’s anorexigenic action, whereas an Astressin2-B analog, devoid of CRF-receptor binding affinity, did not. Nesfatin-1 icv induced a dose-dependent reduction of GE by 26 and 43% that was not modified by icv Astressin2-B. Nesfatin-1 into the 4v (0.05 μg/rat) or ic (0.5 μg/rat) decreased cumulative dark-phase FI by 29 and 60% at 1 h and by 41 and 37% between 3 and 5 h, respectively. This effect was neither altered by ic Astressin2-B nor associated with changes in GE. Cholecystokinin (ip) induced Fos expression in 43% of nesfatin-1 neurons in the paraventricular hypothalamic nucleus and 24% of those in the nucleus tractus solitarius. These data indicate that nesfatin-1 acts centrally to reduce dark phase FI through CRF2-receptor-dependent pathways after forebrain injection and CRF2-receptor-independent pathways after hindbrain injection. Activation of nesfatin-1 neurons by cholecystokinin at sites regulating food intake may suggest a role in gut peptide satiation effect.
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peripheral corticotropin releasing factor crf and a novel crf1 receptor agonist stressin1 a activate crf1 receptor expressing cholinergic and nitrergic myenteric neurons selectively in the colon of conscious rats
Neurogastroenterology and Motility, 2007Co-Authors: Pu Qing Yuan, Mulugeta Million, Jean Rivier, Yvette TachéAbstract:Intraperitoneal (i.p.) corticotropin releasing factor (CRF) induced a CRF(1) receptor-dependent stimulation of myenteric neurons and motility in the rat proximal colon. We characterize the colonic enteric nervous system response to CRF in conscious rats. Laser capture microdissection combined with reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry in longitudinal muscle myenteric plexus whole-mount colonic preparations revealed CRF(1) receptor expression in myenteric neurons. CRF (i.p., 10 microg kg(-1)) induced Fos immunoreactivity (IR) (cells per ganglion) selectively in myenteric plexus of proximal (18.3 +/- 2.4 vs vehicle: 0.0 +/- 0.0) and distal colon (16.8 +/- 1.2 vs vehicle: 0.0 +/- 0.0), but not in that of gastric corpus, antrum, duodenum, jejunum and ileum. The selective CRF(1) agonist, stressin(1)-A (i.p., 10 microg kg(-1)) also induced Fos IR in myenteric but not in submucosal plexus of the proximal and distal colon. Fos IR induced by CRF was located in 55 +/- 1.9% and 53 +/- 5.1% of CRF(1) receptor-IR myenteric neurons and in 44 +/- 2.8% and 40 +/- 3.9% of cholinergic neurons with Dogiel type I morphology, and in 20 +/- 1.6% and 80 +/- 3.3% of nitrergic neurons in proximal and distal colon respectively. CRF and stressin(1)-A elicit defecation and diarrhoea. These data support that one mechanism through which peripherally injected CRF ligands stimulate colonic function involves a direct action on colonic cholinergic and nitrergic myenteric neurons expressing CRF(1) receptor.
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Differential Actions of Peripheral Corticotropin-Releasing Factor (CRF), Urocortin II, and Urocortin III on Gastric Emptying and Colonic Transit in Mice: Role of CRF Receptor Subtypes 1 and 2
Journal of Pharmacology and Experimental Therapeutics, 2002Co-Authors: Vicente Martinez, Lixin Wang, Jean Rivier, Yvette TachéAbstract:Peripheral CRF inhibits gastric emptying and stimulates colonic motor function in rats. We investigated the role of CRF 1 and CRF 2 receptors in i.p. CRF-induced alterations of gut transit in conscious mice using selective CRF 1 and CRF 2 ligands injected i.p. Gastric emptying 2 h after ingestion of a solid chow meal and colonic transit (time to expel a bead inserted into the distal colon) were determined simultaneously. Rat/human (r/h)CRF, which has CRF 1 > CRF 2 binding affinity, decreased distal colonic transit time at lower doses (6–12 μg/kg) than those inhibiting gastric emptying (20–60 μg/kg). Ovine CRF, a preferential CRF 1 receptor agonist (6–60 μg/kg), reduced significantly the colonic transit time without altering gastric emptying, whereas the selective CRF 2 receptor agonists mouse urocortin II (20–60 μg/kg) and urocortin III (120 μg/kg) inhibited significantly gastric emptying without modifying colonic transit. The CRF 1 /CRF 2 receptor antagonist, Astressin (30–120 μg/kg), dose dependently prevented r/hCRF (20 μg/kg)-induced inhibition of gastric emptying and reduction of colonic transit time. The selective CRF 1 receptor antagonists, NBI-27914 (C 18 H 20 Cl 4 N 4 C 7 H 8 O 3 S) and CP-154,526 (butyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-yl]ethylamine) (5–30 mg/kg), dose dependently blocked r/hCRF action on the colon without influencing the gastric response, whereas the CRF 2 receptor antagonist, antisauvagine-30 (30–100 μg/kg), dose dependently abolished r/hCRF-induced delayed gastric emptying and had no effect on colonic response. These data show that i.p. r/hCRF-induced opposite actions on upper and lower gut transit in conscious mice are mediated by different CRF receptor subtypes: the activation of CRF 1 receptors stimulates colonic propulsive activity, whereas activation of CRF 2 receptors inhibits gastric emptying.
Toshikatsu Okumura - One of the best experts on this subject based on the ideXlab platform.
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water avoidance stress induces visceral hyposensitivity through peripheral corticotropin releasing factor receptor type 2 and central dopamine d2 receptor in rats
Neurogastroenterology and Motility, 2016Co-Authors: Tsukasa Nozu, Saori Miyagishi, Rintaro Nozu, Kaoru Takakusaki, Toshikatsu OkumuraAbstract:Background Water avoidance stress (WAS) is reported to induce functional changes in visceral sensory function in rodents, but the results which have been demonstrated so far are not consistent, i.e., hypersensitivity or hyposensitivity. We determined the effect of WAS on visceral sensation and evaluated the mechanisms of the action. Methods Visceral sensation was assessed by abdominal muscle contractions induced by colonic balloon distention, i.e., visceromotor response (VMR), measured electrophysiologically in conscious rats. The electromyogram electrodes were acutely implanted under anesthesia on the day of the experiment. The threshold of VMR was measured before and after WAS for 1 h. To explore the mechanisms of WAS-induced response, drugs were administered 10 min prior to the initiation of WAS. Key Results WAS significantly increased the threshold of VMR, and this effect was no longer detected at 24 h after. Intraperitoneal injection of Astressin2-B (200 μg/kg), a corticotropin releasing factor (CRF) receptor type 2 antagonist abolished the response by WAS. Subcutaneous (sc) injection of sulpiride (200 mg/kg), a dopamine D2 receptor antagonist blocked the response, while sc domperidone (10 mg/kg), a peripheral dopamine D2 receptor antagonist did not alter it. Naloxone (1 mg/kg, sc), an opioid antagonist did not modify it either. Conclusions & Inferences WAS induced visceral hyposensitivity through peripheral CRF receptor type 2 and central dopamine D2 receptor, but not through opioid pathways. As altered pain inhibitory system was reported to be observed in the patients with irritable bowel syndrome, CRF and dopamine signaling might contribute to the pathophysiology.
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a balance theory of peripheral corticotropin releasing factor receptor type 1 and type 2 signaling to induce colonic contractions and visceral hyperalgesia in rats
Endocrinology, 2014Co-Authors: Tsukasa Nozu, Kaoru Takakusaki, Toshikatsu OkumuraAbstract:Several recent studies suggest that peripheral corticotropin-releasing factor (CRF) receptor type 1 (CRF1) and CRF2 have a counter regulatory action on gastrointestinal functions. We hypothesized that the activity balance of each CRF subtype signaling may determine the changes in colonic motility and visceral sensation. Colonic contractions were assessed by the perfused manometry, and contractions of colonic muscle strips were measured in vitro in rats. Visceromotor response was determined by measuring contractions of abdominal muscle in response to colorectal distensions (CRDs) (60 mm Hg for 10 min twice with a 30-min rest). All drugs were administered through ip route in in vivo studies. CRF increased colonic contractions. Pretreatment with Astressin, a nonselective CRF antagonist, blocked the CRF-induced response, but Astressin2-B, a selective CRF2 antagonist, enhanced the response by CRF. Cortagine, a selective CRF1 agonist, increased colonic contractions. In in vitro study, CRF increased contractions...
Frank M Dautzenberg - One of the best experts on this subject based on the ideXlab platform.
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binding differences of human and amphibian corticotropin releasing factor type 1 crf1 receptors identification of amino acids mediating high affinity Astressin binding and functional antagonism
Regulatory Peptides, 2004Co-Authors: Frank M Dautzenberg, Sandra WilleAbstract:The corticotropin-releasing factor (CRF) type 1 receptors (CRF(1)) from human (hCRF(1)) and Xenopus (xCRF(1)) differ from one another by their agonist- and antagonist-binding preference. While the agonist-binding site of the xCRF(1) receptor has been mapped, the amino acids that mediate binding of the potent peptide antagonist Astressin are unknown. By constructing receptor chimeras followed by site-directed mutagenesis, the Astressin-binding site of the xCRF(1) receptor was located between residues 76 and 83. This region partially overlaps with the agonist-selective domain of the xCRF(1) receptor (residues 76-89). Mutagenesis of the amphibian residues Gln(76), Gly(81) and Val(83) to the human sequence (Arg(76)Asn(81)Gly(83)) generated a receptor mutant that bound Astressin with even higher affinity than the native hCRF(1) receptor. An amino acid doublet (Glu(70)Tyr(71)) that is conserved in the xCRF(1) and hCRF(2(a)) receptor after incorporation into the hCRF(1) receptor sequence was found to facilitate antagonist binding up to 15-fold higher. In agreement with the binding data, Astressin was a more potent functional antagonist at receptors expressing the Glu(70)Tyr(71) motif. These data show that the agonist- and antagonist-binding sites of the hCRF(1) receptor partially overlap and that two amino acids within the N terminus of the hCRF(1) receptor negatively influence binding and functional antagonism of Astressin.
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125i antisauvagine 30 a novel and specific high affinity radioligand for the characterization of corticotropin releasing factor type 2 receptors
Neuropharmacology, 2001Co-Authors: Jacqueline Higelin, Gabrielle Pylang, Cristina Paternoster, Gareth J Ellis, Arvind Patel, Frank M DautzenbergAbstract:Corticotropin-releasing factor (CRF) receptors type 1 (CRF1) and type 2 (CRF2) differ from each other in their pharmacological properties. The human and ovine CRF versions bind to CRF1 receptors with significantly higher affinity than to CRF2 receptors. Recently antisauvagine-30, an N-terminally truncated version of the CRF analog sauvagine, was characterized as a specific antagonist to mouse CRF2B. We have synthesized the radiolabeled version 125I-antisauvagine-30 and tested it for its affinity at human CRF1 (hCRF1), hCRF2A, Xenopus CRF1 (xCRF1) and xCRF2 receptors. In control binding studies 125I-labeled hCRF, sauvagine and Astressin were also bound to these receptors. 125I-antisauvagine-30 exclusively bound to hCRF2A and xCRF2 but not to hCRF1 and xCRF1 receptors. 125I-antisauvagine-30 binding to hCRF2A and xCRF2 receptors was saturable and of high affinity (hCRF2A: Kd=125 pM; xCRF2: Kd=1.1 nM). In displacement binding experiments using 125I-antisauvagine-30 as radioligand several CRF analogs bound to hCRF2A and xCRF2 receptors with similar rank orders as reported with other CRF radioligands. Finally, preliminary studies using 125I-antisauvagine-30 binding to membrane homogenates prepared from different rat brain structures showed that the peptide bound specifically to brain areas expressing CRF2 receptors. These data demonstrate that 125I-antisauvagine-30 is the first high-affinity ligand to specifically label CRF2 receptors.
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identification of amino acids in the n terminal domain of corticotropin releasing factor receptor 1 that are important determinants of high affinity ligand binding
Journal of Neurochemistry, 1999Co-Authors: Sandra Wille, Frank M Dautzenberg, Joachim Spiess, Sabine Sydow, Monika R PalchaudhuriAbstract:Abstract : The aim of the present study was to identify the N-terminal regions of human corticotropin-releasing factor (CRF) receptor type 1 (hCRF-R1) that are crucial for ligand binding. Mutant receptors were constructed by replacing specific residues in hCRF-R1 with amino acids from the corresponding position in the N-terminal region of the human vasoactive intestinal peptide receptor type 2 (hVIP-R2). In cyclic AMP stimulation and CRF binding assays, it was established that two regions within the N-terminal domain were crucial for the binding of CRF receptor agonists and antagonists : one region mapping to amino acids 43-50 and a second amino acid sequence extending from position 76 to 84 of hCRF-R1. Recently, it was found that the latter sequence plays a very important role in determining the high ligand selectivity of the Xenopus CRF-R1 (xCRF-R1). Replacement of amino acids 76-84 of hCRF-R1 with residues from the same segment of the hVIP-R2 N terminus markedly reduced the binding affinity of CRF ligands. Mutation of Arg76 or Asn81 but not Gly83 of hCRF-R1 to the corresponding amino acids of xCRF-R1 or hVIP-R2 resulted in 100-1,000-fold lower affinities for human/rat CRF, rat urocortin, and Astressin. These data underline the importance of the N-terminal domain of CRF-R1 in high-affinity ligand binding.
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corticotropin releasing factor receptor type 1 from tupaia belangeri cloning functional expression and tissue distribution
FEBS Journal, 1998Co-Authors: Monika Palchaudhuri, Frank M Dautzenberg, Joachim Spiess, Sandra Wille, Gregor Mevenkamp, Eberhard FuchsAbstract:A cDNA clone encoding corticotropin-releasing factor (CRF) type 1 (CRF-R1) has been isolated from the tree shrew Tupaia belangeri with a PCR-based approach. The full-length cDNA encoded a 415-amino-acid protein with highest sequence identity (approximately 98%) to human CRF-R1 and slightly less identity to rat or mouse CRF-R1 (approximately 97%). Only eight amino acids (residues 3, 4, 6, 35, 36 and 39 in the N-terminus, residue 232 in transmembrane domain 4 and residue 410 in the C-terminus) differed between tree shrew CRF-R1 (tCRF-R1) and human CRF-R1 (hCRF-R1). tCRF-R1 mRNA was detected by semiquantitative RT-PCR and RNase protection analysis in the pituitary and in brain areas such as amygdala, brainstem, cerebellum, cortex, olfactory bulb, and striatum. In peripheral organs, only weak expression of tCRF-R1 mRNA was observed in ovary, testis, and adrenal gland. Binding studies using human embryonic kidney 293 (HEK293) cells stably transfected with tCRF-R1 showed that the CRF agonists ovine CRF (KD = 1.28 nM), human/rat CRF (KD = 1.09 nM), urocortin (KD = 0.37 nM) and sauvagine (KD = 0.77 nM), respectively, were bound with significantly higher affinities than the CRF antagonist Astressin (KD = 12.4 nM). In agreement with the binding data half maximum effective EC50 values of 0.83 nM (human/rat CRF), 1.41 nM (ovine CRF), 1.25 nM (rat urocortin) and 0.71 nM (sauvagine) were calculated when the cAMP production in HEK293 cells stably transfected with tCRF-R1 was stimulated with the four CRF analogues. These data underline the close relationship between human and tree shrew CRF-R1.
