Corticotropin Releasing Factor Receptor 1–Deficient Mice Display Decreased Anxiety, Impaired Stress Response, and Aberrant Neuroendocrine Development (original) (raw)
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Endocrinology, 2000
Background & Aims: Corticotropin-releasing factor (CRF) signaling pathways play a key role in the stress response through the activation of CRF 1 and CRF 2 receptors. We investigated the CRF receptor subtypes involved in gastric postoperative ileus. Methods: Adult male mice (C57BL/6, CRF 1 -deficient, and wild-type), fasted for 16 -18 hours, were anesthetized for 10 minutes and had a midline celiotomy and cecal exteriorization and palpation for 30 or 60 seconds or no surgery (sham). Phenol red was given by gavage 100 minutes after anesthesia; 20 minutes later, gastric emptying and blood glucose level were measured. Results: In C57BL/6 mice, cecal palpation for 30 or 60 seconds significantly reduced gastric emptying to 30.3% ؎ 1.4% and 5.8% ؎ 3.4%, respectively, compared with 58.5% ؎ 4.4% in sham. The CRF 1 antagonist CP-154,526 (20 mg/kg subcutaneously) completely prevented the 30-second cecal palpation-induced delayed gastric emptying (53.0% ؎ 7.9% vs. 28.0% ؎ 4.0% in vehicle ؉ surgery), whereas the CRF 2 antagonist astressin 2 -B injected subcutaneously had no effect. In CRF 1 -deficient mice, cecal palpation for 30 seconds did not delay gastric emptying (80.3% ؎ 4.5% compared with 84.7% ؎ 6.3% in sham); in wildtype mice, gastric emptying was decreased to 17.8% ؎ 16.1% (P < 0.05 vs. sham 72.0% ؎ 12.4%). Surgery increased glucose levels by 46% compared with sham in wild-type mice, while glycemia was not altered in CRF 1deficient mice. Basal emptying was similar in wild-type and CRF 1 -deficient mice and not influenced by CRF antagonists in C57BL/6 mice. Conclusions: These data show that CRF 1 activation plays an important role in mediating the early phase of gastric ileus.
Peptides, 1988
TACHI~. lntracisternal injection of CRF antagonist blocks surgical stress-induced inhibition of gastric secretion in the rat. PEPTIDES 9(5) 1067-1070, 1988.--The effects of intracisternal injection of CRF antagonist, a-CRF %41, on the inhibition of gastric acid secretion elicited by intracisternal injection of corticotropin-releasing factor (CRF) and stress were investigated in conscious pylorus-ligated rats. lntracisternal injection of the a-helical CRF %41 (50 ~g) did not influence basal gastric secretion, but injected concomitantly with intracisternal CRF (5/xg), completely blocked CRF (5/~g)-induced inhibition of gastric secretory volume, acid concentration and output. Intracistemal injection of a-helical CRF 9-41 (3, 10, 50/zg) produced a dose-related reversal (0, 52 and 100%) of brain surgery-induced inhibition of gastric acid output. By contrast intravenous injection of CRF antagonist (50/zg) did not inhibit gastric hyposecretory response to brain surgery. These data suggest that endogenous CRF in the brain may mediate stress-induced gastric hyposecretion in the rat.
Pathways mediating CRF-induced inhibition of gastric emptying in rats
Regulatory Peptides, 1997
The corticotrophin-releasing factor (CRF) is shown to be released during stress suggesting that CRF has a physiological role in the mediation of central nervous system (CNS) response to stress, including an inhibitory effect on gastric emptying. In the present study, we have examined the pathways by which intracerebroventricularly (icv) administered CRF and central CRF activation during stress alter the gastric emptying rate of saline (0.14 M), acid (50 mM), peptone (4.5%) and peptone after preload. The emptying rates of all these test meals were significantly ( p , 0.05-0.001) delayed with increasing doses of icv CRF (0.001, 0.003, 0.01, 0.1, 0.3 and 1 nmol / 10 ml), when compared with their icv saline-treated controls. The 1-nmol dose of CRF inhibited the emptying of acid, peptone and peptone after a preload by 43.8%, 64.1% and 81.1%, respectively. Twenty-minute swim stress delayed gastric emptying rate of saline, acid and peptone solutions significantly ( p , 0.001) and the CRF receptor antagonist, a-helical CRF (8 nmol / 10 ml, icv), applied before the swim stress, abolished the inhibitory effect of stress on the emptying rate of these solutions. Acute intragastric administration of capsaicin (2 mg / rat) 21 and systemic capsaicin (125 mg kg ) treatment facilitated the gastric emptying rate of acid, peptone and peptone after preload significantly, almost abolishing the inhibitory effect of central CRF ( p , 0.001). However, either capsaicin treatment had no effect on stress-induced inhibition of the gastric emptying of none of the solutions, except peptone after a preload. Our findings demonstrate that the gastric inhibitory response induced by swimming as a stress-producing stimulus is mediated by the endogenous release of CRF. They also suggest that CRF exerts its CNS actions on the gastrointestinal tract via vago-vagal, capsaicin-sensitive pathways, probably involving the central cholecystokinin (CCK) mechanisms.
Journal of Pharmacology and Experimental Therapeutics, 2002
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 Ͼ CRF 2 binding affinity, decreased distal colonic transit time at lower doses (6-12 g/kg) than those inhibiting gastric emptying (20-60 g/kg). Ovine CRF, a preferential CRF 1 receptor agonist (6-60 g/kg), reduced significantly the colonic transit time without altering gastric emptying, whereas the selective CRF 2 receptor agonists mouse urocortin II (20-60 g/kg) and urocortin III (120 g/kg) inhibited significantly gastric emptying without modifying colonic transit. The CRF 1 /CRF 2 receptor antagonist, astressin (30-120 g/kg), dose dependently prevented r/hCRF (20 g/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)-7H-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 g/ 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.
Peripheral urocortin delays gastric emptying: role of CRF receptor 2
American Journal of Physiology-Gastrointestinal and Liver Physiology, 1999
Urocortin, a new mammalian member of the corticotropin-releasing factor (CRF) family has been proposed to be the endogenous ligand for CRF receptor 2 (CRF-R2). We studied the influence of intravenous urocortin on gastric emptying and the role of CRF-R2 in peptide action and postoperative gastric ileus in conscious rats. The intravenous doses of rat CRF and rat urocortin producing 50% inhibition of gastric emptying were 2.5 and 1.1 μg/kg, respectively. At these intravenous doses, CRF and urocortin have their actions fully reversed by the CRF-R1/CRF-R2 antagonist astressin at antagonist/agonist ratios of 5:1 and 67:1, respectively. Astressin (12 μg/kg iv) completely prevented abdominal surgery-induced 54% inhibition of gastric emptying 3 h after surgery while having no effect on basal gastric emptying. The selective nonpeptide CRF-R1 antagonists antalarmin (20 mg/kg ip) and NBI-27914 (400 μg/kg iv) did not influence intravenous CRF-, urocortin- or surgery-induced gastric stasis. These...
The Journal of physiology, 2004
Recently characterized selective agonists and developed antagonists for the corticotropin releasing factor (CRF) receptors are new tools to investigate stress-related functional changes. The influence of mammalian CRF and related peptides injected intracerebroventricularly (i.c.v.) on gastric and colonic motility, and the CRF receptor subtypes involved and their role in colonic response to stress were studied in conscious mice. The CRF(1)/CRF(2) agonists rat urocortin 1 (rUcn 1) and rat/human CRF (r/h CRF), the preferential CRF(1) agonist ovine CRF (oCRF), and the CRF(2) agonist mouse (m) Ucn 2, injected i.c.v. inhibited gastric emptying and stimulated distal colonic motor function (bead transit and defecation) while oCRF(9-33)OH (devoid of CRF receptor affinity) showed neither effects. mUcn 2 injected peripherally had no colonic effect. The selective CRF(2) antagonist astressin(2)-B (i.c.v.), at a 20 : 1 antagonist: agonist ratio, blocked i.c.v. r/hCRF and rUcn 1 induced inhibition...
The Journal of pharmacology and experimental therapeutics, 1999
The effect of the corticotropin-releasing factor (CRF) receptor antagonists astressin and D-Phe CRF(12-41) injected i.v. on CRF-induced delayed gastric emptying (GE) was investigated in conscious rats. Gastric transit was assessed by the recovery of methyl cellulose/phenol red solution 20 min after its intragastric administration. The 55% inhibition of GE induced by CRF (0.6 microgram i.v.) was antagonized by 87 and 100% by i.v. astressin at 3 and 10 microgram, respectively, and by 68 and 64% by i.v. D-Phe CRF(12-41) at 10 and 20 microgram, respectively. CRF (0.6 microgram)-injected intracisternally (i.c.) induced 68% reduction of GE was not modified by i.v. astressin (10 microgram) whereas i.c. astressin (3 or 10 microgram) blocked by 58 and 100%, respectively, i.v. CRF inhibitory action. Abdominal surgery with cecal manipulation reduced GE to 7.1 +/- 3.1 and 27.5 +/- 3.3% at 30 and 180 min postsurgery, respectively, compared with 40.3 +/- 4.3 and 59.5 +/- 2.9% at similar times aft...
American journal of physiology. Gastrointestinal and liver physiology, 2002
Human urocortin (hUcn) II is a new member of the corticotropin-releasing factor (CRF) family that selectively binds to the CRF(2) receptor. We investigated the CRF receptors involved in mediating the effects of hUcn II and human/rat CRF (h/rCRF) on gut transit. Gastric emptying, 4 h after a solid meal, and distal colonic transit (bead expulsion time) were monitored simultaneously in conscious rats. CRF antagonists were given subcutaneously 30 min before intravenous injection of peptides or partial restraint (for 90 min). hUcn II (3 or 10 microg/kg i.v.) inhibited gastric emptying (by 45% and 55%, respectively) and did not influence distal colonic transit. The CRF(2) peptide antagonist astressin(2)-B blocked hUcn II action. h/rCRF, rat Ucn, and restraint delayed gastric emptying while accelerating distal colonic transit. The gastric response to intravenous h/rCRF and restraint was blocked by the CRF(2) antagonist but not by the CRF(1) antagonist CP-154,526, whereas the colonic respon...
Central CRF inhibits gastric emptying of a nutrient solid meal in rats: the role of CRF2receptors
American Journal of Physiology-Gastrointestinal and Liver Physiology, 1998
Corticotropin-releasing factor (CRF)-related peptides exhibit different affinity for the receptor subtypes 1 and 2 cloned in the rat brain. We investigated, in conscious rats, the effects of intracisternal (IC) injection of CRF (rat/human) on the 5-h rate of gastric emptying of a solid nutrient meal (Purina chow and water ad libitum for 3 h) and the CRF receptor subtype involved. CRF, urotensin I (suckerfish), and sauvagine (frog) injected IC inhibited gastric emptying in a dose-dependent manner, with ED50 values of 0.31, 0.13, and 0.08 μg/rat, respectively. Rat CRF-(6—33) (0.1–10 μg ic) had no effect. The nonselective CRF1and CRF2 receptor antagonist, astressin, injected IC completely blocked the inhibitory effect of IC CRF, urotensin I, and sauvagine with antagonist-to-agonist ratios of 3:1, 10:1, and 16:1, respectively. The CRF1-selective receptor antagonist NBI-27914 injected IC at a ratio of 170:1 had no effect. These data show that central CRF and CRF-related peptides are pote...
Role of CRF in Stress-Related Alterations of Gastric and Colonic Motor Function
Annals of the New York Academy of Sciences, 1993
The impact of emotion on digestive function was recognized nearly 200 years ago. In 1802, the French physiologist, Pierre Jean Georges Cabanis, reported: "Should a man receive bad news, or should sad and baneful passions suddenly arise in his soul, his stomach and intestines will immediately cease to act on the foods contained in them. .. digestion ceases entirely."' In 1833, Beaumont noticed in his fistulous subject that "fear, anger, or whatever depresses or disturbs his nervous system suppresses gastric secretion and delays gastric digestion and emptying of the stomach."* A century later, experimental evidence provided by Cannon3 established that the fight or flight response is associated with a reduction in gastric acid secretion and motor activity. In 1934, Hall proposed using defecation scores as a measure for individual differences in fearfulness in rodents exposed to unfamiliar surroundings or arousing situation^.^ Selyes developed in 1936 the unifying concept of stress and drew attention to the omnipresent sign of alterations in the stomach as part of the bodily response to stress. Since then, the influence and mechanisms of action of stress on gastrointestinal secretory and motor function have been the object of intense investigation in experimental animals and in humans."8 Over the past decade, the characterization of the hypothalamic corticotropinreleasing factor, CRF, by Vale et aL,9 followed by the development of a specific CRF antagonist by Rivier et al., '0 has paved the way to the study of the central mechanisms underlying stress-related alterations of gastrointestinal function. This paper reviews compelling experimental evidence that supports a role of CRF in mediating the stress-related inhibition of gastric motor function and the acceleration of colonic motor activity. The relevance of these findings to the underlying mechanisms of postoperative gastric ileus and irritable bowel syndrome (IBS) is also addressed.