astressin and Disease-Models--Animal

Rapid eye movement sleep (REM) is increased after controllable stress (modeled by escapable footshock, ES) and decreased after uncontrollable stress (modeled by inescapable footshock, IS). Decreases in REM after IS are exacerbated by corticotropin releasing factor (CRF) and attenuated by a CRF antagonist. In this study, we trained mice with ES following injections of CRF, astressin (AST), or saline (SAL) to determine whether CRF would alter REM after ES. Male BALB/cJ mice (n=7) were implanted for recording sleep, activity and body temperature via telemetry and with a guide cannula aimed into a lateral ventricle. After recovery from surgery, sleep following exposure to a novel chamber was recorded as a handling control (HC). The mice received one day of training with ES without injection followed by weekly training sessions in which they received counterbalanced intracerebroventricular (ICV) microinjections of either SAL or CRF (days 7 & 14) or SAL or AST (days 21 & 28) prior to ES. On each experimental day, sleep was recorded for 20 h. Compared to HC, the mice showed significantly increased REM when receiving either SAL or AST prior to ES whereas CRF prior to ES significantly reduced REM. Stress-induced hyperthermia had longer duration after ES compared to HC, and was not significantly altered by CRF or AST compared to SAL. The current results demonstrate that activity in the central CRF system is an important regulator of stress-induced alterations in REM.

Topics: Analysis of Variance; Animals; Body Temperature; Corticotropin-Releasing Hormone; Disease Models, Animal; Drug Interactions; Electroshock; Foot; Injections, Intraventricular; Mice; Peptide Fragments; Sleep, REM; Stress, Psychological; Time Factors

The role of corticotropin-releasing factor (CRF) in the pathogenesis of indomethacin-induced small intestinal lesions was examined in rats.. Animals were given indomethacin (10 mg/kg) subcutaneously and killed 24 h later. Urocortin I [a nonselective CRF receptor (CRFR) agonist], astressin (a nonselective CRFR antagonist), NBI-27914 (a CRFR1 antagonist), or astressin-2B (a CRFR2 antagonist) was given intravenously 10 min before the administration of indomethacin.. Indomethacin caused hemorrhagic lesions in the small intestine, accompanied by intestinal hypermotility, mucosal invasion of enterobacteria, up-regulation of inducible nitric oxide synthase (iNOS) expression, and an increase of mucosal myeloperoxidase (MPO) activity. Pretreatment of the animals with astressin, a non-selective CRFR antagonist, aggravated the lesions in a dose-dependent manner. Likewise, astressin-2B also exacerbated the intestinal ulcerogenic response induced by indomethacin, while NBI-27914 did not. Urocortin I prevented indomethacin-induced intestinal lesions, together with the suppression of bacterial invasion and an increase in mucosal MPO activity and iNOS expression; these effects were significantly reversed by co-administration of astressin-2B but not NBI-27914. Urocortin I suppressed the hypermotility response to indomethacin, and this effect was also abrogated by astressin-2B but not NBI-27914.. These results suggest that urocortin 1 prevents indomethacin-induced small intestinal lesions, and that this action is mediated by the activation of CRFR2 and is functionally associated with the suppression of the intestinal hypermotility response caused by indomethacin. It is assumed that endogenous CRF contributes to the maintenance of the mucosal defensive ability of the small intestine against indomethacin through the activation of CRFR2.

Topics: Aniline Compounds; Animals; Bacterial Translocation; Corticotropin-Releasing Hormone; Cytoprotection; Disease Models, Animal; Dose-Response Relationship, Drug; Gastrointestinal Agents; Gastrointestinal Motility; Indomethacin; Injections, Intravenous; Intestine, Small; Male; Nitric Oxide Synthase Type II; Peptic Ulcer; Peptide Fragments; Peptides, Cyclic; Peroxidase; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptors, Corticotropin-Releasing Hormone; RNA, Messenger; Time Factors; Urocortins

Corticotropin-releasing factor (CRF) 1 receptor (CRF(1)) activation in the brain is a core pathway orchestrating the stress response. Anatomical data also support the existence of CRF signaling components within the colon. We investigated the colonic response to intraperitoneal (ip) injection of cortagine, a newly developed selective CRF(1) peptide agonist. Colonic motor function and visceral motor response (VMR) were monitored by using a modified miniaturized pressure transducer catheter in adult conscious male Sprague-Dawley rats and C57Bl/6 mice. Colonic permeability was monitored by the Evans blue method and myenteric neurons activation by Fos immunohistochemistry. Compared with vehicle, cortagine (10 microg/kg ip) significantly decreased the distal colonic transit time by 45% without affecting gastric transit, increased distal and transverse colonic contractility by 35.6 and 66.2%, respectively, and induced a 7.1-fold increase in defecation and watery diarrhea in 50% of rats during the first hour postinjection whereas intracerebroventricular (icv) cortagine (3 microg/rat) had lesser effects. Intraperitoneal (ip) cortagine also increased colonic permeability, activated proximal and distal colonic myenteric neurons, and induced visceral hypersensitivity to a second set of phasic colorectal distention (CRD). The CRF antagonist astressin (10 mug/kg ip) abolished ip cortagine-induced hyperalgesia whereas injected icv it had no effect. In mice, cortagine (30 microg/kg ip) stimulated defecation by 7.8-fold, induced 60% incidence of diarrhea, and increased VMR to CRD. Stresslike colonic alterations induced by ip cortagine in rats and mice through restricted activation of peripheral CRF(1) receptors support a role for peripheral CRF(1) signaling as the local arm of the colonic response to stress.

Topics: Animals; Colon; Corticotropin-Releasing Hormone; Defecation; Diarrhea; Disease Models, Animal; Dose-Response Relationship, Drug; Gastrointestinal Motility; Gastrointestinal Transit; Hyperalgesia; Injections, Intraperitoneal; Injections, Intraventricular; Male; Mice; Mice, Inbred C57BL; Myenteric Plexus; Neural Pathways; Pain Measurement; Peptide Fragments; Permeability; Physical Stimulation; Pressure; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, Corticotropin-Releasing Hormone; Recombinant Fusion Proteins; Stress, Psychological

Repeated restraint stress (RRS; 3 h of restraint on 3 consecutive days) in rodents produces temporary hypophagia, but a long-term downregulation of body weight. The mild stress (MS) of an intraperitoneal injection of saline and housing in a novel room for 2 h also inhibits food intake and weight gain, but the effects are smaller than for RRS. Previous exposure to RRS exaggerates hypophagia, glucocorticoid release, and anxiety-type behavior caused by MS. Here we tested the involvement of brain stem corticotrophin-releasing factor receptors (CRFR) in mediating energetic and glucocorticoid responses to RRS or MS and in promoting stress hyperresponsiveness in RRS rats. Administration of 1.3 nmol alphahCRF(9-41), a nonspecific CRFR antagonist, exaggerated hypophagia and weight loss in both RRS and MS rats, whereas 0.26 nmol had no effect in RRS or MS rats. In contrast, 2 nmol of the nonspecific antagonist astressin had no effect on weight loss or hypersensitivity to subsequent MS in RRS rats, but blocked weight loss and inhibition of food intake caused by MS alone. MS rats infused with 3 nmol antisauvagine-30, a CRFR2 antagonist, did not lose weight in the 48 h after MS, but 0.3 nmol did not prevent weight loss in MS rats. These data suggest that inhibition of food intake and weight loss induced by RRS or by MS involve different pathways, with hindbrain CRFR mediating the effect of MS on body weight and food intake. Hindbrain CRFR do not appear to influence stress-induced corticosterone release in RRS rats.

Topics: Animals; Behavior, Animal; Corticosterone; Corticotropin-Releasing Hormone; Disease Models, Animal; Dose-Response Relationship, Drug; Eating; Fourth Ventricle; Infusions, Parenteral; Injections, Intraperitoneal; Male; Peptide Fragments; Rats; Rats, Sprague-Dawley; Receptors, Corticotropin-Releasing Hormone; Restraint, Physical; Stress, Psychological; Time Factors; Weight Loss

Visceral hypersensitivity has been implicated as an important pathophysiological mechanism in functional gastrointestinal disorders. In this study, we investigated whether the sustained visceral hyperalgesia induced by repeated psychological stress in rats involves the activation of CRF(1) signaling system using two different antagonists. Male Wistar rats were exposed to 10 consecutive days of water avoidance stress (WAS) or sham stress for 1 h/day, and the visceromotor response to phasic colorectal distension (CRD) was assessed before and after the stress period. Animals were injected subcutaneously with the brain penetrant CRF(1) antagonist, CP-154,526, acutely (30 min before the final CRD) or chronically (via osmotic minipump implanted subcutaneously, during stress) or with the peripherally restricted, nonselective CRF(1) and CRF(2) antagonist, astressin, chronically (15 min before each stress session). Repeated WAS induced visceral hypersensitivity to CRD at 40 and 60 mmHg. CP-154,526 injected acutely significantly reduced stress-induced visceral hyperalgesia at 40 mmHg but not at 60 mmHg. Chronic subcutaneous delivery of astressin reduced the stress-induced visceral hyperalgesia to baseline at all distension pressures. Interestingly, chronically administered CP-154,526 eliminated hyperalgesia and produced responses below baseline at 40 mmHg and 60 mmHg, indicating a hypoalgesic effect of the compound. These data support a major role for CRF(1) in both the development and maintenance of visceral hyperalgesia induced by repeated stress and indicate a possible role of peripheral CRF receptors in such mechanisms.

Topics: Animals; Blood-Brain Barrier; Chronic Disease; Colon; Corticotropin-Releasing Hormone; Disease Models, Animal; Hyperalgesia; Infusion Pumps, Implantable; Injections, Subcutaneous; Male; Mechanotransduction, Cellular; Peptide Fragments; Pressure; Pyrimidines; Pyrroles; Rats; Rats, Wistar; Receptors, Corticotropin-Releasing Hormone; Rectum; Stress, Psychological

Although restraint stress accelerates colonic transit via a central corticotropin-releasing factor (CRF), the precise mechanism still remains unclear. We tested the hypothesis that restraint stress and central CRF stimulate colonic motility and transit via a vagal pathway and 5-HT(3) receptors of the proximal colon in rats. (51)Cr was injected via the catheter positioned in the proximal colon to measure colonic transit. The rats were subjected to a restraint stress for 90 min or received intracisternal injection of CRF. Ninety minutes after the administration of (51)Cr, the entire colon was removed, and the geometric center (GC) was calculated. Four force transducers were sutured on the proximal, mid, and distal colon to record colonic motility. Restraint stress accelerated colonic transit (GC of 6.7 +/- 0.4, n=6) compared with nonrestraint controls (GC of 5.1 +/- 0.2, n=6). Intracisternal injection of CRF (1.0 microg) also accelerated colonic transit (GC of 7.0 +/- 0.2, n=6) compared with saline-injected group (GC of 4.6 +/- 0.5, n=6). Restraint stress-induced acceleration of colonic transit was reduced by perivagal capsaicin treatment. Intracisternal injection of CRF antagonists (10 microg astressin) abolished restraint stress-induced acceleration of colonic transit. Stimulated colonic transit and motility induced by restraint stress and CRF were significantly reduced by the intraluminal administration of 5-HT(3) antagonist ondansetron (5 x 10(-6) M; 1 ml) into the proximal colon. Restraint stress and intracisternal injection of CRF significantly increased the luminal content of 5-HT of the proximal colon. It is suggested that restraint stress stimulates colonic motility via central CRF and peripheral 5-HT(3) receptors in conscious rats.

Topics: Animals; Capsaicin; Central Nervous System; Colon; Consciousness; Corticotropin-Releasing Hormone; Disease Models, Animal; Feces; Gastrointestinal Motility; Male; Ondansetron; Peptide Fragments; Rats; Rats, Sprague-Dawley; Receptors, Corticotropin-Releasing Hormone; Receptors, Serotonin, 5-HT3; Restraint, Physical; Serotonin; Serotonin 5-HT3 Receptor Antagonists; Serotonin Antagonists; Stress, Psychological; Time Factors; Vagotomy, Truncal; Vagus Nerve

This study examines the contribution of central corticotropin-releasing factor (CRF) to pain behavior. CRF is the principal modulator of the hypothalamo-pituitary-adrenal (HPA) axis, in addition to acting on many other areas of the central nervous system. We compared nociceptive thresholds (heat and mechanical) and pain behavior in response to a sustained stimulus (formalin test) between Fischer and Lewis rats that have different HPA axis activity. Intracerebroventricular (i.c.v.) administration of CRF produced dose-dependent antinociception at a lower dose in Lewis (40 ng, paw pinch 71+/-0 g) compared to Fischer rats (200 ng, 112+/-3 g). The antinociceptive effect of CRF was mostly preserved in adrenalectomized Fischer rats. The i.c.v. administration of the CRF receptor antagonist, astressin, had a hyperalgesic effect, suggesting that CRF is tonically active. Lewis rats required higher doses of astressin (5 ng, paw pinch 51+/-1 g) to show nociceptive effects compared to Fischer rats (1 ng, 79+/-1 g). Only Lewis rats vocalized during mechanical stimulus, and this behavior was prevented by diazepam or morphine but was worsened by CRF, despite its antinociceptive property. In the formalin test, CRF and astressin had the largest effect on the interphase suggesting that they act on the endogenous pain inhibitory system. CRF also increased anxiety/fear-like behaviors in the forced swim and predator odor tests. Our results establish that central CRF is a key modulator of pain behavior and indicates that CRF effects on nociception are largely independent of its mood modulating effect as well as its control of the HPA axis.

Topics: Adrenalectomy; Analgesics; Animals; Anxiety; Corticotropin-Releasing Hormone; Disease Models, Animal; Dose-Response Relationship, Drug; Fear; Female; Hyperalgesia; Hypothalamo-Hypophyseal System; Injections, Intraventricular; Neuroprotective Agents; Pain; Pain Measurement; Peptide Fragments; Pituitary-Adrenal System; Rats; Rats, Inbred F344; Rats, Inbred Lew; Receptors, Corticotropin-Releasing Hormone; Vocalization, Animal

Intermedin/Adrenomedullin-2 (IMD), a newly described peptide with structural homology to adrenomedullin (AM), is present in brain and pituitary gland and binds to the same receptors as AM and calcitonin gene-related peptide (CGRP). We hypothesized that IMD would exert actions similar to AM and CGRP and previously have demonstrated that indeed IMD, like AM and CGRP, increases sympathetic tone and inhibits feeding and drinking when administered centrally. Here, we extend those observations by demonstrating that like AM, IMD acts in brain to stimulate the secretions of prolactin (PRL) and adrenocorticotropin (ACTH) and to inhibit the secretion of growth hormone (GH) in conscious rats. In addition, in conscious rats, central administration of IMD results in increased plasma levels of oxytocin (OT) and vasopressin (AVP). The ability of IMD to activate the hypothalamo-pituitary-adrenal (HPA) axis can be blocked by intravenous pretreatment with the corticotropin releasing factor (CRF) antagonist, astressin. These results suggest that multiple members of the AM family of peptides may be involved in the cardiovascular, behavioral and neuroendocrine responses to stress.

Topics: Adrenocorticotropic Hormone; Adrenomedullin; Animals; Corticotropin-Releasing Hormone; Disease Models, Animal; Growth Hormone; Hypothalamo-Hypophyseal System; Male; Neuropeptides; Neurosecretory Systems; Oxytocin; Peptide Fragments; Pituitary Hormones; Prolactin; Rats; Rats, Sprague-Dawley; Stress, Physiological; Vasopressins