Stimulation Of Colonic Transit Research Articles

A novel water-soluble selective CRF 1 receptor antagonist, NBI 35965, blunts stress-induced visceral hyperalgesia and colonic motor function in rats

The stress response involves the activation of two corticotropin-releasing factor (CRF) receptor subtypes. We investigated the role of CRF 1 in stress-related visceral responses. A novel water-soluble tricyclic CRF 1 antagonist, NBI 35965 was developed that displayed a high affinity for CRF 1 ( K i∼4 nM) while having no binding affinity to CRF 2. This antagonist also inhibited the stimulation of cAMP induced by sauvagine in CRF 1 transfected cells. NBI 35965 administered per orally (p.o.) in rats (1, 3, 10 or 30 mg/kg) inhibited dose-dependently [ 125I]sauvagine binding selectively at brain sites of CRF 1 distribution as shown by ex vivo receptor autoradiography. At the highest doses, NBI 35965 completely prevented [ 125I]sauvagine labeling in the cortex. NBI 35965 (10 mg/kg) administered p.o. or subcutaneously (sc) 1 h before intravenous CRF completely blocked the 81% shortening of distal colonic transit time induced by CRF. NBI 35965 (20 mg/kg s.c.) significantly reduced the defecation in response to water avoidance stress but not that induced by s.c. carbachol. In adult male Long-Evans rats that had undergone maternal separation, acute water avoidance stress significantly increased the visceromotor response to colorectal distention (20–80 mmHg) by 42±19% compared with the response before stress. Stress-induced visceral hyperalgesia was abolished by NBI 35965 (20 mg/kg, s.c.). The data show that NBI 35965 is a novel water-soluble selective CRF 1 antagonist with bioavailability to the brain upon peripheral administration and that CRF 1 receptor signaling pathways are involved in water avoidance stress-induced hyperalgesia to colorectal distention and stimulation of colonic transit.

Differential role of CRF receptor 1 (CRF-R1) and CRF-R2 in peripheral CRF or stress-induced inhibition of gastric emptying and stimulation of colonic transit in rats

Differential role of CRF receptor 1 (CRF-R1) and CRF-R2 in peripheral CRF or stress-induced inhibition of gastric emptying and stimulation of colonic transit in rats

Differential role of CRF receptor 1 (CRF-R1) and CRF-R2 in peripheral CRF or stress-induced inhibition of gastric emptying and stimulation of colonic transit in rats

Differential role of CRF receptor 1 (CRF-R1) and CRF-R2 in peripheral CRF or stress-induced inhibition of gastric emptying and stimulation of colonic transit in rats

Neuropeptide Y in the paraventricular nucleus of the hypothalamus stimulates colonic transit by peripheral cholinergic and central CRF pathways

There is evidence suggesting that neuropeptide Y (NPY) as well as corticotropin-releasing factor (CRF) in the paraventricular nucleus of the hypothalamus (PVN) are involved in the CNS regulation of gastrointestinal (GI) function. We studied the effects of NPY or Y1-and Y2-receptor agonists microinjected into the PVN on colonic transit. Microinjection of NPY into the PVN at doses of 0.15-1.5 microg decreased the colonic transit time of conscious rats up to 49%. Pretreatment with the peripherally acting cholinergic antagonist atropine methyl nitrate (0.1 mg kg-1 i.p.) blocked the NPY into PVN-induced effect on colonic motor function.The agonist of the Y1-receptor, NPY(Leu31, Pro34), as well as the Y2-receptor agonist, NPY(13-36), dose-dependently decreased colonic transit time when microinjected into the PVN (0.05, 0.15 and 0.5 microg). However, the Y1-receptor agonist was more effective. Intracerebroventricular (ICV) application of the CRF-receptor antagonist, alpha-helical-CRF9-41 (50 microg/rat), blocked the NPY effect in the PVN on colonic motor function. In conclusion, stimulation of colonic transit by NPY acting in the PVN was observed. The PVN is more sensitive to agonists acting on the Y1- than on the Y2-receptor to mediate stimulation of propulsive colonic motility. The effect of NPY in the PVN on colonic motor function depends on central CRF and peripheral cholinergic pathways.

Stress-induced changes in the gastrointestinal motor system.

Several autonomic, hormonal, behavioural and neuropeptidergic bodily responses to stressful stimuli have been described over the past few decades. Both animal models and human paradigms have been explored. It is acknowledged that stress modulates gastrointestinal (GI) motility through central mechanisms including corticotropin-releasing-factor. This process requires the integrity of autonomic neural pathways. It has become evident that the effects of stress on GI motility vary according to the stressful stimulus, its intensity, the animal species under study and the time course of the study. Recent evidence suggests that chronic or possibly permanent changes develop in enteric smooth muscle properties in response to stress. In animals, the most consistent findings include retardation of gastric emptying in response to various stressors; acceleration of gastric emptying upon cold stress, presumably through the secretion of brain thyroglobulin-hormone; acceleration of intestinal transit; and stimulation of colonic transit and fecal output. In humans, the cold water immersion test has been associated with an inhibition of gastric emptying, while labyrinthine stimulation induces the transition from postprandial to fasting motor patterns in the stomach and the small bowel. Psychological stress has been shown to induce a reduction in the number and amplitude of intestinal migrating motor complexes and to neither affect nor stimulate colonic motility. These various responses to stress are presumably attributed to the preferential activation of specific neuronal pathways under the influence of a given stimulus or its intensity. The significance of these findings and the directions of further studies are discussed.

Microinfusion of corticotropin releasing factor into the locus coeruleus/subcoeruleus nuclei stimulates colonic motor function in rats

Convergent evidence indicates that brain corticotropin-releasing factor (CRF) participates in stress-related alterations of gastric and colonic motor function. CRF in the locus coeruleus has been shown to induce anxiogenic response. Whether the locus coeruleus/subcoeruleus nucleus (LC/SC) is a site of action for CRF to alter gastric and colonic transit was investigated in conscious, chronically cannulated rats. CRF (0.2 nmol) microinjected into the LC/SC did not influence gastric emptying of a non-caloric semi-liquid meal while stimulating colonic transit by 57% as assessed by the geometric center in fasted rats. Under the same conditions, i.c.v. injection of CRF (0.2 nmol) delayed gastric emptying by 31% and increased colonic transit by 103%. When colonic transit was evaluated as the time of appearance in the feces of a marker placed in the proximal colon, CRF (0.2 nmol) injected into the LC/SC or i.c.v. stimulated colonic transit by 77% and 48% respectively and fecal output/6h by 3.8 and 2.8 fold respectively. Microinjection of CRF into the medial and lateral parabrachial nucleus, postero-dorsal tegmental nucleus, dorsomedial tegmental area and the ventral part of the nucleus subcoeruleus did not influence colonic transit. These data indicate that CRF acts in the LC/SC to induce a long lasting stimulation of colonic transit and bowel discharge without influencing gastric emptying. These findings suggest a possible role of the LC/SC in the regulation of colonic motor function and of endogenous CRF at these sites in the stress-related activation of colonic motor function.

CRF in the paraventricular nucleus mediates gastric and colonic motor response to restraint stress

The role of corticotropin-releasing factor (CRF) in the paraventricular nucleus of the hypothalamus (PVN) in the control of gastric emptying of a nonnutrient meal and colonic transit was investigated in conscious fasted rats chronically implanted with hypothalamic cannulas and catheters in both the stomach and proximal colon. CRF (0.06-0.6 nmol) microinfused unilaterally into the PVN resulted in a dose-dependent inhibition of gastric emptying (0-51%) and stimulation of colonic transit (0-93%). CRF (0.6 nmol)-induced delay in gastric emptying was inhibited by 50% by subdiaphragmatic vagotomy or atropine methyl nitrate (1 mg/kg ip), whereas the stimulation of colonic transit was completely abolished by atropine methyl nitrate and reduced by 19% by vagotomy. Microinfusion of CRF (0.6 nmol) into the lateral hypothalamus or central amygdala had no effect. Restraint exposure for 1 h delayed gastric emptying and stimulated colonic transit by 28 and 78%, respectively. Bilateral microinfusion of the CRF antagonist alpha-helical CRF-(9-41) (13 nmol) into the PVN before restraint abolished stress-induced alterations of gastric and colonic transit. The CRF antagonist did not alter basal gastric and colonic transit under basal conditions. These data indicate that the PVN is a specific responsive site for central CRF-induced alterations of gastric and colonic transit and suggest that endogenous CRF in the PVN plays a role in mediating restraint stress-related alterations of gastrointestinal transit.

Corticotropin-releasing factor directly mediates colonic responses to stress.

A new stress model in rats produced changes in intestinal function that resemble patterns of intestinal dysfunction associated with stress in humans: small intestinal transit was inhibited, large intestinal transit was stimulated, and fecal excretion was stimulated. To evaluate the role of corticotropin-releasing factor (CRF) in mediating the effects of stress on the intestine, we studied the actions of exogenous CRF on small and large intestinal transit in the rat and characterized the effects of pharmacological blockade of CRF receptors on stress-induced intestinal dysfunction. Administration of exogenous CRF (0.3-10.0 micrograms iv or icv) resulted in dose-related inhibition of gastric emptying, inhibition of small intestinal transit, stimulation of colonic transit, and stimulation of fecal excretion. The actions of exogenous CRF mimicked the effects of stress on the motor activity of the gastrointestinal tract. Administration of alpha-helical CRF-(9-41) (50 micrograms iv or icv), an antagonist of CRF, prevented the stress-induced increase in large intestinal transit and the associated increase in fecal excretion. These data suggest that endogenous CRF may mediate stress-induced changes in colonic function.

Blockade by Naloxone and Naltrexone of the TRH-induced Stimulation of Colonic Transit in the Rabbit

Blockade by Naloxone and Naltrexone of the TRH-induced Stimulation of Colonic Transit in the Rabbit