THE EFFECTS OF STRESS ON GASTROINTESTINAL FUNCTION: INTERACTIONS OF NEURAL AND ENDOCRINE SYSTEMS IN MEDIATING STRESS-INDUCED INTESTINAL DYSFUNCTION IN RATS.

摘要

Stress-related functional bowel disease is a common, often incapacitating, problem in humans; the symptomatology of stress-related intestinal dysfunction is: (1) impaired small intestinal transit and motility, and (2) increased large intestinal transit and, commonly, diarrhea. The etiology of stress-induced intestinal dysfunction is completely unresolved, and the lack of an appropriate animal model has hindered studies of causality. We compared a number of stressors and their resultant effects on intestinal transit, a measure of the propulsive motor activity of the gut, in the rat. We found that the response of the intestine to stress, and the neural systems activated by stress, were dependent on the type and duration of stress, as well as the animal strain, and gender. We developed a model, acute wrapping restraint stress, to fully characterize the effects of stress on intestinal transit. Wrap restraint stress is a nonulcerogenic model in which rats are subjected to acute restraint by wrapping them in a harness of paper tape to restrict, but not prevent movement of the upper body and forelimbs. Transit was evaluated by the geometric center method, in which a radiomarker (⁵¹Cr) is instilled directly into the proximal duodenum and proximal colon via a surgically placed intestinal cannula, in fasted, adult female Sprague Dawley rats (150-200g). Subjecting animals to 35 min. of wrap restraint stress resulted in (1) inhibition of small intestinal transit, and (2) increased large intestinal transit and increased fecal output. The effects of stress on intestinal transit in rats resembled symptoms associated with stress in humans, suggesting that wrap restraint stress may be suitable as a model of stress-induced intestinal dysfunction. We found a close correlation between stress-induced intestinal dysfunction and stress-activation of endocrine systems. Stress-induced changes in intestinal function was strongly influenced by circadian variations in endocrine levels, suggesting that stress-induced intestinal dysfunction may be hormonally mediated. However, neither pituitary nor adrenal factors mediated the effects of stress on the gut. To evaluate the role of corticotropin-releasing factor (CRF), the major hypothalamic factor released in response to stress, in stress-induced intestinal dysfunction, we studied the effects of exogenous CRF on intestinal transit. CRF resulted in (1) a potent, dose-dependent inhibition of small intestinal transit, (2) a dose-dependent increase in large intestinal transit, and (3) increased fecal excretion. The effects of exogenously administered CRF closely paralleled the effects of stress on intestinal transit and on ACTH secretion in the rat. Blockade of CRF receptors by means of an antagonist, α helical CRF (9-41), prevented the effects of stress on colonic transit and fecal excretion. These data strongly suggest that endogenous CRF may mediate the effects of wrap restraint stress on intestinal motor activity and coordination in the rat.