Stress is implicated as the causative or complicating factor of symptoms of several diseases including altered bowel habits and visceral hyperalgesia in Irritable Bowel Syndrome (IBS) patients. Our previous work as well as other studies show that the activation of corticotropin-releasing factor (CRY) receptors mediates various stressors-induced alterations of gut motor function and that CRF1 receptor is mostly involved in the colonic response. Recent evidence also suggests a role of this pathway in stress-relatcd colonic hypersensitivity to colorectal distention. Despite the greater prevalence of stress-related IBS symptoms in women, most of the experimental knowledge of the effects and mechanisms of stress on gut motor alterations and visceral hyperalgesia derives from studies performed in male rodents. The overall goal of the proposal is to characterize the neuroanatomical and biochemical substrata underlying for sex-related differences in stress-induced colonic responses (motility and visceral pain) in rats. Based on presence of estrogen responsive elements on the CRF gene and its modulation by estrogen in the hypothalamus, we will test the hypothesis that estrogen-induced modulation of CRF signaling pathways contributes to the enhanced colonic responses of female rodents to stress. In the specific aim 1, we will build on our data preliminary data and characterizes sex-related differences in stress-induced colonic motor activation and visceral hyperalgesia using psychological and visceral stressors in model of IBS. We will assess with the newly developed CRF1 and CRF2 selective receptor antagonists the role of activation of CRF receptors in stress-related colonic responses in female rats and modulation by sex hormones.
In specific aim 2, we will define the sex-related differential activation of brain, spinal and enteric circuitry induced by stress, particularly at neuronal sites involved in autonomic and pain modulation and known to express estrogen receptors using Fos expression as a marker of neuronal activation. Double labeling will be used to identify the presence of estrogen receptors and identified CRF and/or oxytocin and noradrenergic neurons.
Specific Aim 3 will determine the modulation of CRF and CRF1 gene transcription by estrogen at specific sites involved in the colonic responses to stress. The regulation of rat and human CRF and CRF1 receptor promoter activity by estrogens will be further investigated in naive and transfected cells. These studies using functional, neuroanatomical, neurochemical and molecular approaches in rodent model will provide new insight on the interactions between estrogens and CRF pathways as it relates to the visceral response to stress and the underlying mechanisms at the levels of gene regulation and will have relevance to the pathophysiology of stress-related exacerbation of IBS.
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