Corticotropin-releasing factor (CRF) and urocortin (Ucn) 1 interact with two Gs coupled CRF1 and CRF2 receptors. Recently, new CRF-related peptides, Ucn 2 and Ucn 3 were discovered as selective CRF2 agonists. Activation of CRF1 signaling pathway in the brain reproduces the overall endocrine and behavioral responses to stress. In the last granting period, we established that activation of brain CRF1 signaling plays also a prominent role in stress-related stimulation of colonic motor function and visceral hyperalgesia in rodents. The overall objective of the proposal, based on preliminary data, is to establish that activation of brain CRF2 curtails CRF1-mediated stress-related stimulation of colonic motility (aim 1) and hyperalgesia (aim 2) while both CRF1 and CRF2 receptors are recruited to inhibit gastric motor function in a stressor specific manner (aim 3). Colonic motility and visceral hypersensitity will be monitored using novel non-invasive methods that we developed in conscious rats.
Aims will be achieved using selective CRF1 and CRF2 agonists and antagonists. The paraventricular nucleus of the hypothalamus and Barrington-sacral spinal cord projections to the sacral parasympathetic nucleus that influence colonic myenteric neurons will be targeted as sites of receptor interactions and pathways to influence colonic motility. The locus coeruleus activated by colorectal distention through CRF1 receptor and expressing Ucn 2 will be investigated as a site to modulate visceral hyperalgesia. Role and brain sites of action will be assessed pharmacologically and using laser capture microdissection combined with quantitative PCR to reveal stress-related alterations in gene expression pattern of Ucn 2, CRF1, CRF2 and novel functional CRF1a2 variants that we recently isolated from the rat brain. These studies will provide accurate expression of CRF ligands and cognate receptors and their variants and regulation at brain sites responsive to stress not achieved before. It will provide new insight to the role of brain CRF2 and CRF1 signaling and their interactions in stress-related alterations of gut motor function and visceral pain induced by stress. The preclinical studies may have implications in functional bowel diseases fo which mounting evidence involve the brain-gut axis.
Brain peptide corticotropin-releasing factor (CRF) signaling pathways which are involved in stress response can initiate and aggravate functional bowel diseases, such as irritable bowel syndrome, dyspepsia and cyclic vomiting syndrome. We will study the mechanisms through which CRF, its related peptides acting on two distinct receptors in the brain, exert differential or convergent effects to influence gut motor function and hypersensitivity of the colon. These studies have the potential to underpin molecular mechanisms of stress-related gut diseases leading to new treatment targeting these stress pathways.
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