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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
Program Officer
Serrano, Jose
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
Zip Code
Tache, Yvette; Adelson, David; Yang, Hong (2014) TRH/TRH-R1 receptor signaling in the brain medulla as a pathway of vagally mediated gut responses during the cephalic phase. Curr Pharm Des 20:2725-30
Goebel-Stengel, Miriam; Stengel, Andreas; Wang, Lixin et al. (2014) Orexigenic response to tail pinch: role of brain NPY(1) and corticotropin releasing factor receptors. Am J Physiol Regul Integr Comp Physiol 306:R164-74
Karasawa, Hiroshi; Yakabi, Seiichi; Wang, Lixin et al. (2014) Orexin-1 receptor mediates the increased food and water intake induced by intracerebroventricular injection of the stable somatostatin pan-agonist, ODT8-SST in rats. Neurosci Lett 576:88-92
Stengel, A; Mori, M; Tache, Y (2013) The role of nesfatin-1 in the regulation of food intake and body weight: recent developments and future endeavors. Obes Rev 14:859-70
Stengel, Andreas; Rivier, Jean; Taché, Yvette (2013) Modulation of the adaptive response to stress by brain activation of selective somatostatin receptor subtypes. Peptides 42:70-7
Wang, Lixin; Stengel, Andreas; Goebel-Stengel, Miriam et al. (2013) Intravenous injection of urocortin 1 induces a CRF2 mediated increase in circulating ghrelin and glucose levels through distinct mechanisms in rats. Peptides 39:164-70
Yuan, Pu-Qing; Wu, S Vincent; Tache, Yvette (2012) Urocortins and CRF type 2 receptor isoforms expression in the rat stomach are regulated by endotoxin: role in the modulation of delayed gastric emptying. Am J Physiol Gastrointest Liver Physiol 303:G20-31
Stengel, Andreas; Tache, Yvette (2012) Ghrelin - a pleiotropic hormone secreted from endocrine x/a-like cells of the stomach. Front Neurosci 6:24
Larauche, Muriel; Mulak, Agata; Yuan, Pu-Qing et al. (2012) Stress-induced visceral analgesia assessed non-invasively in rats is enhanced by prebiotic diet. World J Gastroenterol 18:225-36
Tache, Y (2012) Brainstem neuropeptides and vagal protection of the gastric mucosal against injury: role of prostaglandins, nitric oxide and calcitonin-gene related peptide in capsaicin afferents. Curr Med Chem 19:35-42

Showing the most recent 10 out of 135 publications