Irritable bowel syndrome (IBS) is a stress-sensitive disorder for which abdominal pain is a cardinal symptom that drives illness severity more than other motor symptoms. Early life events and female sex are risk factors for the onset and symptom exacerbation of IBS in most patients. In the somatic pain field, there is vast literature on the phenomenon named """"""""stress-induced analgesia"""""""". This contrasts with the paucity of experimental data and knowledge on stress-induced visceral analgesia (SIVA), where there is mounting evidence that IBS patients have compromised engagement of this stress-related inhibitory descending pain modulation. We have validated a novel non-invasive technique to monitor visceral pain in rodents and uncovered that psychological stressors induces SIVA in naive rodents which is partly opiate dependent in female and opiate-independent in male rats. We also obtained preliminary data that uncovered in the colon a local CRF-proopiomelanocortin (POMC)-beta-endorphin system that is subject to upregulation by stress. Based on these novel findings, the overall objective of the proposal is to unravel the neurochemical and molecular physiological mechanisms in the brain and the colon underlying SIVA and to test the hypothesis that an early life event in the form of repeated neonatal maternal separation (MS) impairs SIVA response in adulthood. This will be achieved in three aims targeting specific pathways.
AIM 1 will characterize SIVA in adult male and female rats, naive and exposed to MS in our model of repeated water avoidance stress, delineate the neuronal substrates of SIVA in the brain and spinal cord using ?Fos? expression as long-term markers of adaptive changes with double labeling to identify chemical coding of activated neurons, and delineate the receptor subtypes and ligand mediating the naloxone-dependent component SIVA in female rats.
AIM 2 will delineate the role of key components of the stress response, the brain corticotropin releasing factor (CRF) and oxytocin signaling pathways.
AIM 3 we will unravel in the colon the functional CRF-POMC-derived peptides homolog system to the pituitary, its regulation under stress conditions, and its functionality as potential modulator of visceral pain under conditions of psychological (aim 1) vs. local immune stressors using iRNA silencing of POMC in the colon.
These aims will be achieved using pharmacological, neuroanatomical, molecular, and genetic approaches targeting the opiate, CRF and oxytocin signaling pathways along with functional studies in rats and genetically targeted mice. Overall advances in the understanding of neuronal substrata and biochemical coding of SIVA and their alterations in a model of chronic stress (MS) is of prime importance to advance understanding of physiological mechanisms underpinning SIVA. The demonstration of sex-differences in these mechanisms underlying SIVA as established in somatic pain field will highlight the importance of sex- specific interventions to modulate visceral pain that may have therapeutic significance in IBS woman patients.
Despite continued effort, the pathophysiology of IBS is still not well understood and IBS symptoms, particularly IBS-related abdominal pain treatment, remains an unmet medical need. Similarly, while early life stress and sex differences are key factors in IBS symptom development, the link between stress or sex difference and symptoms are poorly understood. The study using rodent models proposes a new concept and novel approaches to fill the knowledge gap in the understanding of molecular mechanisms of stress-related visceral pain modulation in IBS.
|Moussaoui, Nabila; Jacobs, Jonathan P; Larauche, Muriel et al. (2017) Chronic Early-life Stress in Rat Pups Alters Basal Corticosterone, Intestinal Permeability, and Fecal Microbiota at Weaning: Influence of Sex. J Neurogastroenterol Motil 23:135-143|
|Rolland-Fourcade, Claire; Denadai-Souza, Alexandre; Cirillo, Carla et al. (2017) Epithelial expression and function of trypsin-3 in irritable bowel syndrome. Gut 66:1767-1778|
|Walker, Claire-Dominique; Bath, Kevin G; Joels, Marian et al. (2017) Chronic early life stress induced by limited bedding and nesting (LBN) material in rodents: critical considerations of methodology, outcomes and translational potential. Stress 20:421-448|
|Yuan, Pu-Qing; Wu, S Vincent; Pothoulakis, Charalabos et al. (2016) Urocortins and CRF receptor type 2 variants in the male rat colon: gene expression and regulation by endotoxin and anti-inflammatory effect. Am J Physiol Gastrointest Liver Physiol 310:G387-98|
|Duboc, Henri; Tolstanova, Ganna; Yuan, Pu-Qing et al. (2016) Reduction of epithelial secretion in male rat distal colonic mucosa by bile acid receptor TGR5 agonist, INT-777: role of submucosal neurons. Neurogastroenterol Motil 28:1663-1676|
|Erchegyi, Judit; Wang, Lixin; Gulyas, Jozsef et al. (2016) Characterization of Multisubstituted Corticotropin Releasing Factor (CRF) Peptide Antagonists (Astressins). J Med Chem 59:854-66|
|Taché, Yvette; Million, Mulugeta (2015) Role of Corticotropin-releasing Factor Signaling in Stress-related Alterations of Colonic Motility and Hyperalgesia. J Neurogastroenterol Motil 21:8-24|
|Akiba, Yasutada; Kaunitz, Jonathan D; Million, Mulugeta (2015) Peripheral corticotropin-releasing factor receptor type 2 activation increases colonic blood flow through nitric oxide pathway in rats. Dig Dis Sci 60:858-67|
|Stengel, Andreas; Karasawa, Hiroshi; Taché, Yvette (2015) The role of brain somatostatin receptor 2 in the regulation of feeding and drinking behavior. Horm Behav 73:15-22|
|Taché, Y (2015) Corticotrophin-releasing factor 1 activation in the central amygdale and visceral hyperalgesia. Neurogastroenterol Motil 27:1-6|
Showing the most recent 10 out of 71 publications