Brain corticotropin releasing factor (CRF) signaling in gut response to stress

Research over the years, including by a team of postdoctoral fellows and in collaboration with Dr. Jean Rivier (Salk Institute), allowed us to be the first to establish that a) CRF and related peptides, urocortins, act in the brain to alter autonomic outflow (inhibition of gastric vagal activity and activation of sacral parasympathetic neurons), leading to the inhibition of gastric transit and stimulation of colon motility; b) brain CRF signaling pathways are involved in the delayed gastric emptying induced by psychological (restraint), immune (increased cytokines into the circulation or the brain), and visceral (surgery) stressors; c) the responsive sites of action of CRF interaction with CRF receptors are located in the paraventricular nucleus of the hypothalamus (PVN) and coeruleus/subcoeruleus to stimulate colonic motor function through activation of sacral parasympathetic outflow; and d) the brain CRF signaling pathways have relevance in the defecation, diarrheal and visceral hypersensitivity responses induced by various acute or repeated psychological stressors.

Peripheral CRF signaling in the gut responses to stress

Additionally, we demonstrated the expression of CRF receptor signaling in the gut and its role as effector of stress-related alterations of gastric and colonic motility and visceral hypersensitivity. In the colon, we delineated that a) CRF urocortins and CRF receptors are expressed at the level of immune (mast cells, macrophages), endocrine (enterochromaffin cells releasing serotonin) and neuronal (myenteric and submucosal neurons) cells in rats and/or humans; b) peripheral administration of CRF and urocortin 1 stimulates colonic myenteric cholinergic and nitriergic neurons and ileal vasointestinal peptide expressed in submucosal neurons, colonic motility, and secretion, and induces defecation, diarrhea and visceral hyperalgesia in rodents; and c) peripheral administration of peptide CRF receptor antagonists blocked the colonic responses to exogenous CRF and was able to attenuate the colonic responses to stress.

Stress, CRF signaling IBS

These observations led us to test their implications in stress-sensitive functional bowel diseases. In particular, irritable bowel syndrome (IBS) is characterized by recurrent abdominal pain and altered bowel habits (diarrhea, constipation or alternating between both) without structural abnormalities. As stress plays a major role in the onset, maintenance and/or exacerbation of IBS symptoms, long-acting CRF receptor antagonists developed by J. Rivier are presently being evaluated by Dr. Muriel Larauche for their ability to prevent visceral pain and diarrhea in experimental models of IBS.

Approach

  • Determination of gastric emptying
  • Determination of colonic transit
  • Gastric and colonic motility measurements using intraluminal pressure
  • Measurement of visceral pain without surgical intervention
  • Functional brain mapping of neuronal activation in the brain and spinal cord at cellular levels
  • Brain-gut modulation through pharmacological microinjections
  • Monitoring enteric neuron activity in whole mount preparation
  • Models of acute and chronic stress
  • Models of visceral pain in rodents

Grants

  • NIH R43 DK116362-01A1 Targeting IBS with Astressins. J. Rivier, PI, M. Larauche, Subcontract PI, Y. Taché, Co-Investigoator. 06/01/2018-05/30/2019
  • NIDDK R01 DK 57238 Peripheral Mechanisms of Stress-induced Activation of Colonic Motor Function. Y. Taché, PI. 09/05/2000-09/31/2017
  • NIH DK-41301 Digestive Diseases Center Grant. Animal Core. Y. Taché, Director, M. Million, Associate Director, L. Wang, Co-Investigator. 11/01/2014-10/31/2019

Publications

  1. Larauche M, Kim YS, Mulak A, Duboc H, Taché Y. Intracerebroventricular administration of TRH Agonist, RX-77368 alleviates visceral pain induced by colorectal distension in rats. Peptides, Volume 17, May 2024, 171181
  2. Larauche M, Erchegyi J, Miller C, Sim MS, Rivier J, Behan D, Taché Y.  Peripheral CRF-R1/CRF-R2 antagonist, astressin C, induces a long-lasting blockade of acute stress-related visceral pain in male and female rats. Peptides. 2022 Nov;157:170881. doi: 10.1016/j.peptides.2022.170881. Epub 2022 Sep 19
  3. Yakabi S, Wang L, Karasawa H, Yuan PQ, Koike K, Yakabi K, Taché YF. VIP is involved in peripheral CRF-induced stimulation of propulsive colonic motor function and diarrhea in male rats. Am J Physiol Gastrointest Liver Physiol. 2018 Feb 8
  4. Stengel A, Taché YF. Activation of brain somatostatin signaling suppresses CRF receptor-mediated stress response. Front Neurosci. 11:231 (2017)
  5. Erchegyi J, Wang L, Gulyas J, Samant M, Perrin MH, Lewis K, Miller C, Vaughan J, Donaldson C, Fischer W, Low W, Yakabi S, Karasawa H, Taché Y, Rivier C, Rivier J. Characterization of multisubstituted corticotropin releasing factor (CRF) peptide antagonists (Astressins). J Med Chem. 59(3):854-66 (2016)
  6. Taché Y, Million M. Role of corticotropin-releasing factor signaling in stress-related alterations of colonic motility and hyperalgesia. J Neurogastroenterol Motil. 21:8-24 (2015)
  7. Yuan PQ, Wu SV, Pothoulakis C, Taché Y. 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(6):G387-98 (2016)
  8. Wang L, Goebel-Stengel M, Stengel A, Wu SV, Ohning G, Taché Y. Comparison of CRF-immunoreactive neurons distribution in mouse and rat brains and selective induction of Fos in rat hypothalamic CRF neurons by abdominal surgery. Brain Res. 2011 Sep 30;1415:34-46
  9. Larauche MH, Gourcerol G, Wang L, Pambukchian K, Brunnhuber S, Adelson D, Rivier J, Million M, Taché Y. Cortagine, a CRF1 agonist, induces stress-like alterations of colonic function and visceral hypersensitivity in rodents primarily through peripheral pathways. Am J Physiol Gastrointest Liver Physiol 297:G215-27 (2009)
  10. Million M, Grigoriadis DE, Sullivan S, Crowe PD, McRoberts JA, Zhou H, Saunders PR, Maillot C, Mayer EA, and Taché Y. A novel water-soluble selective CRF1 receptor antagonist, NBI 35965, blunts stress-induced visceral hyperalgesia and colonic motor function in rats. Brain Res 985: 32-42 (2003)
  11. Maillot C, Million M. Gauthier A and Taché Y. Peripheral corticotropin-releasing factor receptor and stress-stimulated colonic motor activity involves type 1 receptor in rats. Gastroenterology. 119: 1569-1579 (2000)
  12. Mönnikes H, Schmidt BG, Taché Y. Psychological stress-induced accelerated colonic transit in rats involves hypothalamic corticotropin-releasing factor. Gastroenterology. 1993 Mar;104(3):716-23