Activation of Corticotropin-Releasing Factor Receptor 2 Mediates the Colonic Motor Coping Response to Acute Stress in Rodents

Abstract

Background & Aims Corticotropin-releasing factor receptor-1 (CRF1) mediates the stress-induced colonic motor activity. Less is known about the role of CRF2 in the colonic response to stress. Methods We studied colonic contractile activity (CCA) in rats and CRF2-/-, CRF-overexpressing, and wild-type mice using still manometry; we analyzed defecation induced by acute, partial-restraint stress (PRS), and/or intraperitoneal (IP) injection of CRF ligands. In rats, we monitored activation of the colonic longitudinal muscle myenteric plexus (LMMP) neurons and localization of CRF1 and CRF2 using immunohistochemical and immunoblot analyses. We measured phosphorylation of ERK1/2 by CRF ligands in primary cultures of LMMP-neurons (PC-LMMPn) and cAMP production in HEK-293 cells transfected with CRF1 and/or CRF2. Results In rats, a selective agonist of CRF2 (urocortin 2) reduced CRF-induced defecation (>50%), CCA, and Fos expression in the colonic LMMP. A selective antagonist of CRF2 (astressin2-B) increased these responses. Urocortin 2 reduced PRS-induced CCA in wild-type and CRF-overexpressing mice, whereas disruption of CRF2 increased PRS-induced CCA and CRF-induced defecation. CRF2 co-localized with CRF1 and neuronal nitric oxide synthase in the rat colon, LMMP, and PC-LMMPn. CRF-induced phosphorylation of ERK in PC-LMMPn; this was inhibited or increased by a selective antagonist of CRF1 (NBI35965) or astressin2-B, respectively. The EC50 for the CRF-induced cAMP response was 8.6 nM in HEK-293 cells that express only CRF1; this response was suppressed 10-fold in cells that express CRF1 and CRF2. Conclusions In colon tissues of rodents, CRF2 activation inhibits CRF1 signaling in myenteric neurons and the stress-induced colonic motor responses. Disruption of CRF2 function impairs colonic coping responses to stress.

Sex- and corticotropin-releasing factor receptor 2- dependent actions of urocortin 1 during inflammation

“…Both p38 and ERK1/2 activation are important signaling cascades for mediating various CRF 2 physiological effects (18,45,54). We and others have shown that phosphorylation of ERK1/2 is altered during inflammation and during TNBS colitis (7,25). How the perturbation or lack of CRF 2 may influence p38 signaling was previously unknown; we have now shown that, during colitis, p-p38 levels are decreased in CRF 2 Ht male and female mice.…”

Alteration of antral and proximal colonic motility induced by chronic psychological stress involves central urocortin 3 and vasopressin in rats

“…play roles that suppress food intake and induce anxiety-related behavior (10,21,41) via activation of CRF type 1 and/or type 2 receptors (34). The roles of Ucn or Ucn 2 on the GI motility have been well known; for example, hypothalamic Ucn reduces the gastric motility, while Ucn 2 prevents the increase in distal colonic motility induced by CRF (14,19). Whereas the roles of Ucn 3 on the GI motility have not been fully examined.…”

Role of Corticotropin-releasing Factor Signaling in Stress-related Alterations of Colonic Motility and Hyperalgesia

“…Functional studies showed that CRF and Ucn1 injected peripherally are as potent as injected centrally to increase propagative clustered spike-burst activity in the proximal colon and to stimulate distal colonic transit, defecation and to induce prominent diarrhea in rodents. 54,72,76,[108][109][110][111][112][113][114][115] The stimulation of colonic secretory-motor function after peripheral administration of CRF or Ucn1 involves CRF 1 receptors in rats and mice. This is supported by the fact that elective CRF 1 agonist, cortagine or stressin1 injected intraperitoneally stimulates colonic motor function and induces diarrhea while the CRF 2 agonists, Ucn2 has not effect under the same conditions.…”

“…This is supported by the fact that elective CRF 1 agonist, cortagine or stressin1 injected intraperitoneally stimulates colonic motor function and induces diarrhea while the CRF 2 agonists, Ucn2 has not effect under the same conditions. 54,108,110,111,116,117 The colonic CRF-CRF 1 signaling may have relevance as peripheral effector of the acute stress response. There is evidence that stressors that stimulate colonic motor function such as endotoxin or early maternal separation upregulates CRF-CRF 1 signaling in the colon.…”