Impact of corticotropin-releasing hormone on gastrointestinal motility and adrenocorticotropic hormone in normal controls and patients with irritable bowel syndrome (original) (raw)
Related papers
PLOS ONE, 2016
Irritable bowel syndrome (IBS) often comorbids mood and anxiety disorders. Corticotropinreleasing hormone (CRH) is a major mediator of the stress response in the brain-gut axis, but it is not clear how CRH agonists change human brain responses to interoceptive stimuli. We tested the hypothesis that brain activation in response to colorectal distention is enhanced after CRH injection in IBS patients compared to healthy controls. Brain H 2 15 Opositron emission tomography (PET) was performed in 16 male IBS patients and 16 agematched male controls during baseline, no distention, mild and intense distention of the colorectum using barostat bag inflation. Either CRH (2 μg/kg) or saline (1:1) was then injected intravenously and the same distention protocol was repeated. Plasma adrenocorticotropic hormone (ACTH), serum cortisol and plasma noradrenaline levels were measured at each stimulation. At baseline, CRH without colorectal distention induced more activation in the right amygdala in IBS patients than in controls. During intense distention after CRH injection, controls showed significantly greater activation than IBS patients in the right amygdala. Plasma ACTH and serum cortisol secretion showed a significant interaction between drug (CRH, saline) and distention. Plasma noradrenaline at baseline significantly increased after CRH injection compared to before injection in IBS. Further, plasma noradrenaline showed a significant group (IBS, controls) by drug by distention interaction.
A role for corticotropin-releasing factor in functional gastrointestinal disorders
Current Gastroenterology Reports, 2009
Functional gastrointestinal disorders (FGIDs), which include irritable bowel syndrome (IBS), encompass a heterogeneous group of diseases identified by chronic or recurrent symptom-based diagnostic criteria. Psychosocial factors are key components in the outcome of clinical manifestations of IBS symptoms. Anxiogenic and endocrine responses to stress are mediated by the corticotropin-releasing factor (CRF)-CRF 1 receptor pathway. Preclinical studies show that activation of the CRF 1 receptor by exogenous CRF or stress recapitulates many functional symptoms of IBS diarrhea-predominant patients as related to anxiogenic/hypervigilant behavior, autonomic nervous system alterations, induction of diarrhea, visceral hyperalgesia, enhanced colonic motility, mucus secretion, increased permeability, bacterial translocation, and mast cell activation, which are all alleviated by selective CRF 1 receptor antagonists. Clinical studies also support that CRF administration can induce IBS-like symptoms in healthy subjects and heighten colonic sensitivity in IBS patients. Yet to be ascertained is whether CRF 1 receptor antagonists hold promise as a new therapy in IBS treatment.
Journal of neurogastroenterology and motility, 2015
The corticotropin-releasing factor (CRF) signaling systems encompass CRF and the structurally related peptide urocortin (Ucn) 1, 2, and 3 along with 2 G-protein coupled receptors, CRF₁ and CRF₂. CRF binds with high and moderate affinity to CRF₁ and CRF₂ receptors, respectively while Ucn1 is a high-affinity agonist at both receptors, and Ucn2 and Ucn3 are selective CRF₂ agonists. The CRF systems are expressed in both the brain and the colon at the gene and protein levels. Experimental studies established that the activation of CRF₁ pathway in the brain or the colon recaptures cardinal features of diarrhea predominant irritable bowel syndrome (IBS) (stimulation of colonic motility, activation of mast cells and serotonin, defecation/watery diarrhea, and visceral hyperalgesia). Conversely, selective CRF1 antagonists or CRF₁/CRF₂ antagonists, abolished or reduced exogenous CRF and stress-induced stimulation of colonic motility, defecation, diarrhea and colonic mast cell activation and vi...
Neurogastroenterology and Motility, 2006
Stress is known to affect symptoms of irritable bowel syndrome (IBS) probably by an alteration of visceral sensitivity. We studied the impact of maximal tolerable rectal distensions on cortisol levels in patients with IBS, chronic constipation and controls, and evaluated the effect of the experimental situation per se. In twenty-four IBS patients, eight patients with chronic constipation and 15 controls salivary cortisol was measured before and after repetitive maximal tolerable rectal balloon distensions and at similar times in their usual environment. Rectal sensitivity thresholds were determined. IBS patients but not controls and constipation patients had higher cortisol levels both before and after the experiment compared with similar times on an ordinary day in their usual environment (P ¼ 0.0034 and 0.0002). There was no difference in salivary cortisol level before compared with after rectal distensions. The IBS patients had significantly lower thresholds for first sensation, urge and maximal tolerable distension than controls (P ¼ 0.0247, 0.0001 and <0.0001) and for urge and maximal tolerable distension than patients with constipation (P ¼ 0.006 and 0.013). IBS patients may be more sensitive to expectancy stress than controls and patients with constipation according to salivary cortisol. Rectal distensions were not associated with a further significant increase in cortisol levels.
Gastroenterology, 2005
Background & Aims: The corticotropin-releasing hormone receptor 1 mediates stress-induced changes in colonic motor activity and emotion. We tested the hypothesis that pretreatment with JTC-017, a specific corticotropin-releasing hormone receptor 1 antagonist, blocks colorectal distention-induced hippocampal noradrenaline release and visceral perception in rats. We also investigated whether pretreatment with JTC-017 blocks acute or chronic colorectal distentioninduced adrenocorticotropic hormone release, anxiety, and stress-induced changes in colonic motility. Methods: Rats were pretreated intrahippocampally with ␣-helical corticotropin-releasing hormone (1.25 g/kg; vehicle), a nonspecific corticotropin-releasing hormone receptor antagonist, or intraperitoneally with JTC-017 (10 mg/kg). Hippocampal noradrenaline release after microdialysis and the frequency of abdominal contractions were measured in response to acute colorectal distention. Plasma adrenocorticotropic hormone levels, anxiety-related behavior, and stress-induced changes in colonic motility were evaluated after acute or chronic colorectal distention followed by exposure to an elevated plus maze. Results: Administration of ␣-helical corticotropin-releasing hormone or JTC-017 significantly attenuated hippocampal noradrenaline release and reduced the frequency of abdominal contractions induced by acute distention. In addition, JTC-017 significantly reduced plasma adrenocorticotropic hormone and anxiety after acute distention. After chronic distention, changes in plasma adrenocorticotropic hormone and anxiety were not significant because of habituation. In contrast, a significant increase in fecal pellet output during the elevated plus maze was observed after chronic distention. This increase in fecal pellet output was blocked by pretreatment with JTC-017. Conclusions: Our results suggest that JTC-017, a specific corticotropin-releasing hormone receptor 1 antagonist, attenuates hippocampal noradrenaline release, visceral perception, adrenocorticotropic hormone release, and anxiety after acute colorectal distention in rats. In addition, JTC-017 blocks stress-induced changes in colonic motility after chronic colorectal distention in rats.
Peptides, 2010
Early-life stress is a key predisposing factor to the development of functional gastrointestinal (GI) disorders. Thus, changes in stress-related molecular substrates which influence colonic function may be important in understanding the pathophysiology of such disorders. Activation of peripheral corticotropin-releasing factor (CRF) receptors is thought to be important in the maintenance of GI function homeostasis. Therefore, immunofluorescent and Western blotting techniques were utilized to investigate colonic expression of CRF receptors in the maternal separation (MS) model as compared to non-separated (NS) rats. Receptor expression was also assessed following exposure to two different acute stressors, the open field (OF) and colorectal distension (CRD). Immunofluorescent dual-labeling demonstrated increased activation of both CRFR1 (MS: 79.6+/-4.4% vs. NS: 43.8+/-6.8%, p<0.001) and CRFR2 (MS: 65.9+/-3.2% vs. NS: 51.6+/-5.8%, p<0.05) positive cells in MS rats. Protein express...
Corticotropin-Releasing Hormone Receptor 2 Gene Variants in Irritable Bowel Syndrome
PloS one, 2016
Corticotropin-releasing hormone (CRH) plays an important role in the pathophysiology of irritable bowel syndrome (IBS) and regulates the stress response through two CRH receptors (R1 and R2). Previously, we reported that a CRHR1 gene polymorphism (rs110402, rs242924, and rs7209436) and haplotypes were associated with IBS. However, the association between the CRHR2 gene and IBS was not investigated. We tested the hypothesis that genetic polymorphisms and haplotypes of CRHR2 are associated with IBS pathophysiology and negative emotion in IBS patients. A total of 142 IBS patients and 142 healthy controls participated in this study. Seven single nucleotide polymorphisms (SNPs) of the CRHR2 gene (rs4722999, rs3779250, rs2240403, rs2267710, rs2190242, rs2284217, and rs2284220) were genotyped. Subjects' psychological states were evaluated using the Perceived-Stress Scale, the State-Trait Anxiety Inventory, and the Self-Rating Depression Scale. We found that rs4722999 and rs3779250, loc...