The Effect of Corticotrophin-releasing Hormone (CRH) on Esophageal Sensitivity in Healthy Volunteers: A Randomized, Single-blind, Placebo-controlled Study

1. INTRODUCTION Gastro-esophageal reflux disease (GERD) is the presence of symptoms (heartburn, regurgitation) or lesions that can be attributed to the reflux of gastric contents into the esophagus. In humans, pain is a multimodal experience composted of sensory, physiological and psychological aspects. In order to mimic the clinical situation, experimental models should be based on multimodal testing regimens in which different receptors and central nervous system mechanisms are activated. Typical and atypical symptoms may not only arise from acid reflux, but also from reflux with less acidic pH (pH 4-7). In GERD patients with persisting symptoms on proton pump inhibitor (PPI) therapy, ongoing weakly acidic reflux is well established as an important underlying factor. The basis for symptom generation during weakly acidic reflux remains to be determined, but acid sensitivity in the pH range 4-7, mechanical distension, sensitivity to other chemical factors and esophageal hypersensitivity to physiological levels of reflux have been proposed. The investigators speculate that visceral hypersensitivity plays an important role in symptom perception. This is suggested by the reflux parameters that are usual within the physiological number during PPI therapy. Also, the investigators previously demonstrated that refractory GERD patients have increased visceral hypersensitivity for thermal, chemical and mechanical esophageal stimulation compared to HV.

Stress is well known to affect visceral sensitivity in humans. A majority of patients with GERD report stress as an important factor triggering symptom exacerbation. A real-life stressor could exacerbate heartburn in GERD patients by enhancing perceptual response to esophageal acid exposure. The interaction between psychological state and GI function is a complex and developing field. The brain-gut axis, mediating the effects of stress on the Gastrointestinal (GI) tract, has been considered a pivotal player in the pathogenesis of functional GI disorders like irritable bowel syndrome (IBS) and functional dyspepsia (FD). A possible mechanism of stress-induced visceral sensitivity could be the barrier dysfunction. A study performed in humans, showed that an acute psychological stressor induces hyperpermeability in a mast cell dependent fashion and exogenous peripheral CRH recapitulated its effects on barrier function. This increase in intestinal permeability is a phenomenon which appears as a prerequisite for visceral hypersensitivity. The acute role of CRH on esophageal sensitivity has not been studied. 2. OBJECTIVE Stress increases permeability via CRH-mediated mast cell activation. The investigators hypothesize that stress mediated through CRH-release increases esophageal sensitivity. Therefore, the aim of our study is to investigate the effect of CRH-administration on esophageal sensitivity in a group of HV. 3. GENERAL DESCRIPTION Studies will be performed in HV. All participants will receive and sign a copy of the informed consent before initiation of the study. Esophageal sensitivity will be tested by multimodal stimulation on two sessions (placebo and CRH-administration). 4. MATERIALS AND METHODS Studies will be performed using a multimodal esophageal stimulation probe which allows esophageal thermal, mechanical, electrical and chemical stimulations.

During each stimulation, HV will record symptom perception using VAS. First perception (VAS=1), pain perception threshold (VAS=5) and pain tolerance threshold (VAS=7) will be recorded. All stimulations will be immediately terminated when the VAS 7 is reached. At the time of VAS 7, subjects will be asked to draw the referred pain area, to identify pain location.

Thermal stimulation will be performed by re-circulating a saline solution, heated by a water bath, through the balloon mounted on the probe. Stimulation temperature will be steadily increased by increasing the flow rate from the water bath to the balloon. The volume in the balloon will be kept constant (5ml) to avoid mechanical stimulation. A temperature sensor in the balloon will continuously monitor the stimulation temperature, which is displayed online on a computer throughout the study.

Mechanical stimulation will be performed by distension of the balloon. The flow of saline into the balloon, inducing the distension, is regulated by a computer controlled pump. The volume in the balloon is displayed on the computer screen throughout the stimulation. Mechanical stimulations will be performed with water of 37 degrees Celsius, to avoid thermal stimulation.