Mechanisms of Perception during Jejunal Capsaicin Perfusion

We have recently shown that in fasted healthy volunteers jejunal perfusion with capsaicin causes upper abdominal pain in a dose dependent manner and therefore may be used as a tool for further assessment of physiologic and pathophysiologic mechanisms of painful and nonpainful sensations in healthy subjects and patients with functional bowel disorders. AIM: To demonstrate for the first time that chemical stimulation of nociceptors in the small intestine can cause nonpainful and painful sensations, independent of effects on small intestinal motility, and that patients with functional bowel disorders have quantitative but not qualitative differences in their response to chemical stimulation of nociceptors in the small intestine. HYPOTHESES: Symptoms elicited by perfusion of the jejunum with capsaicin are due to chemical stimulation of nociceptive afferents and cannot be explained by changes of jejunal motor activity (phasic and/or tonic) and/or by changes in the mechanosensory function of the jejunum. Patients with functional bowel disorders have increased sensitivity to capsaicin. METHODS AND MATERIAL: Studies will be performed in fasting healthy subjects (n= 35) without any abdominal symptoms and in patients with functional bowel disorders [non-ulcer dyspepsia (n=14) and irritable bowel syndrome (n=14)]: Phasic motor activity will be measured by perfusion manometry, tonic activity will be measured using a barostat device. Mechanosensory function will be assessed also utilising the barostat device. After the volunteers have swallowed the tube assembly, recording of phasic and tonic activity and infusion of one of five different capsaicin concentrations (0 mg/l to 100 mg/l) at a rate of 10 ml/min will commence. The concentrations of capsaicin will be randomised and double blinded. Thereafter, jejunal distension (phasic distensions in random order) with the barostat balloon will be performed. 8 different pressures, from 6 to 48 mmHg above the operating pressure of the barostat, will be used for this distension protocol. A sham distension (no increase of the operating pressure) will also be included. DATA ANALYSIS: Tonic activity will be measured as volume changes in the barostat bag in 5 minute periods. Phasic activity will be assessed as motility index/10 min. Further, motility patterns, especially during episodes of perception of sensations, will be evaluated visually. Symptom assessment: Subjects will receive two questionnaires evaluating the localisation, extension, intensity and type of the symptoms they might experience. The questionnaire will be fully explained to the participants in a standard manner before the study. Mechanosensory function: The intensity of sensations at different levels of distension will be compared in the different infusion groups. SUMMARY: This study is designed to identify - for the first time - a possible chemical nociceptive pathway in the generation of pain arising from the gut. It will give new insights into the pathophysiological mechanisms of gastrointestinal pain in normal subjects and in patients with functional bowel disorders.

Chemonociception in the human small intestine has been little studied. Although capsaicin can cause intestinal sensation it is unknown whether this is due to stimulation of chemoreceptors or to motor changes. Our aims were to evaluate motor activity during capsaicin-induced nociception and to compare qualities of jejunal nociception induced by capsaicin and mechanical distension. Methods and Results: Twenty-nine healthy subjects swallowed a tube with a perfusion site at the ligament of Treitz and, 7 cm distally, a barostat balloon. Phasic motor activity was measured around the perfusion site and the balloon. Capsaicin solutions (40, 200 and 400 g/ml; 2.5 ml/min were perfused for 60 min or until severe discomfort arose. A graded questionnaire for 7 different sensations was filled out every 10 min, and when the capsaicin perfusion was replaced by saline perfusion because of severe discomfort. Sensations arising from pressure-controlled distensions were assessed before and after the capsaicin perfusion when sensations had stopped (n=19), or during the capsaicin application when no discomfort was reported (n=5). Capsaicin perfusion induced the feeling of pressure, cramps, pain and warmth. The quality and abdominal location of these sensations were similar to those induced by distension except for warmth (p<0.01) and pressure (p<0.05). Seven out of 12 subjects receiving 40 g/ml capsaicin and all subjects receiving higher capsaicin concentrations developed discomfort. Perfusion had to be stopped after 553.3, 155.7 and 102.2 min during perfusion with 40, 200 and 400 g/ml capsaicin, respectively, whereafter the sensations disappeared within 10 min. Repeated capsaicin (200 g/ml) applications significantly reduced the time until discomfort arose (p=0.01). Jejunal tone was not altered by capsaicin, but phasic activity proximal to the perfusion site was reduced during capsaicin-induced discomfort (p<0.001). Pain thresholds during distensions were not different before and after capsaicin perfusion. Summary: Despite the similarities in abdominal localization and perceptional quality of the capsaicin- and distension-induced sensations, our results rule out that the abdominal discomfort evoked by capsaicin involves sensitization of mechanoreceptors or an increase in phasic and tonic motor activity. Capsaicin evokes abdominal sensations by stimulation of chemoreceptors, which proves the existence of chemonociception in the human small intestine.