Desensitization of nociception in the duodenum by capsaicin

We have recently shown that small intestinal perfusion with capsaicin causes upper abdominal sensation in a dose dependent manner and that this sensation is not mediated by mechanoreceptors. We have proposed that chemically induced intestinal perception by capsaicin is brought about via stimulation of the polymodal capsaicin receptor VR1. Others have shown that oral application of red pepper powder, containing capsaicin, induced pain and discomfort initially but symptoms diminished after repeated application and symptoms of functional dyspepsia improved. The present protocol is designed to evaluate the effect of prolonged capsaicin application on intestinal perception and its possible therapeutic implication. AIMS: (I) To demonstrate that repeated capsaicin application, that is known to desensitize the VR1 receptor, can also desensitize the duodenum in vivo against chemical stimulants but not against mechanical distension in healthy subjects. (II) To evaluate whether hypersensitivity against capsaicin perfusion exists in patients with functional dyspepsia. (III) To evaluate the effect of prolonged capsaicin application on capsaicin induced symptoms in patients with functional dyspepsia. HYPOTHESES: (I) After repeated capsaicin application over a four week period, duodenal capsaicin perfusion will be tolerated for a prolonged period of time in health and patients with functional dyspepsia. (II) Repeated capsaicin application will leave mechanical nociception unaltered. (III) In functional dyspepsia thresholds for duodenal chemonociception are reduced compared to healthy controls. METHODS AND MATERIAL: Studies will be performed in fasting subjects (health: n = 40; functional dyspepsia: n = 40). Pressure-controlled balloon distension will be performed in the duodenum before a perfusion with a solution containing capsaicin (200ug/ml; 2.5 ml/min), with the infusion port placed in the descending part of the duodenum. This protocol will be performed twice, at baseline and again after 4 weeks of ingestion of either capsaicin (gelatine capsules containing 0.5 mg capsaicin tid) or placebo. SUMMARY: This study is designed to improve our understanding of the mechanisms of chemical nociception in the generation of pain arising from the gut and modulation of intestinal nociception. It will give new insights into the pathophysiological mechanisms of gastrointestinal pain and into possible new treatment modalities.

The first observation that intraluminal capsaicin in the upper gastrointestinal tract induces abdominal discomfort and overt pain was an unexpected finding when investigating the effects of jejunal capsaicin on mucosal function in humans. Meanwhile we have demonstrated that the effect of capsaicin on abdominal symptoms is time and dose dependent and is mediated through a specific, capsaicin-sensitive chemoreceptive pathway. In a recent FWF supported project (P17201) we have shown that luminal contents are able to alter capsaicin induced chemonociception. The present project was designed to study the effect of prolonged intraluminal capsaicin application on intestinal nociceptive pathways, mediated either by mechanical distension or chemical stimulation. In several protocols, healthy subjects ingested capsules containing capsaicin or placebo for either one single occasion or three times daily for 1 week and for 4 weeks, respectively. Before and after capsule ingestion, mechano- and chemonociception was determined using an established protocol with a distending balloon and intraluminal capsaicin infusion. Patients with functional dyspepsia, also swallowed capsaicin capsules at one occasion, and the severity of symptoms induced by capsaicin were compared to symptoms in healthy volunteers. One week of ingestion of capsaicin sensitized chemonociceptors, while sensitivity of mechanonociceptors for distension decreased. In contrast to one week capsaicin ingestion, four weeks ingestion of capsaicin desensitized both chemonociceptive and mechanonociceptive pathways in healthy volunteers. These findings might explain why patients, who receive capsaicin as a treatment option for upper gastrointestinal symptoms, often experience painful sensations in the first week of treatment, while after prolonged treatment with capsaicin patients may experience a relief of symptoms, due to a dual desensitizing effect of capsaicin on chemonociceptors and mechanonociceptors. Finally, patients with functional dyspepsia who swallowed a single capsule containing a predefined amount of capsaicin powder, experienced significantly more intense symptoms (discomfort and overt pain) than healthy controls. These observations were first made in an open label study and later confirmed in a placebo controlled, double-blind study design. More than 50% of patients turned out to be hypersensitive to capsaicin (chemical hypersensitivity). Clinically patients with hypersensitivity for capsaicin were not different from the group of patients testing negative, besides being on average younger and suffering more from bloating. We concluded that an oral capsaicin load (capsaicin test) might be useful to stratify patients according to the pathophysiological mechanisms underlying the symptoms.