This is an application for competitive renewal of a grant to study the irritable bowel syndrome, a disorder characterized by abdominal pain and altered bowel habits, which affects up to 17% of the population and accounts for 20-50% of referrals to gastroenterologists. Altered pain perception appears to be its cardinal symptom. Patients with irritable bowel are more likely to report tenderness over the colon on abdominal palpation, and they report pain and (non-painful) urgency to defecate at lower thresholds of balloon distension. The mechanism responsible for altered pain perception are not known, but basic research on visceral pain suggests four possibilities: altered numbers or types of sensory nerve endings in muscle or mesentery, altered muscle tone or motility with secondary hypersensitivity, sensitization of mucosal receptors by inflammatory processes, and CNS-mediated psychological influences on pain threshold. Experiment I will investigate these hypotheses by comparing 20 health controls to 30 irritable bowel patients. The thresholds for three sensations associated with distension of the sigmoid colon-smallest detectable distension, urge to defecate, and pain - will be tested by a psychophysical tracking procedure to control for perceptual bias. Lidocaine will be used to determine whether the receptors for these three sensations lie in the mucosa or in the muscle or surrounding mesentery. Contractile activity will be measured as pressure changes detected through perfused catheters proximal and distal to the balloon. Muscle tone will be measured by the barostat technique in which the volume of air required to maintain a constant low pressure (10 mm Hg) in a distending balloon is monitored for 10 minutes. In Experiment II, pain thresholds will be tested throughout the colon in 18 patients with irritable bowel to identify zones of increased sensitivity (reported by other investigators). In these areas, lidocaine will be infused to determine whether the pain receptors are located in the mucosa or in deeper structures, and biopsies will be obtained by endoscope to determine whether pain is related to increased synthesis of cytokines or neuropeptides. In Experiment III, the effects of physiological bias on the perception of pain will be investigated by a signal detection paradigm in which 20 patients and 20 controls are asked to discriminate between two different amounts of colonic distension at approximately the threshold for pain. Groups will be compared with respect to both perceptual sensitivity and response bias.