Irritable bowel syndrome (IBS) is a common condition with high impact on quality of life, health care costs, and incidence of abdominal or pelvic surgery. There is no effective treatment of this heterogeneous disorder: two pathophysiologic mechanisms are heightened visceral sensitivity and/or abnormal motor function, particularly among IBS patients with increased frequency of bowel movements or urgency to defecate. We have previously shown that the adrenergic nervous system is involved in mediating and modulating visceral sensation in health humans; specifically, alpha2-adrenergic agonists relax the colon and rectum and reduce sensation of pain during distention. We hypothesize that, in IBS associated with increased frequency of bowel movement of urgency, colonic pain sensation is reduced by alpha2-adrenergic modulation, and that lower doses of the alpha2-agonist, clonidine, are required to reduce colonic pain sensation in IBS than in health. Moreover, we hypothesize that these anti-nociceptive actions of alpha2 modulation are achieved without significantly altering colonic motor functions. Our first and second aims are to study health subjects to evaluate the dose- related effects of the alpha2-agonist, clonidine (p.o. up to 0.3 mg b.i.d.), on colonic transit, compliance, tone and sensation. Thirdly, we aim to study the effects of lower levels of alpha2-adrenergic modulation by lower disease (0.0125 to 0.1mg b.i.d.) of clonidine on colonic transit, tone, compliance and sensation in patients with IBS associated with increased frequency of bowel movements or urgency. A subsidiary aim is to determine whether disturbances of the autonomic nervous system in patients with IBS influence the nature or magnitude of responses to alpha2-adrenergic modulation. Validated methods to be used include scintigraphic measurement of gastrointestinal and colonic transit, autonomic function tests, and intubated studies of colonic motor and sensory functions. The significance of this project is that it will provide novel, comprehensive information regarding the effect of the alpha2-adrenergic system in the control of colonic sensorimotor function in health and disease, and establish the rationale and dosage for these agents in the treatment of a subset of IBS patients.
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