Agonists of ghrelin receptors that cross the blood-brain barrier, but not ghrelin itself, administered peripherally (intravenous or subcutaneous), cause defecation by acting on centres in the lumbo-sacral spinal cord. It is not established whether orally administered ghrelin receptor agonists can have this action. We tested GSK894281 for its effectiveness at the ghrelin receptor and its ability to cross the blood-brain barrier. GSK894281 was effective at the human and rat ghrelin receptors at 1-10 nmol L(-1), but was >1000-fold less potent at the motilin receptor. It achieved a similar blood concentration by oral or intravenous administration. Oral bioavailability was 74% and brain : blood ratio at steady state was 0.7 : 1. GSK894281 administered orally (1-100 mg kg(-1)) caused a prompt, dose-related production of faecal pellets; at 10 mg kg(-1) faecal output was four times greater than after carrier. The output was the greatest in the first half hour and subsided over the next 90 min. At an oral dose of 10 mg kg(-1), the compound was effective on eight successive days. Faecal output was, on average, increased threefold over control in the 2 h after administration on each of the 8 days. This dose also significantly increased food consumption. Rats showed no adverse behavioural effects to the drug on a single application, but at the end of a week of administration they avoided the gavaging pipette. Oral administration of ghrelin receptor agonists that enter the central nervous system could possibly be used to relieve acute cases of constipation or to clear the bowel for colonoscopy.