The mechanism of enhanced defecation caused by the ghrelin receptor agonist, ulimorelin

• Published in: Neurogastroenterology and motility 2014-02, Vol.26 (2), p.264-271
• Main Authors: Pustovit, R. V., Callaghan, B., Kosari, S., Rivera, L. R., Thomas, H., Brock, J. A., Furness, J. B.
• Format: Article
• Language: English
• Subjects: Acetylcholine receptors (nicotinic); Animals; Colon - drug effects; Colon - physiology; defecation; Defecation - drug effects; ghrelin; ghrelin receptors; Injections, Spinal; Macrocyclic Compounds - administration & dosage; Macrocyclic Compounds - pharmacology; Male; Rats; Rats, Sprague-Dawley; Receptors, Ghrelin - agonists; Rectum - drug effects; Rectum - physiology; Spinal Cord - drug effects; Spinal Cord - physiology
• ISSN: 1350-1925; 1365-2982
• DOI: 10.1111/nmo.12259

Background Discovery of adequate pharmacological treatments for constipation has proven elusive. Increased numbers of bowel movements were reported as a side‐effect of ulimorelin treatment of gastroparesis, but there has been no investigation of the site of action. Methods Anesthetized rats were used to investigate sites and mechanisms of action of ulimorelin. Key Results Intravenous ulimorelin (1–5 mg/kg) caused a substantial and prolonged (~1 h) increase in colorectal propulsive activity and expulsion of colonic contents. This was prevented by cutting the nerves emerging from the lumbosacral cord, by the nicotinic receptor antagonist hexamethonium and by antagonists of the ghrelin receptor. The effect of intravenous ulimorelin was mimicked by direct application of ulimorelin (5 μg) to the lumbosacral spinal cord. Conclusions & Inferences Ulimorelin is a potent prokinetic that causes propulsive contractions of the colorectum by activating ghrelin receptors of the lumbosacral defecation centers. Its effects are long‐lasting, in contrast with other colokinetics that target ghrelin receptors. Previous investigations in human showed that ulimorelin, a ghrelin receptor agonist, increased the frequency of bowel movements. The present study used rats to investigate the mode of action of ulimorelin. Intravenous ulimorelin caused propulsive activity and emptying of the colorectum. This was blocked by cutting the pelvic nerves, by hexamethonium and by ghrelin receptor antagonists. Direct application to the lumbosacral defecation centers mimicked the effect of intravenous ulimorelin. The results suggest that ulimorelin and other centrally penetrant ghrelin receptor agonists have potential to treat constipation.