Site and mechanism of the colokinetic action of the ghrelin receptor agonist, HM01. Issue 12 (28th September 2015) - Naitou, K.
Abstract: Background: It has been recently demonstrated that the ghrelin receptor agonist, HM01, caused defecation in rats that were treated to provide a model for the constipation of Parkinson's disease. HM01 significantly increased fecal output and increased Fos activity in neurons of the hypothalamus and hindbrain, but not in the spinal defecation center. Other ghrelin agonists act on the defecation center. Methods: Receptor pharmacology was examined in ghrelin receptor (GHSR1a) transfected cells. Anesthetized rats were used to investigate sites and mechanisms of action. Key Results: HM01 activated rat GHSR1a at nanomolar concentrations and was antagonized by the GHSR1a antagonist, YIL781. HM01, intravenous, was potent to activate propulsive colorectal contractions. This was prevented by pelvic nerve section and by intravenous YIL781, but not by spinal cord section rostral to the defecation centers. Direct intrathecal application of HM01 to the defecation center at spinal level L6‐S1 initiated propulsive contractions of the colorectum. Conclusions & Inferences: HM01 stimulates GHSR1a receptors on neurons in the lumbosacral defecation centers to cause propulsive contractions and emptying of the colorectum. It has greater potency when given systemically, compared with other GHSR1a agonists. Abstract : This paper describes the effects of a newly developed small molecule ghrelin receptor agonist, HM01, on colorectal activity in the rat. HM01 acted in the lumbosacral defecation center to initiate defecation. It was more potent than other agents. Its effects were blocked by an antagonist of the conventional ghrelin receptor, GHSR1a. This drug may be effective as an anti‐constipatory drug. View the podcast on this paper at the following sites: iTunes:https://itunes.apple.com/dk/podcast/neurogastroenterology-motility/id1045910387 Youtube:https://www.youtube.com/watch?v=ObA6w9w9_sM&feature=em-upload_owner