title: Site and mechanism of the colokinetic action of the ghrelin receptor agonist, HM01.
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.
  
  
  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
  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.
authors.affiliation: Department of Anatomy & Neuroscience, University of Melbourne, Parkville, VIC, Australia.|Department of Basic Veterinary Science, Laboratory of Physiology, The United Graduate School of Veterinary Sciences, Gifu University, Gifu, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Naitou
authors.affiliation: Department of Anatomy & Neuroscience, University of Melbourne, Parkville, VIC, Australia.
authors.forename: T P
authors.initials: TP
authors.lastname: Mamerto
authors.affiliation: Department of Anatomy & Neuroscience, University of Melbourne, Parkville, VIC, Australia.
authors.forename: R V
authors.initials: RV
authors.lastname: Pustovit
authors.affiliation: Department of Anatomy & Neuroscience, University of Melbourne, Parkville, VIC, Australia.
authors.forename: B
authors.initials: B
authors.lastname: Callaghan
authors.affiliation: Department of Anatomy & Neuroscience, University of Melbourne, Parkville, VIC, Australia.
authors.forename: L R
authors.initials: LR
authors.lastname: Rivera
authors.affiliation: Department of Anatomy & Neuroscience, University of Melbourne, Parkville, VIC, Australia.
authors.forename: A J
authors.initials: AJ
authors.lastname: Chan
authors.affiliation: Department of Anatomy & Neuroscience, University of Melbourne, Parkville, VIC, Australia.
authors.forename: M T
authors.initials: MT
authors.lastname: Ringuet
authors.affiliation: Helsinn Research and Preclinical Department, Lugano, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Pietra
authors.affiliation: Department of Anatomy & Neuroscience, University of Melbourne, Parkville, VIC, Australia.|Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia.
authors.forename: J B
authors.initials: JB
authors.lastname: Furness
mesh_terms: D000818:Animals; D003248:Constipation / Q000209:etiology; D003672:Defecation / Q000187:drug effects; D004195:Disease Models, Animal; D005769:Gastrointestinal Motility / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D008161:Lumbosacral Region; D008297:Male; D010300:Parkinson Disease / Q000150:complications; D051381:Rats; D017207:Rats, Sprague-Dawley; D054440:Receptors, Ghrelin / Q000819:agonists*; D013116:Spinal Cord / Q000187:drug effects*; D014162:Transfection
chemical_list: C571124:Ghsr1a protein, rat; D054440:Receptors, Ghrelin
keywords: defecation; ghrelin; ghrelin receptors