title: Characterization of two models of drug-induced constipation in mice and evaluation of mustard oil in these models.
abstract: Although it is known that both clonidine and loperamide cause delayed colonic transit in mice, these models of drug-induced experimental constipation have not yet been fully characterized. Therefore, the aims of this study were to validate the clonidine- and loperamide-induced delays of colonic transit in mice as models of atonic and spastic constipation, respectively, and to evaluate the effect of mustard oil, a TRPA1 agonist, in both models. Colonic transit was evaluated in mice by determining the time needed to evacuate a bead inserted into the distal colon. Both loperamide and clonidine dose-dependently prolonged the evacuation time. Clonidine (10 microg/kg) and loperamide (0.3 mg/kg) tripled the evacuation time compared to controls. These delays were antagonized by the administration of yohimbine and naloxone, respectively. Tegaserod, a gastrointestinal motor-stimulating drug, reversed the delay in both models, but the effects were diminished at high doses. Atropine, an antispastic drug, improved the loperamide-induced delay, but did not affect the clonidine-induced delay. Mustard oil accelerated the colonic transit dose-dependently in both models of drug-induced constipations. These results indicate that clonidine- and loperamide-induced delays in colonic transit are models of atonic and spastic constipation, respectively, and that mustard oil may be effective on both types of constipation.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan. ryosuke.kojima@jp.astellas.com
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Kojima
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Doihara
authors.forename: Katsura
authors.initials: K
authors.lastname: Nozawa
authors.forename: Eri
authors.initials: E
authors.lastname: Kawabata-Shoda
authors.forename: Toshihide
authors.initials: T
authors.lastname: Yokoyama
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ito
mesh_terms: D000818:Animals; D001285:Atropine / Q000494:pharmacology; D003000:Clonidine; D003248:Constipation / Q000139:chemically induced* / Q000188:drug therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005772:Gastrointestinal Transit / Q000187:drug effects*; D007211:Indoles / Q000494:pharmacology; D008139:Loperamide; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009149:Mustard Plant; D009270:Naloxone / Q000494:pharmacology; D010938:Plant Oils / Q000627:therapeutic use*; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000819:agonists; D015016:Yohimbine / Q000494:pharmacology
chemical_list: D007211:Indoles; D010938:Plant Oils; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D015016:Yohimbine; D009270:Naloxone; C105050:tegaserod; D008139:Loperamide; D001285:Atropine; D003000:Clonidine; C027793:mustard oil