Characterization of two models of drug-induced constipation in mice and evaluation of mustard oil in these models.
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.
Kojima
Ryosuke
R
Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan. ryosuke.kojima@jp.astellas.com
Doihara
Hitoshi
H
Nozawa
Katsura
K
Kawabata-Shoda
Eri
E
Yokoyama
Toshihide
T
Ito
Hiroyuki
H
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
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