title: Morphine-Induced Constipation Develops With Increased Aquaporin-3 Expression in the Colon via Increased Serotonin Secretion.
abstract: Aquaporin-3 (AQP3) is a water channel that is predominantly expressed in the colon, where it plays a critical role in the regulation of fecal water content. This study investigated the role of AQP3 in the colon in morphine-induced constipation. AQP3 expression levels in the colon were analyzed after oral morphine administration to rats. The degree of constipation was analyzed after the combined administration of HgCl(2) (AQP3 inhibitor) or fluoxetine (5-HT reuptake transporter [SERT] inhibitor) and morphine. The mechanism by which morphine increased AQP3 expression was examined in HT-29 cells. AQP3 expression levels in rat colon were increased during morphine-induced constipation. The combination of HgCl(2) and morphine improved morphine-induced constipation. Treatment with morphine in HT-29 cells did not change AQP3 expression. However, 5-HT treatment significantly increased the AQP3 expression level and the nuclear translocation of peroxisome proliferator-activated receptor gamma (PPARγ) 1 h after treatment. Pretreatment with fluoxetine significantly suppressed these increases. Fluoxetine pretreatment suppressed the development of morphine-induced constipation and the associated increase in AQP3 expression in the colon. The results suggest that morphine increases the AQP3 expression level in the colon, which promotes water absorption from the luminal side to the vascular side and causes constipation. This study also showed that morphine-induced 5-HT secreted from the colon was taken into cells by SERT and activated PPARγ, which subsequently increased AQP3 expression levels.
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, Tokyo, Japan; and Division of Applied Pharmaceutical Education and Research, Hoshi University, Tokyo, Japan.
authors.forename: Risako
authors.initials: R
authors.lastname: Kon
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, Tokyo, Japan; and Division of Applied Pharmaceutical Education and Research, Hoshi University, Tokyo, Japan Department of Clinical Pharmacokinetics, Hoshi University, Tokyo, Japan; and Division of Applied Pharmaceutical Education and Research, Hoshi University, Tokyo, Japan.
authors.forename: Nobutomo
authors.initials: N
authors.lastname: Ikarashi
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, Tokyo, Japan; and Division of Applied Pharmaceutical Education and Research, Hoshi University, Tokyo, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Hayakawa
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, Tokyo, Japan; and Division of Applied Pharmaceutical Education and Research, Hoshi University, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Haga
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, Tokyo, Japan; and Division of Applied Pharmaceutical Education and Research, Hoshi University, Tokyo, Japan.
authors.forename: Aika
authors.initials: A
authors.lastname: Fueki
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, Tokyo, Japan; and Division of Applied Pharmaceutical Education and Research, Hoshi University, Tokyo, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Kusunoki
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, Tokyo, Japan; and Division of Applied Pharmaceutical Education and Research, Hoshi University, Tokyo, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Tajima
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, Tokyo, Japan; and Division of Applied Pharmaceutical Education and Research, Hoshi University, Tokyo, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Ochiai
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, Tokyo, Japan; and Division of Applied Pharmaceutical Education and Research, Hoshi University, Tokyo, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Machida
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, Tokyo, Japan; and Division of Applied Pharmaceutical Education and Research, Hoshi University, Tokyo, Japan sugiyama@hoshi.ac.jp.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Sugiyama
mesh_terms: D000701:Analgesics, Opioid; D000818:Animals; D051400:Aquaporin 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D003106:Colon / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D003248:Constipation / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D003672:Defecation / Q000187:drug effects; D004195:Disease Models, Animal; D005473:Fluoxetine / Q000494:pharmacology; D019073:HT29 Cells; D006801:Humans; D008297:Male; D008627:Mercuric Chloride / Q000494:pharmacology; D009020:Morphine; D047495:PPAR gamma / Q000378:metabolism; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D015854:Up-Regulation; D014867:Water / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D051400:Aquaporin 3; D005473:Fluoxetine; D008627:Mercuric Chloride; D009020:Morphine; D047495:PPAR gamma; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D014867:Water; C496027:AQP3 protein, human; C496029:Aqp3 protein, rat
keywords: aquaporin-3; constipation; fluoxetine; morphine; serotonin