Marta Zielińska1, Agata Jarmuż1, Maciej Sałaga1, Andrzej W Lipkowski2, Jakub Fichna3. 1. Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland. 2. Mossakowski Medical Research Centre, Polish Academy of Sciences, Warszawa, Poland. 3. Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland; Mossakowski Medical Research Centre, Polish Academy of Sciences, Warszawa, Poland. Electronic address: jakub.fichna@umed.lodz.pl.
Abstract
BACKGROUND: Opioid receptors play a crucial role in the maintenance of homeostasis in the gastrointestinal (GI) tract. The aim of this study was to characterize the effect of biphalin, a mixed MOP/DOP agonist, on mouse intestinal contractility in vitro and GI motility in vivo and in animal models mimicking symptoms of diarrhea-predominant irritable bowel syndrome (IBS-D). METHODS: The effect of biphalin on muscle contractility in vitro was characterized in the ileum and colon. The anti-transit activity of biphalin in vivo was assessed in the following tests: whole gastrointestinal transit, colonic bead expulsion, fecal pellet output and castor oil-induced diarrhea, alone and in the presence of naloxone, and MOP and DOP antagonists. RESULTS: In vitro, biphalin (10(-10)-10(-6)M) inhibited colonic and ileal smooth muscle contractions in a concentration-dependent, opioid antagonist-reversible manner. In vivo, biphalin at the dose of 5mg/kg ip prolonged the whole GI transit and inhibited colonic bead expulsion. Biphalin reversed hypermotility and exerted anti-diarrheal effect in mouse models mimicking IBS-D symptoms. CONCLUSION: Biphalin is an interesting template for novel opioid-based agents to be used in therapy of functional GI diseases.
BACKGROUND: Opioid receptors play a crucial role in the maintenance of homeostasis in the gastrointestinal (GI) tract. The aim of this study was to characterize the effect of biphalin, a mixed MOP/DOP agonist, on mouse intestinal contractility in vitro and GI motility in vivo and in animal models mimicking symptoms of diarrhea-predominant irritable bowel syndrome (IBS-D). METHODS: The effect of biphalin on muscle contractility in vitro was characterized in the ileum and colon. The anti-transit activity of biphalin in vivo was assessed in the following tests: whole gastrointestinal transit, colonic bead expulsion, fecal pellet output and castor oil-induced diarrhea, alone and in the presence of naloxone, and MOP and DOP antagonists. RESULTS: In vitro, biphalin (10(-10)-10(-6)M) inhibited colonic and ileal smooth muscle contractions in a concentration-dependent, opioid antagonist-reversible manner. In vivo, biphalin at the dose of 5mg/kg ip prolonged the whole GI transit and inhibited colonic bead expulsion. Biphalin reversed hypermotility and exerted anti-diarrheal effect in mouse models mimicking IBS-D symptoms. CONCLUSION: Biphalin is an interesting template for novel opioid-based agents to be used in therapy of functional GI diseases.
Authors: Agata Szymaszkiewicz; Marcin Talar; Jakub Włodarczyk; Mikołaj Świerczyński; Adrian Bartoszek; Julia Krajewska; Anna Mokrowiecka; Ewa Małecka-Wojciesko; Jakub Fichna; Marta Zielińska Journal: Int J Mol Sci Date: 2022-03-24 Impact factor: 5.923