414 Reversal of Opioid-Induced Constipation by Lubiprostone (Amitiza®) in Guinea Pig Ileum

Abstract

Background & Aims: Brain-derived neurotrophic factor (BDNF) may play a critical role in gut motility. We aimed to investigate BDNF's physiologic effects on gut motility in slowtransit constipation (STC) and to explore the underlying molecular mechanisms. Methods: BDNF expression and alterations of colonic nerve fiber density in STC patients were first investigated. BDNF's effects on gastrointestinal motility of both BDNF+/− mice and loperamide-induced constipation mice were then examined in vivo and in vitro. Smooth muscle α-actin (α-SMA) expression, and nerve fiber, neuromuscular junction (NMJ), and smooth muscle cell (SMC) alterations were investigated. Finally, the effects of BDNF-induced TrkBphospholipase C/inositol trisphosphate (TrkB-PLC/IP3) pathway activation on gut motility were investigated. Results: In STC patients, BDNF expression and nerve fiber density were decreased, and mucosal nerve fiber ultrastructural degenerations were demonstrated. Gut motility was decreased in vivo and in vitro in BDNF+/− and constipation mice, with BDNF dose-dependently increasing gut motility. In BDNF+/− mice, α-SMA expression and nerve fiber density were decreased, and nerve fiber, NMJ, and SMC ultrastructural degenerations were observed. Finally, TrkB-PLC/IP3 pathway agonists dramatically attenuated BDNF's excitatory effect on gut motility, and exogenous BDNF induced an obvious increase in IP3 expression. Conclusions: BDNF plays an important regulatory role in gut motility in STC. It was mediated by altering the intestinal innervation structure, as well as smooth muscle secondary degeneration through a mechanism involving TrkB-PLC/IP3 pathway activation.