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Visceral hypersensitivity (VH) is a significant contributor to irritable bowel syndrome (IBS). Oxytocin (OT) possesses analgesic effects on the central nervous system (CNS) and attenuates microglial activation, however, little is known about its peripheral effects and involvement in VH of IBS. Reactive enteric glial cells (EGCs) contributes to abnormal motility in gastrointestinal (GI) diseases. The aim of this study was to evaluate the peripheral use of OT to maintain VH and activation of EGCs through involvement of the Toll-like receptor (TLR) 4/MyD88/NF-κB signaling. After assessing a baseline visceromotor response (VMR) to colorectal distension (CRD), rats were exposed to a 1 h water avoidance stress (WAS) session. Before each WAS session, intraperitoneal injection of OT (1 mg/kg body weight, in phosphate-buffered saline (PBS)) atosiban (0.5 mg/kg body weight, in PBS) or PBS (as a vehicle control, 1 ml/kg body weight) was administered. Animas are killed 24 h after the last WAS session. EGCs activity, relative OT receptor expression, glial fibrillary acidic protein (GFAP) expression and TLR4/MyD88/NF-κB signaling were evaluated. Neonatal maternal separation (MS) significantly increased the OT receptor expression and enhanced VMR to CRD. WAS improved VMR to CRD only during neonatal MS. OT treatment prevented WAS-induced higher VMRs to CRD, which was reversed by an OT receptor antagonist administration. Compared to the vehicle, OT pre-treated rats reduced EGCs activation, GFAP expression and TLR4/MyD88/NF-κB signaling. We conclude that neonatal MS induces VH and visceral pain in rats. Furthermore, exogenous OT attenuated stress-induced VH and EGCs activation, which was mediated by TLR4/MyD88/NF-κB signaling.Oxytocin treatment reversed stress-induced visceral hypersensitivity in rats. (A) Maternal separated (MS) rats developed an increased visceromotor response (VMR) to colorectal distension (CRD) compared to non-separated (NS) rats (two-way ANOVA followed by Bonferroni post-test). (B) VMR to CRD was enhanced 24 h post-water avoidance stress (WAS) in MS rats (MS+WAS considered as a baseline). (C) Rats treated with vehicle exhibit no change in VMR to CRD compared with baseline. (D) Oxytocin (OT) inhibited the visceral hypersensitivity increase 24 h post-WAS compared with baseline. (E) OT significantly inhibited the VH increase 24 h post-WAS compared with vehicle. (F) Atosiban reversed the inhibitory effect of OT in VH. Data are expressed as means ± SEM of n=6 experiments.