The Effects and Mechanisms of GES on Visceral Hypersensitivity in a rodent model of FD
BACKGROUND & AIMS: visceral hypersensitivity is considered one of the central mechanisms of FD. Gastric electrical stimulation (GES) has been applied to treat gastric motility disorders. Studies have also shown that GES can reduce visceral sensitivity to gastric distension based on behavioral measurement, suggesting a possible role of GES in treating visceral hypersensitivity in FD. NGF is among the most important and well-characterized molecular mediator of visceral hypersensitivity. This study is to investigate the effects and mechanisms of GES for visceral hypersensitivity in a rodent model of FD. METHODS: Male Sprague-Dawley rat pups at 10-day old received 0.1% iodoacetamide (IA) by oral gavage for 6 days to establish rodent model of gastric hypersensitivity mimicking FD. Visceral hypersensitivity was assessed by the measurement of EMG and AWR score. First, we optimized GES parameters in reducing EMG response to gastric distention (GD), and then we observed short-term effects of GES on visceral hypersensitivity. Furthermore, we investigated mechanisms of GES for visceral hypersensitivity in a rodent model of FD. We observed the difference of EMG between GES and Naloxone+GES/CTOP+GES by intraperitoneal injection of Naloxone/CTOP to investigate the effects of Naloxone and CTOP on GES, and measured the expression NGF protein in the blood, stomach and DRG neurons by ELISA and Western blotting. Results: 1) GES with optimized parameters significantly reduced EMG responses at GD 60, 80, and 100 mmHg. 2) 7-day GES significantly ameliorated visceral hypersensitivity3) The inhibitory effects of GES were blocked by Naloxone and CTOP. EMG% in Naloxone at 60mmHg, 80mmHg and 100mmHg were 272.3±40.7% (vs. GES 193.2±31.0% p<0.001), 315.1±40.5% (vs. GES 243.5±26.0, p<0.001) and 350.2±36.5% (vs. GES 272.5±25.5, p<0.001); EMG% in CTOP+GES at 60mmHg, 80mmHg and 100mmHg were 180.6±10.9% (vs. GES 148.5±16.6% p=0.003), 244.9±48.6% (vs. GES 177.9±19.7, p<0.001) and 270.4±34.2% (vs. GES 179.6±21.19, p<0.001); after the application of naloxone/CTOP, the EMG responses to GD 60, 80 and 100 mmHg were similar among baseline period. 4) The NGF protein in blood, stomach and DRG by ELISA were decreased after GES in a rodent model of FD, and GES also decreased the expression of NGF protein in stomach and DRG by western blotting. Conclusions GES with optimal parameters improves visceral hypersensitivity, and it is effective for treatment of visceral hypersensitivity in FD; the effect of GES on visceral hypersensitivity is mediated via the endogenous opioid system; NGF is also involved in the regulatory mechanism of GES for visceral hypersensitivity.