S1809 Is Visceroperception in Irritable Bowel Syndrome (IBS) Influenced by Meal Ingestion

treated with URB597 [3'-(aminocarbonyl) biphenyl-3-yl cyclohexylcarbamate] (3 mg/kg, SC route) or vehicle (PO route). Two hours later, rats were treated with cortagine (10 μg/kg, IP route). After 15 min, a second CRD was performed. Thirty min after the second CRD, rats were anesthetized with isoflurane, decapitated, and brains collected along with those from naive rats (no CRD, no treatment). AEA and 2-AG levels were quantified in brain extracts by LC-MS/MS. Results: In vehicle-treated rats, cortagine increased the VMR to CRD at 40 and 60 mmHg to 130 ± 20% and 144 ± 14% of baseline, respectively. URB597 blocked the cortagine-induced increase in VMR at 60 mmHg (95 ± 20% vs. 144 ± 14%, p<0.05) and showed a trend for reduction at 40 mmHg. URB597 also decreased the percentage of cortagine treated rats with an increased VMR (45 and 36% of URB597-treated rats at 40 and 60 mmHg vs. 84 and 92% with vehicle, p<0.05). URB597 increased brain AEA levels 5.7-fold (p<0.001) in rats compared to vehicle treatment and significantly elevated levels of other FAAH substrates. AEA levels in vehicle-treated rats were similar to those of naive rats indicating that vehicle, CRD, and cortagine did not affect the basal levels of AEA in the brain. 2-AG levels showed little or no significant change among all 3 groups of rats. Conclusions: These data support a role of eCBs in the control of visceral hypersensitivity induced by CRF1 signaling activation and suggest that FAAH inhibitors may represent a promising therapy for IBS-D.