Mo2029 Extracellular Cyclic GMP (cGMP), the Downstream Mediator Released in Response to Linaclotide-Induced Activation of Guanylate Cyclase-C (GC-C), Reduces Excitability of Murine and Human Dorsal Root Ganglion (DRG) Neurons

Abstract

G A A b st ra ct s that was performed every 4 days to determine the exact timepoint of endoscopic healing in each individual animal. Three days after endoscopic resolution of inflammation, visceral sensitivity was assessed by quantifying visceromotor responses (VMRs) to colorectal distension. A-317491 (10-25 mg/kg) or saline was administered 30 min prior to VMR testing. Compliance was evaluated by applying graded volumes to the colorectally inserted balloon and recording the corresponding colonic pressures. Afterwards remaining signs of inflammation were assessed by endoscopy, macroscopy, histology and myeloperoxidase activity. P2X3R mRNA expression was determined in colon specimens and dorsal root ganglia (DRGs; Th13-L2 and L6-S1) by RT-PCR. Results: Endoscopy demonstrated that colitis was present 3 days after the TNBS enema and had resolved by day 12 (range 10-14); inflammatory markers were normal in control and post-colitis rats at the time of VMR testing. After endoscopic healing of colitis, post-colitis rats displayed significant visceral hypersensitivity compared to controls (table 1). Post-inflammatory hypersensitivity was dose-dependently reduced by A-317491 without affecting VMRs in controls. Colonic compliance was comparable in both groups and remained unaltered by A-317491 (n=5-7). P2X3RmRNAwas similarly expressed in the colon and DRGs of control and post-colitis rats. Conclusion: The selective P2X3R antagonist A-317491 dose-dependently reduced post-inflammatory visceral hypersensitivity, highlighting the modulatory role of P2X3Rs in visceral nociception. Our findings validate this receptor subtype as a potential target in the treatment of abdominal pain syndromes such as irritable bowel syndrome and inflammatory bowel disease. Table 1. Visceromotor responses to colorectal distension in control and post-colitis rats.