Fig. 4.
Colonic hypersensitivity induced by either postinflammatory stress or chronic adult stress is ameliorated by inhibition of RET kinase with GSK3179106. Rats dosed with GSK3179106 for 3.5 days twice a day exhibit an attenuated visceromotor response to colonic distension after colonic hypersensitivity was induced (A) upon the onset and resolution of acute colitis (n = 8) or (B) following exposure to WAS (n = 9). (C) Rats with colonic hypersensitivity after the induction and resolution of acute colitis have a decreased visceral motor response upon intraperitoneal dosing with tegaserod (n = 8), a 5-HT4 agonist, compared with vehicle-dosed rats (n = 8). (D) Rats with colonic hypersensitivity after exposure to WAS have a decreased visceral motor response upon oral dosing with fexofenadine, a histamine receptor 1 antagonist, compared with vehicle-dosed rats. (E) GSK3179106 dosed orally at 10 mg/kg for 3.5 days twice a day had no effect on the visceromotor response in sham-treated rats exposed to saline instead of TNBS (n = 8) in comparison with sham-treated rats dosed with vehicle (n = 6). (F) GSK3179106 dosed orally at 10 mg/kg for 3.5 days twice a day had no effect on the visceromotor response in sham-treated rats (n = 6) in comparison with sham-treated rats dosed with vehicle (n = 8). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 vehicle compared with GSK3179106 treatment, two-way RM-ANOVA, and Bonferroni’s post-test.