Figure 3.

Olorinab reversed hypersensitivity to CRD in CVH mice but had no effect in healthy mice. (A) Representative examples of EMG signals in response to each distension pressure for all mouse cohorts. (B) Vehicle-treated CVH mice exhibited significantly enhanced VMR to CRD compared with vehicle-treated healthy control mice. Significant increases in CVH mice were observed for distension pressures higher than 40 mm Hg. Olorinab treatment of CVH mice with doses of 3 mg/kg, 10 mg/kg, or 30 mg/kg significantly reduced VMR to CRD relative to vehicle-treated colitis mice. Olorinab 1 mg/kg was not effective in reducing VMR to CRD in CVH mice. Comparisons were performed with generalized estimating equation using an LSD post hoc test. **P < 0.01; ‡P < 0.0001. (C) Total AUC of the VMR to CRD showed significantly elevated responses in CVH mice compared with control mice. Olorinab 3 mg/kg, 10 mg/kg, and 30 mg/kg significantly reduced the total AUC of the VMR to CRD relative to vehicle-treated CVH mice. Comparisons were performed using a one-way ANOVA followed by Tukey post hoc tests. *P < 0.05; †P < 0.001; ‡P < 0.0001. (D) No significant changes in colonic compliance were observed between healthy mice treated with vehicle and CVH mice treated with vehicle or olorinab at all doses. Data are presented as mean ± SEM. AUC was calculated as the difference of area values obtained predistension (20 seconds) minus those obtained during distension (20 seconds). ^aSum of all distension pressures. ANOVA, analysis of variance; AUC, area under the curve; CRD, colorectal distension; CVH, chronic visceral hypersensitivity; EMG, electromyography; LSD, least squares difference; VMR, visceromotor response.