Fig. 6.

CatS inhibitors reduce VCR-induced mechanical hypersensitivity only when centrally-penetrant. (A) Mechanical thresholds are significantly higher in VCR-treated male and female mice (days 0–4 inclusive), which also received the centrally-penetrant MIV-247 (MIV) (200 µmol/kg p.o. twice a day, every day) alongside VCR than in VCR/vehicle-treated mice. Data expressed as 50% paw withdrawal thresholds (mean ± SEM, n = 7 mice per group, 4 female and 3 male) measured 3 h after administration. ***p < 0.001 compared to Saline/VEH group; ###p < 0.001 compared to VCR/VEH group, Repeated Measures ANOVA, post hoc Tukey test. (B) Mechanical thresholds in mice treated with VCR (days 0–4 inclusive) are not altered 3 h after administration of the peripherally-restricted RO5461111 (RO5) (200 µmol/kg p.o. twice a day, every day) alongside VCR. Data expressed as 50% paw withdrawal thresholds (mean ± SEM, n = 7 mice per group). ***p < 0.001 compared to Saline/VEH and Saline/RO5 groups Repeated Measures ANOVA, post hoc Tukey test. (C-D) Representative blot (C) and quantification (D) of li p10 fragment expression relative to li in snap frozen spleen from R05-treated and control mice (3 h after administration) (n = 3 mice ± SEM) **p < 0.01, Student’s t-test.