Fig. 2.
Spinal blockade of vascular endothelial growth factor A (VEGF-A)/vascular endothelial growth factor receptor 2 (VEGFR2) attenuates mechanical allodynia, thermal hyperalgesia and spontaneous pain in tumor-bearing rats. (A to D) Single administration of VEGF-A neutralizing antibody or VEGFR2 inhibitor ZM 323881 time-dependently reversed tumor-induced reduction in the threshold (A, B) and latency (C, D) in tumor-bearing rats. VEGF-A neutralizing antibody (anti-VEGF-A, 2 μg, intrathecal), immunoglobulin G (IgG; vehicle control for anti-VEGF-A, 2 μg, intrathecal [i.t.]), ZM 323881 (100 nM, i.t.) or dimethyl sulfoxide (DMSO)(vehicle control for ZM 323881, 1%, i.t.) was injected on day 14 post–tumor inoculation. Data are expressed as mean ± SD. **P < 0.01 versus sham + IgG (or DMSO) group; #P < 0.05, ##P < 0.01 versus tumor + IgG (or DMSO) group, N = 6 for each group, two-way repeated-measures ANOVA with post hoc Bonferroni test. (E to H) Repetitive administration of VEGF-A neutralizing antibody or ZM 323881 significantly attenuated tumor-induced reduction in the threshold (E, F) and latency (G, H) in tumor-bearing rats. VEGF-A neutralizing antibody (anti-VEGF-A, 2 μg, i.t.), IgG (2 μg, i.t), ZM 323881 (100 nM, i.t.) or DMSO (1%, i.t.) was injected once daily on days 12, 13, and 14 post–tumor inoculation. Behavioral tests were performed 4 h after each injection. Data are expressed as mean ± SD. **P < 0.01 versus sham + IgG (or DMSO) group; #P < 0.05, ##P < 0.01 versus tumor + IgG (or DMSO) group, N = 8 for each group, two-way repeated-measures ANOVA with post hoc Bonferroni test. (I, J) Repetitive administration of VEGF-A neutralizing antibody or ZM 323881 significantly attenuated tumor-induced spontaneous pain behaviors (I) and limb uselessness (J) in tumor-bearing rats. VEGF-A neutralizing antibody (anti-VEGF-A, 2 μg, i.t.) or ZM 323881 (100 nM, i.t.) was injected once daily on days 12, 13, and 14 post–tumor inoculation. Behavioral tests were performed 4 h after the last injection on day 14. Data are expressed as mean ± SD. *P < 0.05, **P < 0.01, N = 10 for each group, one-way ANOVA with post hoc Dunnett test.