Duloxetine alleviates PTX-induced hypersensitivity in C57BL/6 mice without affecting their body weight. (A) Paw withdrawal threshold was significantly decreased at week 2 and maintained for more than 3 weeks in mice treated with PTX. Duloxetine at doses of 10, 20, and 30 mg/kg all attenuated PTX-induced mechanical hyperalgesia. (B) Paw withdrawal threshold was significantly decreased at week 1 and maintained for more than 4 weeks in mice treated with PTX. Duloxetine at doses of 10, 20, and 30 mg/kg all attenuated PTX-induced thermal nociception. (C) PTX did not have a significant effect on cold tail withdrawal latency. Similarly, no effect was observed with duloxetine on mice treated with or without PTX. (D) The effect of duloxetine on body weight in mice treated with or without PTX. No significant difference between the model group and the duloxetine-treated group in mice (**P < 0.01; ***P < 0.001 vs. control; ^#P < 0.05; ^##P < 0.01; ^###P < 0.001 vs. PTX, n = 8–10). D, duloxetine; H, high; L, low; M, medium; P, paclitaxel.

Duloxetine has no effect on the antitumour activity of PTX in DRG neurons, but it can alleviate the oxidative stress induced by PTX. (A) When PA-1 cancer cells were grown for 24 hours, PTX showed toxicity and reduced their cell viability by 40%–80%. (B) Various concentrations of duloxetine (10 μM–300 nM) together with PTX (300 nM) showed no significant changes in cell viability compared with treatment with PTX alone. (C) Primary rat DRG neurons were grown for 24 hours and then treated with PTX (300 nM) and/or duloxetine for another 24 hours. Cells were then subjected to MitoTracker Red CM-H2XRos staining. The fluorescence intensity was observed using fluorescence microscopy (original magnification, 200×) (*** vs. control, P < 0.001; ### vs. PTX, P < 0.001, α = 0.05, n = 6). P, paclitaxel; D, duloxetine.

Effect of duloxetine on p53 and PARP1 in DRG tissues and sciatic nerve. (A) Duloxetine significantly decreased the expression of p53 and actived-PARP1 protein in the DRG of PTX-treated mice. (B) Duloxetine significantly decreased the expression of p53 and activated-PARP1 protein in the sciatic nerve of PTX-treated mice. (C) The DRGs were double-stained with DAPI and p53. The fluorescence intensity was observed using fluorescence microscopy (original magnification, 400×). (D) Duloxetine significantly decreased the mRNA expression of p53 and PARP1 in the DRG of PTX-treated mice. (E) Duloxetine significantly decreased the mRNA expression of p53 and PARP1 in the sciatic nerve of PTX-treated mice (*P < 0.05; **P < 0.01; ***P < 0.001 vs. control; ^#P < 0.05; ^##P < 0.01; ^###P < 0.001 vs. PTX, n = 5). D, duloxetine; H, high; L, low; M, medium; P, paclitaxel.

Effect of duloxetine on Bax and Bcl2 in DRG tissues and the sciatic nerve. (A) Duloxetine significantly decreased the expression of Bax/Bcl2 protein in the DRG of PTX-treated mice. (B) Duloxetine significantly decreased the expression of Bax/Bcl2 protein in the sciatic nerve of PTX-treated mice. (C) Duloxetine significantly decreased the mRNA expression of Bax/Bcl2 in the DRG of PTX-treated mice. (D) Duloxetine significantly decreased the mRNA expression of Bax/Bcl2 in the sciatic nerve of PTX-treated mice (**P < 0.01; ***P < 0.001 vs. Control; ^#P < 0.05; ^##P < 0.01; ^###P < 0.001 vs. PTX, n = 5). D, duloxetine; P, paclitaxel.

Effect of pft-α on neurotoxicity and cell apoptosis caused by PTX in primary DRG neurons. (A) Primary rat DRG neurons were grown for 24 hours and then treated with PTX (300 nM) and/or various concentrations of pft-α for another 24 hours. (B) When PA-1 cancer cells were grown for 24 hours, various concentrations of pft-α together with PTX (300 nM) showed slight changes in cell viability compared with treatments with PTX alone. (C) After DRG cells were cultured for 24 hours, they were then exposed to PTX (300 nM) with or without pft-α (18.5 μM) for another 24 hours. Cells were double-stained with Annexin V-FITC/PI (***P < 0.001 vs. control; ^#P < 0.05; ^##P < 0.01; ^###P < 0.001 vs. PTX, n = 6). P, paclitaxel.