Paclitaxel produced allodynia in male and female C57Bl/6 mice ( to ). In the present report, as well as in other ongoing studies in our laboratory, these effects were largely dose independent and more robust in female mice, and peaked in general between days 10 and 12, with the exception of the effect on cold allodynia depicted in . The 4 injections of 1.0 mg/kg paclitaxel dosing regimen only produced cold allodynia in female C57Bl/6 mice (). A 2-way ANOVA revealed significant main effects of sex [F(1,36) = 10.3, P = 0.003] and time [F(2,36) = 5.62, P = 0.008] and a significant interaction [F(2,36) = 6.61, P = 0.004]. Four injections of 2.0 mg/kg paclitaxel produced a more robust cold allodynia, and this effect was significant in female mice (). A 3-way ANOVA revealed a significant effect of sex (female) [F(1,48) = 7.51, P = 0.009], treatment (paclitaxel) [F(1,48) = 10.8, P = 0.002], and time (day 13) [F(1,48) = 5.71, P = 0.02] but no interactions [Fs<1.0]. These data also reveal that treatment with the Cremophor vehicle alone increases cold allodynia in relation to baseline. On the basis of these findings, we increased the paclitaxel doses to 4.0 and 8.0 mg/kg, proceeded with only females, and added a mechanical allodynia measurement. In this study, 4 injections of paclitaxel produced significant cold allodynia () and mechanical allodynia () in female mice. For cold allodynia, a 2-way ANOVA revealed a significant effect of treatment [F2203 = 7.62, P = 0.0002] and time [F(6203) = 2.75, P = 0.0008], and a significant interaction [F(12,203) = 2.22, P = 0.0261]. For mechanical allodynia, a 2-way ANOVA revealed a significant effect of treatment [F(2126) = 9.35, P <0.0001] and time [F(2126) = 2.51, P = 0.046], but no significant interaction [F<1.0]. Lastly, we assessed the effect of 5.0 and 10.0 mg/kg CBD on paclitaxel-induced allodynia (8.0 mg/kg), and we also added a saline control group given the behavioral effects observed with the Cremophor vehicle (). Control and drug data are depicted separately for visual clarity, but all subjects were run in cohorts together, and data were analyzed together for each allodynia measurement by 2-way ANOVAs. Both doses of CBD prevented the development of paclitaxel-induced cold and mechanical allodynia. For cold allodynia (), a 2-way ANOVA revealed significant effects of treatment [F(4345) = 56.0, P <0.0001] and time [F(10,345) = 8.16, P <0.0001] and a significant interaction [F(39,345) = 5.51, P <0.0001]. For mechanical allodynia (), a 2-way ANOVA revealed significant effects of treatment [F(4392) = 236, P <0.0001] and time [F(11,392) = 32.4, P <0.0001] and a significant interaction [F(44,392) = 11.0, P <0.0001]. Bonferroni post-tests revealed significant differences between saline and Cremophor, Cremophor and paclitaxel, and paclitaxel and 5.0 and 10.0 CBD treatments on both measures.
Figure 1 Effect of 4 1.0 mg/kg (A) and 2.0 mg/kg (B) paclitaxel injections on cold allodynia in male and female C57Bl/6 mice. Paclitaxel 1.0 mg/kg × 4 injections produced significant main effects of sex (P = 0.003) and time (P = 0.008) (P = 0.004). Paclitaxel (more ...)
Figure 3 Effect of repeated cannabidiol (5.0 to 10.0 mg/kg) on paclitaxel-induced cold (A) and mechanical (B) allodynia in female C57Bl/6 mice. For cold and mechanical allodynia, significant effects of treatment (Ps<0.0001) and time (Ps<0.0001) (more ...)
Figure 2 Effect of 4 4.0 mg/kg and 8.0 mg/kg paclitaxel on cold (A) and mechanical (B) allodynia in female C57Bl/6 mice. Paclitaxel produced a significant effect of treatment (P = 0.0002) and time (P = 0.0008) and a significant interaction (P = 0.0261) on cold (more ...)