Cannabidiol prevents the development of cold and mechanical allodynia in paclitaxel-treated female C57Bl6 mice

Abstract

The taxane chemotherapeutic paclitaxel frequently produces peripheral neuropathy in humans. Rodent models to investigate mechanisms and treatments are largely restricted to male rats, whereas female mouse studies are lacking. We characterized a range of paclitaxel doses on cold and mechanical allodynia in male and female C57Bl/6 mice. Because the nonpsychoactive phytocannabinoid cannabidiol attenuates other forms of neuropathic pain, we assessed its effect on paclitaxel-induced allodynia. Paclitaxel produced allodynia that was largely dose independent and more robust in female mice, and this effect was prevented by treatment with cannabidiol. Our preliminary findings therefore indicate that cannabidiol may prevent the development of paclitaxel-induced allodynia in mice and therefore be effective at preventing dose-limiting paclitaxel-induced peripheral neuropathy in humans.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

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 2.0 mg/kg × 4 injections produced significant effect of sex (female: P = 0.009), treatment (paclitaxel: P = 0.002), and time (day 13: P = 0.02) but no interactions. X-axes: Timepoints pre- or postday 1 injection (Bl = baseline). Paclitaxel (PAC) or Cremophor (Crem) was injected on days 1, 3, 5, and 7. Y-axes: Time spent by mice lifting, fluttering, or licking hindpaw after administration of 10 μL acetone. Data points represent the mean time spent attending to the hindpaw in seconds and SEM (vertical bars); n = 6 to 10 per group.

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 allodynia. X-axes: Paclitaxel produced a significant effect of treatment (P < 0.0001) and time (P = 0.046), but no significant interaction on mechanical allodynia. Timepoints pre- or postday 1 injection (Bl = baseline). Paclitaxel (PAC) or Cremophor (Crem) was injected on days 1, 3, 5, and 7. Y-axes: Time spent by mice lifting, fluttering, or licking hindpaw after administration of 10 μL acetone (A) or threshold pressure, which evoked a paw lift (B). Data points represent mean time spent attending to the hindpaw in seconds (A) or mean pressure required to evoke a lift of the hindpaw in grams (B) and SEM (vertical bars); n = 8 to 12 per group.

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) and a significant interaction (Ps<0.0001) were observed. Bonferroni posttests revealed significant differences between saline and Cremophor, Cremophor and paclitaxel, and paclitaxel and 5.0 and 10.0 cannabidiol (CBD) treatments on both measures. X-axes: Time points pre- or postday 1 injection. Paclitaxel (PAC), Cremophor, or saline was injected on days 1, 3, 5, and 7 (indicated by arrows). CBD or Cremophor was injected on days 1 to 14 (indicated by black line). Y-axes: Time spent by mice lifting, fluttering, or licking hindpaw after administration of 10 μL acetone (A) or threshold pressure, which evoked a paw lift (B). Data points represent mean time spent attending to the hindpaw in seconds (A) or mean pressure required to evoke a lift of the hindpaw in grams (B) and SEM (vertical bars); n = 8 per group. Bonferroni posttests revealed significant differences between saline and Cremophor, Cremophor and paclitaxel, and paclitaxel and 5.0 and 10.0 CBD treatments on both measures.