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. 2017 Sep;174(17):2832-2841.
doi: 10.1111/bph.13887. Epub 2017 Jul 27.

Single and Combined Effects of Δ 9 -Tetrahydrocannabinol and Cannabidiol in a Mouse Model of Chemotherapy-Induced Neuropathic Pain

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Free PMC article

Single and Combined Effects of Δ 9 -Tetrahydrocannabinol and Cannabidiol in a Mouse Model of Chemotherapy-Induced Neuropathic Pain

Kirsten M King et al. Br J Pharmacol. .
Free PMC article

Abstract

Background and purpose: The non-psychoactive phytocannabinoid cannabidiol (CBD) can affect the pharmacological effects of Δ9 -tetrahydrocannabinol (THC). We tested the possible synergy between CBD and THC in decreasing mechanical sensitivity in a mouse model of paclitaxel-induced neuropathic pain. We also tested the effects of CBD on oxaliplatin- and vincristine-induced mechanical sensitivity.

Experimental approach: Paclitaxel-treated mice (8.0 mg·kg-1 i.p., days 1, 3, 5 and 7) were pretreated with CBD (0.625-20.0 mg·kg-1 i.p.), THC (0.625-20.0 mg·kg-1 i.p.) or CBD + THC (0.04 + 0.04-20.0 + 20.0 mg·kg-1 i.p.), and mechanical sensitivity was assessed on days 9, 14 and 21. Oxaliplatin-treated (6.0 mg·kg-1 i.p., day 1) or vincristine-treated mice (0.1 mg·kg-1 i.p. days 1-7) were pretreated with CBD (1.25-10.0 mg·kg-1 i.p.), THC (10.0 mg·kg-1 i.p.) or THC + CBD (0.16 mg·kg-1 THC + 0.16 mg·kg-1 CBD i.p.).

Key results: Both CBD and THC alone attenuated mechanical allodynia in mice treated with paclitaxel. Very low ineffective doses of CBD and THC were synergistic when given in combination. CBD also attenuated oxaliplatin- but not vincristine-induced mechanical sensitivity, while THC significantly attenuated vincristine- but not oxaliplatin-induced mechanical sensitivity. The low dose combination significantly attenuated oxaliplatin- but not vincristine-induced mechanical sensitivity.

Conclusions and implications: CBD may be potent and effective at preventing the development of chemotherapy-induced peripheral neuropathy, and its clinical use may be enhanced by co-administration of low doses of THC. These treatment strategies would increase the therapeutic window of cannabis-based pharmacotherapies.

Figures

Figure 1
Figure 1
Effect of paclitaxel on mechanical sensitivity in three separate groups of mice on different days. Paclitaxel (8.0 mg·kg−1 per injection) is administered on experimental days 1, 3, 5 and 7 following baseline measurement of mechanical sensitivity. Three separate groups of paclitaxel‐treated mice were run in order to provide appropriate non‐cannabinoid treated control data along the length of the study. n = 8 per group.
Figure 2
Figure 2
Effect of CBD or THC on paclitaxel‐induced mechanical sensitivity 9, 14 and 21 days after the start of treatment. Paclitaxel alone (8.0 mg·kg−1 per injection) or following pretreatment with CBD (A) or THC (B) (0.625–20 mg·kg−1 i.p.) was administered on experimental days 1, 3, 5 and 7, following baseline measurement of mechanical sensitivity. Mechanical sensitivity was tested 9, 14 and 21 days following initiation of treatment. n = 8 per group, with the exception of the 10 mg·kg−1 CBD group which was n = 7 due to one mouse found dead in home cage. *P < 0.05, significantly different from ??? ; Dunnett's multiple comparisons test.
Figure 3
Figure 3
Effect of CBD + THC on paclitaxel‐induced mechanical sensitivity 14 days after the start of treatment. Paclitaxel alone (8.0 mg·kg−1 per injection) or following pretreatment with CBD + THC (combined doses 0.08–40.0 mg·kg−1 per injection i.p.) is administered on experimental days 1, 3, 5 and 7 following baseline measurement of mechanical sensitivity. n = 12 per group, with the xexception of the 10 mg·kg−1 dose, where two mice were removed from the study due to skin lesions from a dominant cage mate. *P < 0.05, significantly different from paclitaxel alone; one‐way ANOVA with Dunnett's multiple comparisons test.
Figure 4
Figure 4
Linear regression analysis of ascending limbs of the observed single and combined agent dose–response curves and predictive additive curve. Data were transformed to %MPE (see text for details) in order to determine relative effective dose levels. Eobs is the observed dose effect levels of CBD + THC combinations along the ascending limb of the combination dose response curve. Eadd is the predicted additive dose effect levels of those same doses based on the ascending limb of the single agent dose response curves.
Figure 5
Figure 5
Effect of CBD, THC and their combination on oxaliplatin‐ or vincristine‐induced mechanical sensitivity. Oxaliplatin (6.0 mg·kg−1 i.p.) alone or following pretreatment with CBD (doses 1.25–10.0 mg·kg−1 per injection i.p.), THC (10.0 mg·kg−1 i.p.) or THC + CBD (0.16 mg·kg−1 THC + 0.16 mg·kg−1 CBD i.p.) was administered on experimental day 1 following baseline measurement of mechanical sensitivity. Vincristine (0.1 mg·kg−1 i.p.) alone or following pretreatment with CBD (doses 1.25–10.0 mg·kg−1 per injection i.p.), THC (10.0 mg·kg−1 i.p.) or THC + CBD (0.16 mg·kg−1 THC + 0.16 mg·kg−1 CBD i.p.) was administered on experimental days 1–7 following baseline measurement of mechanical sensitivity. n = 8 per group, with the exception of the oxaliplatin group in B and C, which is n = 6 due to two mice being killed because of urinary blockage. # P < 0.05, significant main effect of time; * P < 0.05, significant main effect of treatment; & P < 0.05, significant interaction.

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