Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2014 Feb;171(3):636-45.
doi: 10.1111/bph.12439.

Cannabidiol Inhibits Paclitaxel-Induced Neuropathic Pain Through 5-HT(1A) Receptors Without Diminishing Nervous System Function or Chemotherapy Efficacy

Affiliations
Free PMC article

Cannabidiol Inhibits Paclitaxel-Induced Neuropathic Pain Through 5-HT(1A) Receptors Without Diminishing Nervous System Function or Chemotherapy Efficacy

Sara Jane Ward et al. Br J Pharmacol. .
Free PMC article

Abstract

Background and purpose: Paclitaxel (PAC) is associated with chemotherapy-induced neuropathic pain (CIPN) that can lead to the cessation of treatment in cancer patients even in the absence of alternate therapies. We previously reported that chronic administration of the non-psychoactive cannabinoid cannabidiol (CBD) prevents PAC-induced mechanical and thermal sensitivity in mice. Hence, we sought to determine receptor mechanisms by which CBD inhibits CIPN and whether CBD negatively effects nervous system function or chemotherapy efficacy.

Experimental approach: The ability of acute CBD pretreatment to prevent PAC-induced mechanical sensitivity was assessed, as was the effect of CBD on place conditioning and on an operant-conditioned learning and memory task. The potential interaction of CBD and PAC on breast cancer cell viability was determined using the MTT assay.

Key results: PAC-induced mechanical sensitivity was prevented by administration of CBD (2.5 - 10 mg·kg⁻¹) in female C57Bl/6 mice. This effect was reversed by co-administration of the 5-HT(1A) antagonist WAY 100635, but not the CB₁ antagonist SR141716 or the CB₂ antagonist SR144528. CBD produced no conditioned rewarding effects and did not affect conditioned learning and memory. Also, CBD + PAC combinations produce additive to synergistic inhibition of breast cancer cell viability.

Conclusions and implications: Our data suggest that CBD is protective against PAC-induced neurotoxicity mediated in part by the 5-HT(1A) receptor system. Furthermore, CBD treatment was devoid of conditioned rewarding effects or cognitive impairment and did not attenuate PAC-induced inhibition of breast cancer cell viability. Hence, adjunct treatment with CBD during PAC chemotherapy may be safe and effective in the prevention or attenuation of CIPN.

Keywords: 5-HT1A; CIPN; breast cancer; cannabidiol; cannabinoid; chemotherapy-induced neuropathic pain; mechanical sensitivity; paclitaxel.

Figures

Figure 1
Figure 1
Effect of CBD pretreatment (2.5, 5.0 mg·kg−1, i.p.) on PAC-induced mechanical allodynia in female C57Bl/6 mice. Baseline sensitivity to von Frey filaments was assessed on the day before drug administration and continued weekly for 10 weeks. Mice received the following two i.p. injections spaced 15 min apart on days 1, 3, 5 and 7: CRM vehicle, CRM vehicle; CRM vehicle, 4.0 mg·kg−1 PAC; CRM vehicle, 8.0 mg·kg−1 PAC; 2.5 mg·kg−1 CBD, 8.0 mg·kg−1 PAC; 5.0 mg·kg−1 CBD, 8.0 mg·kg−1 PAC. Two-way anova revealed significant main effects of treatment [F(4, 310) = 27.71, P < 0.0001] and time [F(9, 310) = 5.001, P < 0.001] and no significant interaction (F < 1.0). Bonferroni post-tests revealed a significant increase in sensitivity in both the 4.0 and 8.0 mg·kg−1 PAC groups compared with Veh/Veh. In contrast, the PAC groups pretreated with either 2.5 or 5.0 mg·kg−1 CBD were not significantly different from Veh/Veh in their mechanical sensitivity. X-axis: time points pre- or post-day first injection. Y-axis: threshold pressure to elicit hind paw withdrawal from von Frey filament. Data points represent the mean and SEM, n = 8 per group.
Figure 2
Figure 2
Effect of WAY100635 pretreatment (1.0 mg·kg−1, i.p.) on CBD prevention of PAC-induced mechanical allodynia in female C57Bl/6 mice. Baseline sensitivity to von Frey filaments was assessed on the day before drug administration and continued weekly for 10 weeks. Mice received the following three i.p. injections spaced 15 min apart on days 1, 3, 5 and 7: saline, CRM vehicle, CRM vehicle; saline, CRM vehicle, 8.0 mg·kg−1 PAC; saline, 5.0 mg·kg−1 CBD, 8.0 mg·kg−1 PAC; 1.0 mg·kg−1 WAY100635, 5.0 mg·kg−1 CBD, 8.0 mg·kg−1 PAC. Two-way anova revealed significant effects of treatment [F(3, 280) = 24.66, P < 0.0001] and time [F(9, 280) = 5.058, P < 0.001] and no significant interaction (F <1.0). Bonferroni post-test revealed a significant increase in the sensitivity of the PAC group and the WAY/CBD/PAC groups compared with Veh/Veh/Veh. In contrast, the Veh/CBD/PAC group did not differ significantly from the Veh/Veh/Veh group on mechanical sensitivity. X-axis: time points pre- or post-day first injection. Y-axis: threshold pressure to elicit hind paw withdrawal from von Frey filament. Data points represent the mean and SEM, n = 8 per group.
Figure 3
Figure 3
Effect of CB1 (SR141716; SR1) or CB2 (SR144528; SR2) receptor antagonism on CBD prevention of PAC-induced mechanical allodynia in female C57Bl/6 mice. Sensitivity to von Frey filaments was assessed on day 15 post-treatment. Mice received the following three i.p. injections spaced 15 min apart on days 1, 3, 5 and 7: saline, CRM vehicle, CRM vehicle; saline, CRM vehicle, 8.0 mg·kg−1 PAC; saline, 5.0 mg·kg−1 CBD, 8.0 mg·kg−1 PAC; 1.0 mg·kg−1 WAY, 5.0 mg·kg−1 CBD, 8.0 mg·kg−1 PAC; 3.0 mg·kg−1 SR141716, 5.0 mg·kg−1 CBD, 8.0 mg·kg−1 PAC; 3.0 mg·kg−1 SR144528, 5.0 mg·kg−1 CBD, 8.0 mg·kg−1 PAC; 1.0 mg·kg−1 WAY, CRM, 8.0 mg·kg−1 PAC; 3.0 mg·kg−1 SR141716, CRM, 8.0 mg·kg−1 PAC; 3.0 mg·kg−1 SR144528, CRM, 8.0 mg·kg−1 PAC. One-way anova revealed a significant effect of treatment [F(8, 79) = 7.647, P < 0.05]. Dunnett's multiple comparison test determined that only the Veh/Veh/PAC, WAY/CBD/PAC, SR1/Veh/PAC and SR2/Veh/PAC groups were statistically different from the Veh/Veh/Veh control group (P < 0.05). X-axis: treatment. Y-axis: threshold pressure to elicit hind paw withdrawal from von Frey filament. Data points represent the mean and SEM, n = 8 per group.
Figure 4
Figure 4
Ability of CBD (2.5–10 mg·kg−1, i.p.) or morphine (2.5–10 mg·kg−1, i.p.) to produce place conditioning in female C57Bl/6 mice. Mice received vehicle or morphine (2.5–10 mg·kg−1, i.p.; 15 min pretreatment) or vehicle or CBD (2.5–10 mg·kg−1, i.p.; 30 min pretreatment) on alternate days for 30 min conditioning sessions for 6 successive days. One-way anovas revealed no significant effect of CBD treatment [F(3, 31) = 2.477, n.s.] and a significant effect of morphine treatment on time spent in the white compartment compared with saline vehicle control [F(3, 30) = 15.66, P < 0.0001]. X-axis: treatment. Y-axis: the time spent in the drug-paired (white) compartment on the treatment-free test day.
Figure 5
Figure 5
Effect of CBD administration (2.5–20 mg·kg−1, i.p.) on acquisition and retention of a conditioned food reward task. Nose-poke responses are reinforced when made within 8 s following a tone signalling availability of the sweet liquid reinforcer (50% vanilla Ensure in tap water). Each session lasted for 2 h or until 20 reinforced nose pokes were recorded. CBD treatment had no effect on the time to earn 10 reinforcers during the acquisition [F(3, 32) = <1] or retention [F(3, 25) = 1.692, n.s.] sessions. X-axis: treatment. Y-axis: the time elapsed between the first earned reinforcer and the tenth reinforcer.
Figure 6
Figure 6
Treatments combining CBD and PAC produce additive to synergistic inhibition of breast cancer cell viability. Cell viability was measured using the MTT assay. (A) 4T1 and MDA-MB231-luc-D3H2LN (LN 231) cells were treated for 2 days with vehicle, CBD or PAC. Specific dose ratios of CBD and Pac where then combined in (B) 4T1 and (C) MDA-MB231-luc-D3H2LN cells. Cell viability (%) was calculated as the MTT product absorbance in the treated cells/control cells × 100. These data were used to calculate (D) CI values as described in Methods. A CI value of <1, 1 and >1 indicates synergism, additivity and antagonism respectively (Chou et al., 1993). Data are the mean of at least three independent experiments; bars, ±SEM.

Similar articles

See all similar articles

Cited by 43 articles

See all "Cited by" articles

MeSH terms

Feedback