PURPOSE:

Paclitaxel (PAC) is associated with a chemotherapy-induced neuropathic pain (CIPN) state that can lead to the cessation of treatment in late stage breast cancer patients, even in the absence of alternate therapies. Indeed, to date no one drug or drug class is considered to be effective for reversal of CIPN. We have recently reported that chronic administration of the non-psychoactive and non-toxic cannabinoid, cannabidiol (CBD) prevents the onset of PAC-induced mechanical and thermal sensitivity in a mouse model of CIPN. In this investigation, we sought to discover pathways through which CBD inhibits CIPN and to determine whether the cannabinoid had any unforeseen deleterious effects on nervous system function or chemotherapy efficacy.

METHOD:

The ability of acute CBD pretreatment to prevent PAC-induced mechanical sensitivity was assessed using Von Frey filament testing. The effect of CBD on place conditioning and on autoshaping, a conditioned learning and memory task, were determined to determine whether the cannabinoid produced any negative CNS effects. The potential positive or negative interaction of CBD and PAC on breast cancer cell viability was determined using the MTT assay and the combination index (CI).

RESULTS:

Treatment with PAC (4.0 and 8.0 mg/kg X 4 inj) produced significant mechanical sensitivity in female C57Bl/6 mice that was prevented by administration of CBD (2.5 – 10 mg/kg). The protective effect of CBD was reversed by co-administration of the 5-HT1A antagonist WAY 100635, but not the CB₁ antagonist SR141716 or the CB₂ antagonist SR144528. CBD produced no conditioned rewarding effects in comparison to morphine which served as a positive control. CBD also did not affect acquisition or retention in the autoshaping procedure. At optimal concentrations, CBD+PAC combinations produce additive to synergistic inhibition of breast cancer cell viability.

CONCLUSIONS:

Our data suggest that CBD is protective against PAC-induced neurotoxicity and that this effect is in part mediated by the 5-TH1A receptor system. Furthermore, CBD treatment was devoid of other nervous system effects such as conditioned reward or cognitive impairment. CBD also did not attenuate the efficacy of PAC in inhibiting breast cancer cell viability. Taken together, adjunct treatment with CBD during PAC chemotherapy treatment may be safe and effective in the prevention or attenuation of CIPN.
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PMID:

 24117398
[PubMed – as supplied by publisher]