Cannabidiol and mitragynine exhibit differential interactive effects in the attenuation of paclitaxel-induced mechanical allodynia, acute antinociception, and schedule-controlled responding in mice

Background For many chemotherapy patients peripheral neuropathy is a debilitating side effect. Mitragyna speciosa (kratom) contains the alkaloid mitragynine (MG), which produces analgesia in multiple preclinical pain models. In humans, anecdotal reports suggest cannabidiol (CBD) may enhance kratom-related analgesia. We examined the interactive activity of MG and CBD in a mouse chemotherapy-induced peripheral neuropathy (CIPN) model. We also examined MG + CBD in acute antinociception and schedule-controlled responding assays, as well as examined underlying receptor mechanisms. Methods Male and female C57BL/6J mice received a cycle of intraperitoneal ( ip ) paclitaxel injections (cumulative dose 32 mg/kg). The von Frey assay was utilized to assess CIPN allodynia. In paclitaxel-naïve mice, schedule-controlled responding for food was conducted under a fixed ratio (FR)-10, and hot plate antinociception was examined. Results MG dose-relatedly attenuated CIPN allodynia (ED 50 102.96 mg/kg, ip ), reduced schedule-controlled responding (ED 50 46.04 mg/kg, ip ), and produced antinociception (ED 50 68.83 mg/kg, ip ). CBD attenuated allodynia (ED 50 85.14 mg/kg, ip ) but did not decrease schedule-controlled responding or produce antinociception. Isobolographic analysis revealed 1:1, 3:1 MG + CBD mixture ratios additively attenuated CIPN allodynia. All combinations decreased schedule-controlled responding and produced antinociception. WAY-100635 (serotonin 5-HT1A receptor antagonist) pretreatment (0.01 mg/kg, ip ) antagonized CBD anti-allodynia. Naltrexone (pan opioid receptor antagonist) pretreatment (0.032 mg/kg, ip ) antagonized MG anti-allodynia and acute antinociception but produced no change in MG-induced decreased schedule-controlled behavior. Yohimbine (α 2 receptor antagonist) pretreatment (3.2 mg/kg, ip ) antagonized MG anti-allodynia and produced no change in MG-induced acute antinociception or decreased schedule-controlled behavior. Conclusions Although more optimization is needed, these data suggest CBD combined with MG may be useful as a novel CIPN therapeutic.