Remedy with cannabidiol ( CBD) or KLS-13019 (novel CBD analog), has previously been shown to protect against paclitaxel-induced mechanical allodynia in a mouse model of chemotherapy-induced peripheral neuropathy (CIPN). The mechanism of action for CBD- and KLS-13019-mediated protection now has been explored with dissociated dorsal root ganglion (DRG) cultures employing tiny interfering RNA (siRNA) to the mitochondrial Na+ Catwo+ exchanger-1 (mNCX-1). Remedy with this siRNA developed a 50-55% reduce in the immunoreactive (IR) location for mNCX-1 in neuronal cell bodies and a 72-80% reduce in neuritic IR location as determined with higher-content material image evaluation. Just after therapy with 100 nM KLS-13019 and siRNA, DRG cultures exhibited a 75 ± 5% reduce in protection from paclitaxel-induced toxicity whereas siRNA research with 10 μM CBD developed a 74 ± 3% reduce in protection. Remedy with mNCX-1 siRNA alone did not make toxicity. The protective action of cannabidiol and KLS-13019 against paclitaxel-induced toxicity throughout a five-h test period was substantially attenuated following a four-day knockdown of mNCX-1 that was not attributable to toxicity. These information indicate that decreases in neuritic mNCX-1 corresponded closely with decreased protection following siRNA therapy. Pharmacological blockade of mNCX-1 with CGP-37157 developed total inhibition of cannabinoid-mediated protection from paclitaxel in DRG cultures, supporting the observed siRNA effects on mechanism.