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Cisplatin and oxaliplatin are treatment options for a variety of cancer types. While highly efficient in killing cancer cells, both chemotherapeutics cause severe side effects, e.g., peripheral neuropathies. Using a cell viability assay, a mitochondrial stress assay, and live-cell imaging, the effects of cis- or oxaliplatin on the mitochondrial function, reactive oxygen species (ROS) production, and mitochondrial and cytosolic calcium concentration of transient receptor potential ankyrin 1 (TRPA1)- or vanilloid 1 (TRPV1)-positive dorsal root ganglion (DRG) neurons of adult Wistar rats were determined. Mitochondrial functions were impaired after exposure to cis- or oxaliplatin by mitochondrial respiratory chain complex I-III inhibition. The basal respiration, spare respiratory capacity, and the adenosine triphosphate (ATP)-linked respiration were decreased after exposure to 10 µM cis- or oxaliplatin. The ROS production showed an immediate increase, and after reaching the peak, ROS production dropped. Calcium imaging showed an increase in the cytosolic calcium concentration during exposure to 10 µM cis- or oxaliplatin in TRPA1- or TRPV1-positive DRG neurons while the mitochondrial calcium concentration continuously decreased. Our data demonstrate a significant effect of cis- and oxaliplatin on mitochondrial function as an early event of platinum-based drug exposure, suggesting mitochondria as a potential target for preventing chemotherapy-induced neuropathy.

Tumor necrosis factor- (TNF-) α is a proinflammatory cytokine involved in the development and maintenance of inflammatory and neuropathic pain. Its effects are mediated by two receptors, TNF receptor-1 (TNFR-1) and TNF receptor-2 (TNFR-2). These receptors play a crucial role in the sensitization of voltage-gated sodium channels (VGSCs), a key mechanism in the pathogenesis of chronic pain. Using the whole-cell patch-clamp technique, we examined the influence of TNFR-1 and TNFR-2 on VGSCs and TTX-resistant NaV1.8 channels in isolated rat dorsal root ganglion neurons by using selective TNFR agonists. The TNFR-1 agonist R32W (10 pg/mL) caused an increase in the VGSC current (I Na(V)) by 27.2 ± 5.1%, while the TNFR-2 agonist D145 (10 pg/mL) increased the current by 44.9 ± 2.6%. This effect was dose dependent. Treating isolated NaV1.8 with R32W (100 pg/mL) resulted in an increase in I NaV(1.8) by 18.9 ± 1.6%, while treatment with D145 (100 pg/mL) increased the current by 14.5 ± 3.7%. Based on the current-voltage relationship, 10 pg of R32W or D145 led to an increase in I Na(V) in a bell-shaped, voltage-dependent manner with a maximum effect at −30 mV. The effects of TNFR activation on VGSCs promote excitation in primary afferent neurons and this might explain the sensitization mechanisms associated with neuropathic and inflammatory pain.