Tuesday, September 20th
Insights into the Contribution of Nav Channels to CIPN
The microtubule-targeting chemotherapeutic agents paclitaxel (PTX, stabilizer) and vincristine (Vin, destabilizer) produce painful peripheral neuropathy (CIPN), but the underlying mechanisms are not well understood. We now show that Vin-treated mice develop allodynia not accompanied by nerve damage . We also showed an up-regulation of TTX-S Na+ current in medium but not small neurons, which is mediated by Nav1.6, because mechanical allodynia was attenuated in conditional Nav1.6 KO, but not Nav1.7 KO mice. By contrast, ptx increases NaV1.7 expression in sensory neurons. Using our recently developed optical pulse-chase axonal long distance live-imaging approach , we demonstrated concentration- and time-dependent increase in vesicular trafficking and membrane localization of NaV1.7 in sensory axons. Concurrent treatment with inflammatory mediators to mimic the inflammatory condition accompanying chemotherapy, both NaV1.7 surface levels and vesicular transport are increased. Overall, our results show that Vin and PTX treatment increases levels of functional endogenous NaV1.6 and NaV1.7 channels in DRG neurons in a drug and cell-type dependent manner, and show that PTX enhances trafficking and surface distribution of NaV1.7 in sensory axons, which are augmented in the presence of an inflammatory milieu.