Overtime Characterization of Vascular Network in the Peripheral Nervous System of Rats With Paclitaxel-Induced Painful Peripheral Neuropathy

Introduction: Painful peripheral neurotoxicity, with paresthesia, numbness, dysaesthesia, and neuropathic pain ranks among the most common dose-limiting toxicity of paclitaxel, one of the most widely employed anticancer drugs. Beside peripheral neurons, for several years considered the only reasonable target for neurotoxicity, our recent evaluations in the somatosensory pathway, reveals the microvascular angiogenesis as an important factor in the neuropathic pain development and chronicization. Methods: In this work, we explore the time-dependent changes in the vascular network in the peripheral nervous system during the onset, development, and chronicization of paclitaxel-induced painful neuropathy. To this aim, rats were treated with paclitaxel 10 mg/kg once a week for 4 weeks or with its vehicle. Animals were tested for neurophysiological abnormalities and pain during and after the treatment schedule (24 h after the first infusion, after 2 and 4 drug infusions and after 4 weeks of follow up. Post-mortem samples, collected at each timepoint, were analyzed at synchrotron radiation sources by x-ray tomography. Results: By reconstructing the vascular network of the sciatic nerve we found two differences between the vehicle and the paclitaxel groups over the time points. While the overall vascular density increased between vehicle and paclitaxel groups at 4 and 8 weeks from the first infusion, the average vascular diameter did not vary significantly. Interestingly, a measure of curviness significantly and increasingly dropped starting at 2 weeks in the paclitaxel group indicating that capillaries were more straight. In addition, the average distance to the nearest vessel increased significantly up to 8 weeks. Conclusions: In conclusion, data from tomographic reconstructions of vascular architecture showed that paclitaxel produced aberrant remodelling in the peripheral nerve where despite the putative angiogenesis occurring as early as at 2 weeks from the starting of paclitaxel infusions, nervous tissue could be hypoperfused.