Angiogenesis-Related New Mechanisms for Chemotherapy-Induced Painful Peripheral Neuropathy in the Rat

Chemotherapy-induced painful peripheral neurotoxicity (painful-CIPN), with paresthesia, numbness, dysaesthesia, and neuropathic pain ranks among the most common dose-limiting toxicity of widely used anticancer drugs. Beside peripheral neurons, for several years considered the only reasonable target for painful-CIPN study, the recent evaluation of the microvascular angiogenesis in the somatosensory pathway, reveals other important actors in the neuropathic pain development and chronicization. To elucidate the relation between chemotherapy-induced neuropathic pain and vascular alterations, we evaluated the microvasculature in central and peripheral nervous compartments of rats exposed to neurotoxic chemotherapy. Rats were treated with paclitaxel 10 mg/kg once a week for 4 weeks, or with cisplatin 2mg/kg twice a week for 4 weeks or with their vehicles. Animals were tested for neurophysiological abnormalities and pain before and after the treatments. Post-mortem samples were analyzed at synchrotron radiation sources by X-ray Phase-Contrast Tomography (XPCT) Imaging and processed for quantitative and morphological analyses of microvascular structures. Complementarily, histochemical and molecular evaluations were performed to validate the results. XPCT analysis revealed that rats exposed to paclitaxel (affected by a painful sensory axonopathy) showed an increased vascular density (putative sprouting angiogenesis) in the crucial districts of the central (somatosensory cortex and lumbar spinal cord) and peripheral nervous system (lumbar Dorsal Root Ganglia and peripheral nerves). However, the complexity of the vascular network and the size of neo-formed vessels were significantly decreased in some specific regions. On the other hand, no significant changes were observed in rats exposed to CDDP (affected by a painless mild neuronopathy) suggesting a specific involvement of neo-angiogenesis in the development of neuropathic pain. Molecular analysis performed on the DRG and S1 cortex confirmed alterations in the expression of genes involved in the angiogenesis. These results can contribute to shed light on new pathogenetic mechanisms and potential novel therapeutic approaches for painful CIPN.