Dynamic long-term microstructural and ultrastructural alterations in sensory nerves of rats of paclitaxel-induced neuropathic pain

Abstract

Background Paclitaxel, as a first line anti-neoplastic compound, frequently produces long-term pain after tumors have been treated. Clinical manifestations are varied and non-specific. Pathology of the nervous system during the development of the neuropathic pain is unclear. Thus, early diagnosis and treatment is often unsatisfying for patients. This study aimed to promote considerate understanding of the structural alteration of sensory nerves. Methods All rats were simply randomized into 3 groups: paclitaxel group, vehicle group and saline group. An established rat model of paclitaxel-induced peripheral neuropathy (2 mg/kg) was chosen for our research, behavior tests were operated during the procedure of 56 days. All rats were sampled on days 0, 3, 7, 28 and 56. The hind paw plantar skin, sciatic nerves, dorsal root ganglion and attached fibers, and lumbar spinal cord were processed for light and electron microscopy. The differences among 3 groups were analyzed with one-way analysis of variance (ANOVA). Results We affirmed that paclitaxel-induced mechano-allodynia and mechano-hyperalgesia occured after a 3-7-day delay, and this pain peaked at day 28 and persisted to day 56. Paclitaxel and vehicle treatment both evoked thermalhyperalgesia. Paclitaxel-induced axonal and myelin sheath degeneration was evident. At days 3 and 7, significant increases in atypical mitochondria in both myelinated axons and C-fibers of paclitaxel-treated nerves indicated that injured mitochondria correlated to specific paclitaxel-induced neuropathic pain, and the abnormity sustained till day 56. Microtubule was unaffected in myelinated axons or C-fibers in paclitaxel- or vehicle-treated rats. Significant increase of G ratio was evident with paclitaxel injection at days 7 and 28. Conclusion Our research suggests a causal role for axonal degeneration, abnormalities in axonal mitochondria, and structural modification of axonal microtubules in paclitaxel-induced neuropathic pain, and the abnormal mitochondria could be connected to the chronic neuropathic pain.