Dynamic long‐term microstructural and ultrastructural alterations in sensory nerves of rats of paclitaxel‐induced neuropathic pain
Dynamic long‐term microstructural and ultrastructural alterations in sensory nerves of rats of paclitaxel‐induced neuropathic pain
复制标题
紫杉醇诱导的神经病理性疼痛大鼠感觉神经的动态长期微观结构和超微结构改变
作者：
Wu Yuan;Li Jun;Junfei Zhou;Feng Yi
背景紫杉醇作为一线抗肿瘤化合物，在肿瘤治疗后经常产生长期疼痛。临床表现多种多样且无特异性。在神经性疼痛的发展过程中神经系统的病理学尚不清楚。因此，早期诊断和治疗往往不能令患者满意。本研究旨在促进对感觉神经结构变化的全面理解。方法将大鼠随机分为紫杉醇组、溶剂组和生理盐水组。选择已建立的紫杉醇诱导的周围神经病变大鼠模型（2 mg/kg）进行研究，在56天的过程中进行行为学测试。在第0、3、7、28和56天对所有大鼠取样。后爪足底皮肤，坐骨神经，背根神经节和附着纤维，和腰脊髓进行光镜和电镜处理。采用单因素方差分析（ANOVA）分析3组之间的差异。结果我们证实紫杉醇诱导的机械性异常性疼痛和机械性痛觉过敏在延迟3 - 7天后发生，这种疼痛在第28天达到峰值，并持续到第56天。安慰剂和赋形剂治疗均诱发热痛觉过敏。紫杉醇诱导的轴突和髓鞘变性明显。在第3天和第7天，紫杉醇处理的神经的有髓轴突和C纤维中的非典型线粒体显著增加，表明受损的线粒体与特异性紫杉醇诱导的神经性疼痛相关，并且疼痛持续至第56天。紫杉醇或溶剂处理大鼠的有髓轴突或C纤维中微管未受影响。在第7天和第28天注射紫杉醇后，G比明显增加。结论紫杉醇诱导的慢性神经病理性疼痛与轴突变性、轴突线粒体异常及轴突微管结构改变有关，线粒体异常可能与慢性神经病理性疼痛有关。
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.