Department of Anesthesiology, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, China.
Department of Anesthesiology, Jinan Maternity and Child Health Care Hospital, Jinan, China.
Neurosci Lett. 2022 Mar 16;773:136512. doi: 10.1016/j.neulet.2022.136512. Epub 2022 Feb 8.
Painful peripheral neuropathy is a common dose-limiting side effect of chemotherapeutic paclitaxel (PTX) treatment. The American Society of Clinical Oncology (ASCO) recommends duloxetine (DUL) as a promising treatment alternative for chemotherapy-induced peripheral neuropathic pain. However, this recommendation lacks a robust theoretical basis and supporting data. To elucidate the involvement of transient receptor potential vanilloid 1 (TRPV1) in the analgesic effect of DUL for PTX-induced neuropathic pain, TRPV1 expression in the lumbar dorsal root ganglion (DRG) and spinal cord was evaluated following intraperitoneal administration of PTX (2 mg/kg/day) for four alternate days in rats. Western blot and immunohistochemistry suggested that a cumulative dosage of PTX (8 mg/kg) upregulated TRPV1 expression in the lumbar DRG and spinal dorsal horn (SDH) at day 14 post treatment. TRPV1 upregulation in the DRG was mainly expressed in calcitonin gene-related peptide (CGRP) and IB-4 positive small-size sensory neurons. Additionally, PTX increased CGRP and substance P (SP) expression in the DRG and SDH, induced SDH microglia and astrocyte activation, and upregulated spinal tumor necrosis factor-α (TNF-α) but not IL-1β or IL-10 expression. Behavioral detection showed that PTX-related mechanical and thermal hyperalgesia was significantly inhibited by consecutive administration of DUL 20 mg/kg/day greater than 10 mg/kg/day for 5 days starting at day 10 post PTX injection. Furthermore, DUL (20 mg/kg/day) for 5 days markedly ameliorated PTX-induced TRPV1, CGRP, and SP upregulation in the DRG and SDH, and mitigated PTX-induced spinal cord glia activation and TNF-α expression. Moreover, the pharmacological blockade of TRPV1 resulted in an analgesic effect on PTX-induced hyperalgesia. Collectively, these results suggest that DUL alleviates PTX-induced peripheral neuropathic pain by suppressing TRPV1 upregulation in the lumbar DRG and SDH, which is followed by a reduction in CGRP and SP release, as well as spinal glia activation and TNF-α expression.
痛性周围神经病变是化疗药物紫杉醇（PTX）治疗的常见剂量限制副作用。美国临床肿瘤学会（ASCO）建议度洛西汀（DUL）作为治疗化疗诱导性周围神经性疼痛的一种有前途的替代方法。然而，这一建议缺乏强有力的理论基础和支持数据。为了阐明瞬时受体电位香草素 1（TRPV1）在 DUL 治疗 PTX 诱导的神经性疼痛中的作用机制，我们在大鼠中连续 4 天腹腔注射 PTX（2mg/kg/天），评估了 PTX 后第 14 天腰椎背根神经节（DRG）和脊髓中 TRPV1 的表达。Western blot 和免疫组织化学分析表明，累积剂量的 PTX（8mg/kg）在治疗后第 14 天上调了腰椎 DRG 和脊髓背角（SDH）中 TRPV1 的表达。DRG 中 TRPV1 的上调主要在降钙素基因相关肽（CGRP）和 IB-4 阳性小感觉神经元中表达。此外，PTX 增加了 DRG 和 SDH 中 CGRP 和 P 物质（SP）的表达，诱导了 SDH 小胶质细胞和星形胶质细胞的激活，并上调了脊髓肿瘤坏死因子-α（TNF-α）的表达，但不影响白细胞介素-1β（IL-1β）或白细胞介素-10（IL-10）的表达。行为检测表明，从 PTX 注射后第 10 天开始，连续 5 天每天给予 DUL 20mg/kg，对 PTX 相关的机械性和热痛觉过敏有显著抑制作用，大于每天 10mg/kg。此外，DUL（20mg/kg/天）连续 5 天显著改善了 PTX 诱导的 DRG 和 SDH 中 TRPV1、CGRP 和 SP 的上调，并减轻了 PTX 诱导的脊髓胶质细胞激活和 TNF-α的表达。此外，TRPV1 的药理学阻断导致对 PTX 诱导的痛觉过敏有镇痛作用。综上所述，这些结果表明，DUL 通过抑制腰椎 DRG 和 SDH 中 TRPV1 的上调，减轻 PTX 诱导的周围神经性疼痛，从而减少 CGRP 和 SP 的释放，以及脊髓胶质细胞的激活和 TNF-α的表达。
