Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil.
Department of Morphology, Faculty of Medicine, Morpho-Functional Sciences Post Graduation Program, Federal University of Ceará, Fortaleza, CE, Brazil.
Neurotox Res. 2021 Dec;39(6):1782-1799. doi: 10.1007/s12640-021-00442-x. Epub 2021 Nov 18.
Oxaliplatin-induced neurotoxicity is expressed as a dose-limiting peripheral sensory neuropathy (PSN). Cannabinoid substances have been investigated for the analgesic effect. This study aimed to investigate the role of cannabinoid receptors in oxaliplatin-associated PSN. Swiss male mice received nine oxaliplatin injections (2 mg/kg, i.v.). Mechanical and thermal nociceptive tests were performed for 56 days. CB1, CB2, and c-Fos expression were assessed in dorsal root ganglia (DRG), spinal cord (SC), trigeminal ganglia (TG), spinal trigeminal nucleus caudalis (Sp5C), and periaqueductal gray (PAG). Iba-1 expression was assessed in DRG and ATF3 in TG. Cannabidiol (10 mg/kg, p.o.) or a CB1/CB2 non-selective agonist (WIN 55,212-2; 0.5 mg/kg, s.c.) or AM251 (CB1 antagonist) or AM630 (CB2 antagonist) (3 mg/kg, i.p.) were injected before oxaliplatin. Oxaliplatin increased CB1 in DRG, SC, TG, Sp5C, and ventrolateral PAG, with no interference in CB2 expression. Cannabidiol increased CB1 in DRG, reduced mechanical hyperalgesia and c-Fos expression in DRG and SC. Additionally, WIN 55,212-2 increased CB1 in DRG, reduced mechanical hyperalgesia, cold allodynia and c-Fos expression in DRG and SC. CB1 blockage hastened the cold allodynia response, but the CB2 antagonist failed to modulate the oxaliplatin-induced nociceptive behavior. Oxaliplatin also increased Iba-1 in DRG, suggesting immune response modulation which was reduced by cannabidiol and enhanced by AM630. The modulation of the endocannabinoid system, through the CB1 receptor, attenuates the oxaliplatin-associated PNS. The activation of the endocannabinoid system could be considered as a therapeutic target for controlling oxaliplatin-associated neuropathy.
奥沙利铂引起的神经毒性表现为剂量限制的周围感觉神经病（PSN）。大麻素物质已被研究用于镇痛作用。本研究旨在探讨大麻素受体在奥沙利铂相关 PSN 中的作用。瑞士雄性小鼠接受了 9 次奥沙利铂注射（2mg/kg，静脉注射）。在 56 天内进行机械和热痛觉测试。在背根神经节（DRG）、脊髓（SC）、三叉神经节（TG）、尾侧脊髓三叉神经核（Sp5C）和导水管周围灰质（PAG）中评估 CB1、CB2 和 c-Fos 的表达。在 DRG 中评估 Iba-1 的表达，在 TG 中评估 ATF3 的表达。大麻二酚（10mg/kg，口服）或 CB1/CB2 非选择性激动剂（WIN 55,212-2；0.5mg/kg，皮下注射）或 AM251（CB1 拮抗剂）或 AM630（CB2 拮抗剂）（3mg/kg，腹腔注射）在奥沙利铂之前注射。奥沙利铂增加了 DRG、SC、TG、Sp5C 和腹外侧 PAG 中的 CB1，而对 CB2 的表达没有干扰。大麻二酚增加了 DRG 中的 CB1，减轻了机械性痛觉过敏和 DRG 和 SC 中的 c-Fos 表达。此外，WIN 55,212-2 增加了 DRG 中的 CB1，减轻了机械性痛觉过敏、冷痛觉过敏和 DRG 和 SC 中的 c-Fos 表达。CB1 阻断加速了冷痛觉过敏反应，但 CB2 拮抗剂未能调节奥沙利铂引起的痛觉行为。奥沙利铂还增加了 DRG 中的 Iba-1，表明免疫反应调节，大麻二酚减少，AM630 增强。通过 CB1 受体调节内源性大麻素系统可减轻奥沙利铂相关的 PNS。激活内源性大麻素系统可被视为控制奥沙利铂相关神经病变的治疗靶点。
