Liu Jiaxin, Li Dangchao, Huang Jing, Cao Jing, Cai Guohong, Guo Yuexian, Wang Guiying, Zhao Shuang, Wang Xiuli, Wu Shengxi
Department of Anesthesiology, Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, China.
Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China.
Front Psychiatry. 2022 Apr 14;13:869544. doi: 10.3389/fpsyt.2022.869544. eCollection 2022.
Paclitaxel is widely used as a first-line chemotherapy agent to treat malignant tumors. However, paclitaxel causes peripheral nerve fiber damage and neuropathic pain in some patients. In addition, patients received paclitaxel chemotherapy are often accompanied by negative emotions such as anxiety. The amygdala is critically involved in regulating pain signals, as well as anxiety. The purpose of this study is to clarify the role of Ca/calmodulin-dependent protein kinase II (CaMKII)-positive glutamatergic neurons in the amygdala in paclitaxel-induced pain and negative affective symptoms. Intraperitoneal injection of paclitaxel into mice caused mechanical and thermal allodynia, as measured by Von Frey test and Hargreaves test, and anxiety, as measured by open field test and elevated plus maze test. Immunofluorescence staining revealed that c-fos-positive neurons were significantly more in the basolateral amygdala (BLA) and central amygdala (CeA) in paclitaxel-treated mice than untreated mice. Furthermore, part of c-fos-positive neurons in the BLA were immunoreactive of CaMKII. Engineered Designer receptors exclusively activated by designer drugs (DREADD) receptor hM4Di or hM3Dq was selectively expressed on CaMKII neurons by injection of adeno-associated virus (AAV) vectors containing CaMKII and hM4Di or hM3Dq. Administration of DREADD agonist CNO to selectively inhibit the CaMKII neurons in the BLA significantly increased the paw withdrawal thresholds and paw withdrawal latencies. In addition, selectively inhibition of CaMKII neurons in the BLA alleviated anxiety behavior without affecting the motor activity. In summary, our findings suggest that CaMKII neurons in the amygdala are critical for neuropathic pain and anxiety behaviors induced by paclitaxel chemotherapy.
紫杉醇被广泛用作治疗恶性肿瘤的一线化疗药物。然而，紫杉醇会导致一些患者出现外周神经纤维损伤和神经性疼痛。此外，接受紫杉醇化疗的患者常伴有焦虑等负面情绪。杏仁核在调节疼痛信号以及焦虑方面起着关键作用。本研究的目的是阐明杏仁核中钙/钙调蛋白依赖性蛋白激酶II（CaMKII）阳性谷氨酸能神经元在紫杉醇诱导的疼痛和负面情感症状中的作用。给小鼠腹腔注射紫杉醇会导致机械性和热性痛觉过敏，通过von Frey试验和哈格里夫斯试验测量，以及焦虑，通过旷场试验和高架十字迷宫试验测量。免疫荧光染色显示，与未处理的小鼠相比，紫杉醇处理的小鼠基底外侧杏仁核（BLA）和中央杏仁核（CeA）中c-fos阳性神经元明显更多。此外，BLA中部分c-fos阳性神经元对CaMKII呈免疫反应性。通过注射含有CaMKII和hM4Di或hM3Dq的腺相关病毒（AAV）载体，将仅由设计药物激活的工程化设计受体（DREADD）受体hM4Di或hM3Dq选择性地表达在CaMKII神经元上。给予DREADD激动剂CNO以选择性抑制BLA中的CaMKII神经元，显著提高了爪部撤离阈值和爪部撤离潜伏期。此外，选择性抑制BLA中的CaMKII神经元可减轻焦虑行为，而不影响运动活动。总之，我们的研究结果表明，杏仁核中的CaMKII神经元对紫杉醇化疗诱导的神经性疼痛和焦虑行为至关重要。
