Li Xin, Tong Jiayu, Yuan Xinru, Zhang Xiaoxuan, Yu Haonan, Xing Chunlei, Wu Jingxiang, Qiu Yuwei, You Xingji
School of Medicine, Shanghai University, Shanghai, China.
Department of Anesthesiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
Brain Behav. 2025 May;15(5):e70555. doi: 10.1002/brb3.70555.
Bone cancer pain (BCP), characterized by neuropathic and inflammatory components due to bone metastasis and immune responses, remains a significant clinical challenge. Asiaticoside (AS), an active compound derived from Centella asiatica, exhibits diverse pharmacological properties and holds promise for BCP treatment. In this study, we investigated the mechanisms underlying AS-mediated pain relief.
By analyzing the expression of the activity-induced immediate-early gene c-Fos and performing whole-brain mapping to identify activated regions after the treatment of AS. Chemogenetic approaches were employed to selectively activate or inhibit glutamatergic and GABAergic neurons in the IL region.
Our findings revealed that the infralimbic cortex (IL) plays a critical role in AS-induced analgesia. Further analysis demonstrated that GABAergic neurons, rather than glutamatergic neurons, were predominantly activated in the IL region, suggesting their involvement in pain alleviation. Moreover, AS significantly alleviated BCP by activating GABAergic neurons, while their inhibition attenuated the analgesic effect. In contrast, modulation of glutamatergic neurons had no significant impact on pain relief. These findings indicate that GABAergic neurons in the IL are essential for the antinociceptive effects of AS.
In conclusion, our study demonstrates that AS alleviates BCP by selectively targeting GABAergic neurons in the infralimbic cortex, providing a potential therapeutic strategy for managing BCP. This work highlights the importance of GABAergic signaling in pain modulation and offers new insights into the development of targeted therapies for cancer-induced pain.
骨癌疼痛（BCP）由于骨转移和免疫反应具有神经性和炎症性成分，仍然是一个重大的临床挑战。积雪草苷（AS）是一种从积雪草中提取的活性化合物，具有多种药理特性，有望用于治疗BCP。在本研究中，我们调查了AS介导的疼痛缓解机制。
通过分析活性诱导即刻早期基因c-Fos的表达，并进行全脑图谱分析以确定AS治疗后激活的区域。采用化学遗传学方法选择性激活或抑制IL区域的谷氨酸能和γ-氨基丁酸能神经元。
我们的研究结果表明，边缘下皮质（IL）在AS诱导的镇痛中起关键作用。进一步分析表明，IL区域主要激活的是γ-氨基丁酸能神经元而非谷氨酸能神经元，提示它们参与了疼痛缓解。此外，AS通过激活γ-氨基丁酸能神经元显著减轻了BCP，而抑制这些神经元则减弱了镇痛效果。相比之下，调节谷氨酸能神经元对疼痛缓解没有显著影响。这些发现表明，IL中的γ-氨基丁酸能神经元对AS的抗伤害感受作用至关重要。
总之，我们的研究表明，AS通过选择性靶向边缘下皮质中的γ-氨基丁酸能神经元来减轻BCP，为管理BCP提供了一种潜在的治疗策略。这项工作突出了γ-氨基丁酸能信号在疼痛调节中的重要性，并为癌症诱导疼痛的靶向治疗开发提供了新的见解。
