Melatonin Induces Analgesic Effects through MT 2 Receptor-Mediated Neuroimmune Modulation in the Mice Anterior Cingulate Cortex

作者：Jian Wang, Junxiang Gu, Fujuan Ma, Yi Wei, Pan Wang, Shanming Yang, Xianxia Yan, Yifan Xiao, Ke-Ke Xing, Anxin Lou, Liru Zheng, Tingting Cao, Dayu Zhu, Jinlian Li, Luoying Zhang, Yun-Qing Li, Tao Chen · 发表于：Research · 年份：2024 · DOI：10.34133/research.0493 · 被引用次数：12 · 研究领域：Circadian rhythm and melatonin、Stress Responses and Cortisol、Sleep and Wakefulness Research

Neuropathic pain (NP) represents a considerable clinical challenge, profoundly impacting patients’ quality of life. Presently, pharmacotherapy serves as a primary approach for NP alleviation, yet its efficacy often remains suboptimal. Melatonin (MLT), a biologically active compound secreted by the pineal gland, has long been associated with promoting and maintaining sleep. Although recent studies suggest analgesic effects of MLT, the underlying mechanism remains largely unknown, particularly its impact on the cortex. In this study, we induced an NP model in mice through spared nerve injury (SNI) and observed a considerable, dose-dependent alleviation in NP symptoms following intraperitoneal or anterior cingulate cortex (ACC) administration of MLT. Our findings further indicated that the NP management of MLT is selectively mediated by MLT-related receptor 2 (MT 2 R), rather than MT 1 R, on neurons and microglia within the ACC. Transcriptome sequencing, complemented by bioinformatics analysis, implicated MLT in the modulation of Gα(i) and immune-inflammatory signals. Specifically, MLT inhibited the excitability level of pyramidal cells in the ACC by activating the Gα(i) signaling pathway. Simultaneously, MLT attenuated M 1 polarization and promoted M 2 polarization of microglia, thereby mitigating the inflammatory response and type II interferon response within the ACC. These findings unveil a hitherto unrecognized molecular mechanism: an MLT-mediated neuroimmune modulation pat...