Molecular identification of bulbospinal ON neurons by GPER, which drives pain and morphine tolerance.
Molecular identification of bulbospinal ON neurons by GPER, which drives pain and morphine tolerance.
复制标题
DOI：
10.1172/jci154588
复制
发表时间：
2023-01-03
影响因子：
15.9
通讯作者：
Rong, Weifang
中科院分区：
文献类型：
--
作者：
Jiao, Yingfu;Gao, Po;Dong, Li;Ding, Xiaowei;Meng, Youqiang;Qian, Jiahong;Gao, Ting;Wang, Ruoxi;Jiang, Tao;Zhang, Yunchun;Kong, Dexu;Wu, Yi;Chen, Sihan;Xu, Saihong;Tang, Dan;Luo, Ping;Wu, Meimei;Meng, Li;Wen, Daxiang;Wu, Changhao;Zhang, Guohua;Shi, Xueyin;Yu, Weifeng;Rong, Weifang
延髓吻侧腹内侧区(RVM)对痛觉具有双向下行调制作用，这归因于电生理识别的伤害性前感受性神经元和抗伤害性感受性神经元的活动。在此，我们报道了神经元上的GABA能特异性表达G蛋白偶联雌激素受体(GPER)。GPER+神经元对外周伤害性刺激表现出典型的ON反应。GPER+神经元的光发生激活促进了疼痛，但它们的消融作用被取消了。此外，激活GPER可通过脱敏μ阿片受体介导的(MOR介导的)钾电流激活，引起ON细胞的去极化，增强疼痛，并减轻吗啡的镇痛作用。相反，在不同的临床前疼痛模型中，基因消融或药物阻断GPER可以减轻疼痛，增强吗啡镇痛，并延缓吗啡耐受的发展。我们的数据有力地表明GPER是细胞上GABA能的标志物，并阐明了激素调节疼痛和镇痛的机制，从而强调GPER是治疗疼痛和阿片耐受的一个有前途的靶点。
The rostral ventromedial medulla (RVM) exerts bidirectional descending modulation of pain attributable to the activity of electrophysiologically identified pronociceptive ON and antinociceptive OFF neurons. Here, we report that GABAergic ON neurons specifically express G protein–coupled estrogen receptor (GPER). GPER+ neurons exhibited characteristic ON-like responses upon peripheral nociceptive stimulation. Optogenetic activation of GPER+ neurons facilitated, but their ablation abrogated, pain. Furthermore, activation of GPER caused depolarization of ON cells, potentiated pain, and ameliorated morphine analgesia through desensitizing μ-type opioid receptor–mediated (MOR-mediated) activation of potassium currents. In contrast, genetic ablation or pharmacological blockade of GPER attenuated pain, enhanced morphine analgesia, and delayed the development of morphine tolerance in diverse preclinical pain models. Our data strongly indicate that GPER is a marker for GABAergic ON cells and illuminate the mechanisms underlying hormonal regulation of pain and analgesia, thus highlighting GPER as a promising target for the treatment of pain and opioid tolerance.