Molecular identification of bulbospinal ON neurons by GPER, which drives pain and morphine tolerance
Yingfu Jiao, Po Gao, Li Dong, Xiaowei Ding, Youqiang Meng, Jiahong Qian, Ting Gao, Ruoxi Wang, Tao Jiang, Yunchun Zhang, Dexu Kong, Yi Wu, Sihan Chen, Saihong Xu, Dan Tang, Ping Luo, Meimei Wu, Li Meng, Daxiang Wen, Changhao Wu, Guohua Zhang, Xueyin Shi, Weifeng Yu, Weifang Rong
Yingfu Jiao, Po Gao, Li Dong, Xiaowei Ding, Youqiang Meng, Jiahong Qian, Ting Gao, Ruoxi Wang, Tao Jiang, Yunchun Zhang, Dexu Kong, Yi Wu, Sihan Chen, Saihong Xu, Dan Tang, Ping Luo, Meimei Wu, Li Meng, Daxiang Wen, Changhao Wu, Guohua Zhang, Xueyin Shi, Weifeng Yu, Weifang Rong
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Research Article Neuroscience

Molecular identification of bulbospinal ON neurons by GPER, which drives pain and morphine tolerance

Abstract

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.

Authors

Yingfu Jiao, Po Gao, Li Dong, Xiaowei Ding, Youqiang Meng, Jiahong Qian, Ting Gao, Ruoxi Wang, Tao Jiang, Yunchun Zhang, Dexu Kong, Yi Wu, Sihan Chen, Saihong Xu, Dan Tang, Ping Luo, Meimei Wu, Li Meng, Daxiang Wen, Changhao Wu, Guohua Zhang, Xueyin Shi, Weifeng Yu, Weifang Rong

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Figure 1

Estrogen facilitates pain and ameliorates morphine analgesia through activation of GPER.

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Estrogen facilitates pain and ameliorates morphine analgesia through act...
(A) Schematic showing the experimental model in which the influence of E2 on the descending pain modulation system was tested. The image at the upper right corner shows a typical injection site labeled through microinjection of 1% pontamine sky blue. (B) Sequential recordings showing morphine inhibited, whereas E2 potentiated, the VMR. (C) Relative change in CRD-induced VMR responses following local administration of morphine or E2 to the RVM, with the black line showing that morphine analgesia was negated 15 minutes after intracisternal application of E2. n = 6 rats/group. (D) Double immunofluorescence showing distinctive GPER expression in the RVM in adult female rats. Note the lower left panel, which shows that GPER expression was exclusively confined to nonserotonergic neurons. The inset in the upper panel shows a 5-HT+ terminal fiber in close proximity to a GPER+ soma. The lower right panel shows GPER expression in DiI-labeled neurons, with the inset showing DiI fluorescence on the dorsal surface of the thoracic spinal cord (SC) where DiI was applied. Scale bars: 200 μm (upper panel), 10 μm (inset in upper panel, 20 μm (lower panels), and 300 μm (inset in lower right panel). (E) Brain slice electrophysiology showing that E2 caused rapid depolarization of RVM neurons in WT female rats. (F and G) E2-induced membrane depolarization was absent in the presence of G15 and in Gper–/– rats. (H) Average amplitude of membrane depolarization induced by different concentrations of E2. n = 10–14 cells/group. (I) Negating effects of G15 and Gper deficiency on E2-induced membrane depolarization. n = 7–8/group. Data are representative of at least 3 independent experiments and are presented as the mean ± SEM. **P < 0.01 and ****P < 0.0001, by 1-way ANOVA followed by Tukey’s post hoc test (C, H, and I).