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
View: Text | PDF
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

×

Figure 6

Activation of GPER inhibits μ-opioid signaling in a calcium-dependent manner.

Options: View larger image (or click on image) Download as PowerPoint
Activation of GPER inhibits μ-opioid signaling in a calcium-dependent ma...
(A) Immunofluorescence showing coexpression of MOR and GPER in the RVM of female rats. Scale bar: 50 μm. (B) Percentage of neurons coexpressing MOR and GPER in the RVM of WT rats. (C and D) Electrophysiologically identified RVM ON cells (n = 9) were all immunoreactive to MOR. Scale bar: 100 μm. (E and F) Morphine-induced inhibition of RVM ON cells was diminished by prior treatment with E2 in the rat in vivo. n = 5–6 cells/group. (G to J) GPER activation with E2 negated DAMGO-induced hyperpolarization in medulla slices in vitro. The effect of E2 was calcium dependent, since the presence of BAPTA (a calcium chelator) in the pipette solution prevented this effect. n = 6–10 cells/group. Data are representative of at least 3 independent experiments and are presented as the mean ± SEM. *P < 0.05 and **P < 0.01, by 2-way ANOVA followed by Bonferroni’s post hoc test (F) and paired, 2-tailed Student’s t test (I).