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Research Articles, Cellular/Molecular

G-Protein-Coupled Estrogen Receptor (GPER) in the Rostral Ventromedial Medulla Is Essential for Mobilizing Descending Inhibition of Itch

Ting Gao, Li Dong, Jiahong Qian, Xiaowei Ding, Yi Zheng, Meimei Wu, Li Meng, Yingfu Jiao, Po Gao, Ping Luo, Guohua Zhang, Changhao Wu, Xueyin Shi and Weifang Rong
Journal of Neuroscience 15 September 2021, 41 (37) 7727-7741; https://doi.org/10.1523/JNEUROSCI.2592-20.2021
Ting Gao
1Department of Anesthesiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
2Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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Li Dong
1Department of Anesthesiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
2Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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Jiahong Qian
2Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
3Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
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Xiaowei Ding
1Department of Anesthesiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
2Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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Yi Zheng
2Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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Meimei Wu
1Department of Anesthesiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
2Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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Li Meng
2Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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Yingfu Jiao
2Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
3Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
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Po Gao
2Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
3Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
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  • ORCID record for Po Gao
Ping Luo
2Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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Guohua Zhang
2Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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Changhao Wu
4School of Biosciences and Medicine, University of Surrey, Guildford, Surrey GU2 7XH, England
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Xueyin Shi
1Department of Anesthesiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
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Weifang Rong
1Department of Anesthesiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
2Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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Abstract

Chronic itch is a troublesome condition and often difficult to cure. Emerging evidence suggests that the periaqueductal gray (PAG)-rostral ventromedial medulla (RVM) pathway may play an important role in the regulation of itch, but the cellular organization and molecular mechanisms remain incompletely understood. Here, we report that a group of RVM neurons distinctively express the G-protein-coupled estrogen receptor (GPER), which mediates descending inhibition of itch. We found that GPER+ neurons in the RVM were activated in chronic itch conditions in rats and mice. Selective ablation or chemogenetic suppression of RVM GPER+ neurons resulted in mechanical alloknesis and increased scratching in response to pruritogens, whereas chemogenetic activation of GPER+ neurons abrogated itch responses, indicating that GPER+ neurons are antipruritic. Moreover, GPER-deficient mice and rats of either sex exhibited hypersensitivity to mechanical and chemical itch, a phenotype reversible by the µ type opioid receptor (MOR) antagonism. Additionally, significant MOR phosphorylation in the RVM was detected in chronic itch models in wild-type but not in GPER−/− rats. Therefore, GPER not only identifies a population of medullary antipruritic neurons but may also determine the descending antipruritic tone through regulating µ opioid signaling.

SIGNIFICANCE STATEMENT Therapeutic options for itch are limited because of an as yet incomplete understanding of the mechanisms of itch processing. Our data have provided novel insights into the cellular organization and molecular mechanisms of descending regulation of itch in normal and pathologic conditions. GPER+ neurons (largely GABAergic) in the RVM are antipruritic neurons under tonic opioidergic inhibition, activation of GPER promotes phosphorylation of MOR and disinhibition of the antipruritic GPER+ neurons from inhibitory opioidergic inputs, and failure to mobilize GPER+ neurons may result in the exacerbation of itch. Our data also illuminate on some of the outstanding questions in the field, such as the mechanisms underlying sex bias in itch, pain, and opioid analgesia and the paradoxical effects of morphine on pain and itch.

  • µ type opioid receptor
  • G-protein-coupled estrogen receptor
  • itch
  • rostral ventromedial medulla

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The Journal of Neuroscience: 41 (37)
Journal of Neuroscience
Vol. 41, Issue 37
15 Sep 2021
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G-Protein-Coupled Estrogen Receptor (GPER) in the Rostral Ventromedial Medulla Is Essential for Mobilizing Descending Inhibition of Itch
Ting Gao, Li Dong, Jiahong Qian, Xiaowei Ding, Yi Zheng, Meimei Wu, Li Meng, Yingfu Jiao, Po Gao, Ping Luo, Guohua Zhang, Changhao Wu, Xueyin Shi, Weifang Rong
Journal of Neuroscience 15 September 2021, 41 (37) 7727-7741; DOI: 10.1523/JNEUROSCI.2592-20.2021

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G-Protein-Coupled Estrogen Receptor (GPER) in the Rostral Ventromedial Medulla Is Essential for Mobilizing Descending Inhibition of Itch
Ting Gao, Li Dong, Jiahong Qian, Xiaowei Ding, Yi Zheng, Meimei Wu, Li Meng, Yingfu Jiao, Po Gao, Ping Luo, Guohua Zhang, Changhao Wu, Xueyin Shi, Weifang Rong
Journal of Neuroscience 15 September 2021, 41 (37) 7727-7741; DOI: 10.1523/JNEUROSCI.2592-20.2021
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Keywords

  • µ type opioid receptor
  • G-protein-coupled estrogen receptor
  • itch
  • rostral ventromedial medulla

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