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

Chronic itch is a troublesome condition and often difficult to cure. Emerging evidence suggests that the periaqueductal gray-rostral ventromedial medulla (PAG-RVM) pathway may play an important role in 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 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 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 StatementTherapeutic options for itch are limited due to 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 pathological conditions: GPER+ neurons (largely GABAergic) in the RVM are anti-pruritic neurons under tonic opioidergic inhibition; activation of GPER promotes phosphorylation of MOR and dis-inhibition of the anti-pruritic GPER+ neurons from inhibitory opioidergic inputs; failure to mobilize GPER+ neurons may result in 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.