Nonclassical receptor mechanisms by estrogen regulation of pain perception and opioid analgesia and itching

On November 8, the Journal of Clinical Investigation published online the collaborative paper "Molecular identification of bulbospinal ON neurons by GPER which drives pain and" by Rong Weifang's research group from the Department of Anatomy and Physiology of the School of Basic Medical Sciences, Yu Weifeng, Department of Anesthesiology, Renji Hospital, and Shi Xueyin, Department of Anesthesiology, Xinhua Hospital morphine tolerance", reports the mechanism
by which estrogen regulates pain and opioid analgesia through non-classical receptors (G protein-coupled estrogen receptors, GPER).

Pain sensation is an indispensable defense mechanism of the body, but chronic pathological pain also afflicts countless patients
.
Opioids such as morphine have strong analgesic effects, but side effects such as tolerance, addiction, and respiratory depression greatly limit their clinical use
.
Rong Weifang's research group and its collaborative team explored the regulatory role
of estrogen on pain perception based on the significant gender difference between pain and opioid analgesia.
It was found that in the downward regulatory system of pain perception (RVM in the ventral medial part of the medulla oblongata), there is a class of GABA long-term projection neurons that specifically express GPER, and such neurons descend to facilitate the upward transmission of pain information (ON neurons) in the dorsal corner of the spinal cord; Estrogen binds to GPER, promotes phosphorylation of m-type opioid receptor (MOR) through the PLC-Ca2⁺-PKC pathway, and decouples it from potassium channels, thereby mediating the "de-inhibition" of ON neurons, thereby enhancing pain perception and reducing opioid analgesia
.

In 2021, Rong Weifang's research group and Shi Xueyin's team published a collaborative paper in the Journal of Neurosciece, reporting the mechanism
of GPER at the RVM site inhibiting itching by mediating opioid receptor phosphorylation.
These two works provide new evidence
for understanding the receptor and circuit mechanisms of central pain sensitivity, pain suppression, opioid analgesia but itching, and opioid tolerance.

Jiao Yingfu, Gao Po, Dong Li, Ding Xiaowei and Meng Youqiang, doctoral students (graduates) of Rong Weifang's research group, are the co-first authors of the JCI paper, and Gao Ting, Dong Li and Qian Jiahong are the co-first authors
of the Journal of Neurosciece paper.
The research work has been supported
by the National Natural Science Foundation of China, the Shanghai Municipal Science and Technology Commission and the Shanghai Municipal Education Commission.