Recently, Prof. Xie Wei’s team from the School of Life Science and Technology, SEU and the MOE Key Laboratory of Developmental Genes and Human Diseases, in 

collaboration with the research team led by the group from Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, published a research paper titled “Neurexin 

regulates mechanical nociceptive sensitization by central inhibition in Drosophila” in Science Advances, an international academic journal. The study found thatnrx mutations 

result in mechanical nociceptive sensitization in an animal model and systematically elucidated the molecular and neural circuit mechanisms by which NRX regulates this 

process through central inhibition.

Pain is a protective warning signal against potential bodily harm, and its abnormal regulation is closely associated with conditions such conditions as chronic pain. Although 

the mechanisms underlying chronic pain induced by inflammation and nerve injury have been widely studied, the synaptic and circuit mechanisms remain largely elusive. 

Presynaptic adhesion molecules Neurexins (NRXs) are critical regulators of synaptic function, and their genetic variants are closely linked to various neuropsychiatric 

disorders(such as autism spectrum disorder and schizophrenia). Patients with these disorders often exhibit complex sensory abnormalities, such as chronic pain, mechanical 

hypoalgesia, and sensitization, suggesting that NRX, a molecule closely associated with synaptic connectivity, may play a broad and fundamental role in sensory perception.

Using Drosophila as a model, the research team discovered that loss ofnrx significantly enhanced larval responses to mechanical stimuli, manifesting as mechanical 

nociceptive sensitization. Through further circuit mapping in the central nervous system, this study identified and named a pair of central cholinergic neurons in the 

sub-esophageal zone (SEZ), referred to as TENCS (Twelve E Nine Cholinergic neurons in the SEZ), and found that NRX plays a critical inhibitory role in these neurons. 

TENCS neurons form a functional circuit with peripheral C4da nociceptors and downstream Goro neurons, and their excitability is regulated by NRX, thereby maintaining 

the homeostasis of mechanical nociception.

NRX maintains the excitability of TENCS neurons by regulating presynaptic GABAB receptor signaling. Knockdown of nrx reduces the membrane localization of GABAB 

receptors, weakens presynaptic inhibition, increases the excitability of TENCS neurons, and thus amplifies nociceptive signal transmission in the purely modulatory parallel 

pathway of C4da→TENCS→Goro. Further investigation revealed that NRX forms a complex with GABAB receptors and promotes their proper localization at the presynaptic 

membrane. Loss of NRX disrupts this localization and impairs presynaptic GABA inhibition, ultimately leading to nociceptive sensitization.

This study reveals the critical role of NRX in mechanical nociceptive sensitization and elucidates the molecular and circuit mechanisms underlying the maintenance of 

nociceptive balance through regulating presynaptic GABAB signaling in TENCS neurons. The findings provide new experimental evidence for understanding synaptic 

dysfunction in chronic pain and lay a theoretical foundation for neuro-intervention strategies targeting the NRX–GABAB pathway.

Prof. Xie Wei from the School of Life Science and Technology at SEU, and Gu Pengyu from Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, are the 

co-corresponding authors of this study. Meng Zhu, a Ph.D. candidate from the School of Life Science and Technology, SEU, is the first author of the paper. Other co-authors 

contributing to this research include Han Junhai, Geng Junhua, Xu Lizhong, Zhao Yu, and Ou Mengzhu from the School of Life Science and Technology, SEU, Sun Yichen 

from Nanjing Forestry University, and Wang Yuedong from Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, contributed as co-authors to this research.

Source: School of Life Science and Technology, SEU

Translated by: Melody Zhang

Proofread by: Gao Min

Edited by: Li Xinchang