Recently, the research group of Xie Wei from our institute and the Key Laboratory of Developmental Genes and Human Diseases, in collaboration with the research group of Gu Pengyu from Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, discovered that nrx mutations lead to mechanical nociceptive sensitization and systematically elucidated the molecular and neural circuit basis by which NRX regulates this process through central inhibition mechanisms. The related research findings were formally published online on December 17, 2025, in the international academic journal Science Advances (Neurexin regulates mechanical nociceptive sensitization by central inhibition in Drosophila).
Pain is a protective warning from the body against potential harm, and its abnormal regulation is closely associated with conditions such as chronic pain. Although the mechanisms of chronic pain induced by inflammation and nerve injury have been extensively studied, the synaptic and circuit mechanisms are far from being fully understood. The presynaptic adhesion molecule Neurexins (NRXs) are critical regulators of synaptic function, and their genetic variations are closely linked to various neuropsychiatric disorders (such as autism spectrum disorder and schizophrenia). These patients often exhibit complex perceptual abnormalities, including accompanying symptoms like chronic pain, mechanical hypoalgesia, and sensitization, suggesting that NRX, a molecule closely associated with synaptic connectivity, plays a broad and universal role in perception.
Using Drosophila as a model, the research team found that loss of nrx significantly enhances larval responses to mechanical stimuli, manifesting as mechanical nociceptive sensitization. Through further localization analysis of the central nervous system, this study identified and named a pair of central cholinergic neurons located in the subesophageal zone (SEZ) for the first time: TENCS (TwelveENineCholinergic neurons in the SEZ). It was discovered that NRX plays a crucial negative regulatory role in these TENCS neurons. TENCS neurons form a functional circuit with peripheral nociceptors C4da and downstream Goro neurons. The excitability of TENCS neurons is regulated by NRX, thereby maintaining the homeostasis of mechanical nociception.
NRX maintains the excitatory balance 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 consequently amplifies nociceptive signal transmission in the purely modulatory parallel pathway C4da→TENCS→Goro. Further research found that NRX can form a complex with the GABAB receptor and promote its proper localization at the presynaptic membrane. Loss of NRX disrupts this localization, impairs presynaptic GABA inhibition, and ultimately leads to nociceptive sensitization.
In summary, this study reveals the critical role of NRX in mechanical nociceptive sensitization and elucidates the molecular and circuit mechanisms by which it maintains nociceptive balance through regulating presynaptic GABAB signaling in TENCS neurons. This discovery provides new experimental evidence for understanding synaptic dysfunction in chronic pain and lays a theoretical foundation for neural intervention strategies targeting the NRX–GABAB pathway.
Schematic Diagram of NRX Regulating Mechanical Nociceptive Sensitization in Drosophila Larvae
Prof. Xie Wei from the School of Life Science and Technology at Southeast University and Gu Pengyu from Sir Run Run Shaw Hospital, Zhejiang University School of Medicine are the co-corresponding authors of this research paper. Doctoral student Meng Zhu from the School of Life Science and Technology at Southeast University is the first author of this paper. Han Junhai, Geng Junhua, Xu Lizhong, Zhao Yu, and Ou Mengzhu from the School of Life Science and Technology at Southeast University; Sun Yichen from Nanjing Forestry University; and Wang Yuedong from Sir Run Run Shaw Hospital, Zhejiang University School of Medicine participated in this research as co-authors. (School of Life Science and Technology)
Link to the original article: https://doi.org/10.1126/sciadv.adz9682