A recent study published in Proceedings of the National Academy of Sciences (PNAS) reveals the circuit mechanisms of inhibitory synaptic control of spinal GRPR⁺ neurons. This work was performed by researchers in Dr. SUN Yangang’s Lab at the Center for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences. 

　　Itch is a unique sensory experience, different from the sensation of pain, temperature and touch. Itch evokes a desire to scratch in human and many other animals. However, for patients suffering from the chronic itch, uncontrollable scratching causes severe skin and tissue damage. To design better therapeutic approaches for alleviating chronic itch, we need to gain better insight into the mechanisms of itch processing. The gastrin releasing peptide receptor⁺ (GRPR⁺) neurons in the dorsal horn of spinal cord play an important role in itch processing, but it remains unknown how these neurons are modulated by local and long-range inhibitory circuits. 

　　By combining the optogenetics with the patch-clamp recording method, SUN’s Lab found that spinal galanin⁺ inhibitory interneurons form inhibitory synapses with GRPR⁺ neurons in the spinal cord and play an important role in gating the GRPR⁺ neuron-dependent itch signaling pathway. Pharmacogenetic activation of spinal galanin⁺ neurons significantly suppressed the scratching behavior evoked by various pruritogens, but not the pain-related behaviors. Consistently, ablation of spinal galanin⁺ neurons significantly enhanced the scratching behavior evoked by various pruritogens. Furthermore, spinal GRPR⁺ neurons also receive strong inhibitory input from the rostral ventromedial medulla (RVM). Thus, both local and long-range inhibitory neurons play important roles in gating the itch processing in the spinal cord by directly modulating the activity of spinal GRPR⁺ neurons. This study revealed the mechanism underlying the inhibitory control of the spinal itch circuit, providing a basis for further dissection of the possible dysregulation of the itch circuit under pathological conditions leading to chronic itchiness. 

　　This work entitled “Synaptic control of spinal GRPR+ neurons by local and long-range inhibitory inputs” was published online in PNAS on Dec. 5, 2019. It was carried out mainly by LIU Mingzhe and CHEN Xiaojun, with the help from LIANG Tongyu, LI Qing, WANG Meng, ZHANG Xinyan, LI Yuzhuo and SUN Qiang, under the supervision of Dr. SUN Yangang. We would like to thank HU Qian, XIANG Dan, CHEN Xuxin, WANG Yonghong and ZHANG Yumei from the optical imaging Core Facility for their help in image acquisition and analysis. This work was supported by National Natural Science Foundation of China, the Shanghai Municipal Science and Technology Major Project etc. 

A diagram illustrating the local and long-range inputs to spinal GRPR⁺ neurons. 

　　Figure legend: The GRPR⁺ neurons in the dorsal horn of spinal cord receive the inhibitory inputs from local galanin⁺ neurons and GABAergic neurons in the RVM. After ablation of spinal galanin⁺ neurons, the gate-control of GRPR⁺ neurons is disrupted and the scratching behavior evoked by pruritogens is significantly increased. RVM, rostral ventromedial medulla; 5-HT, serotonin; GRPR, gastrin-releasing peptide receptor.  

　　SUN Yangang , Ph.D. 

　　Email：yangang.sun@ion.ac.cn 

　　Website：https://www.pnas.org/content/early/2019/12/04/1905658116 

　　Key words: spinal GRPR⁺ neurons, inhibitory control, galanin⁺ inhibitory interneurons, rostral ventromedial medulla, gating the itch processing