Netrin-3 Suppresses Diabetic Neuropathic Pain by Gating the Intra-epidermal Sprouting of Sensory Axons

 Weiping Pan1,2 · Xueyin Huang3  · Zikai Yu1,2 · Qiongqiong Ding1  · Liping Xia4  · Jianfeng Hua3  · Bokai Gu3  · Qisong Xiong1,2 · Hualin Yu1,2 · Junbo Wang1  · Zhenzhong Xu4  · Linghui Zeng1  · Ge Bai3,5,6,7 · Huaqing Liu1,7
1 Department of Pharmaceutical Sciences, Zhejiang University City College, Hangzhou 310015, China 
2 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China 
3 Department of Neurobiology and Department of Neurology of The Second Afliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China 
4 Department of Anesthesiology and Department of Neurobiology of The First Afliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China 
5 Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain-machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, Hangzhou 311121, China 
6 NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China 
7 Institute of Brain and Cognition, Zhejiang University City College School of Medicine, Hangzhou 310015, China


Diabetic neuropathic pain (DNP) is the most common disabling complication of diabetes. Emerging evidence has linked the pathogenesis of DNP to the aberrant sprouting of sensory axons into the epidermal area; however, the underlying molecular events remain poorly understood. Here we found that an axon guidance molecule, Netrin-3 (Ntn-3), was expressed in the sensory neurons of mouse dorsal root ganglia (DRGs), and downregulation of Ntn-3 expression was highly correlated with the severity of DNP in a diabetic mouse model. Genetic ablation of Ntn-3 increased the intra-epidermal sprouting of sensory axons and worsened the DNP in diabetic mice. In contrast, the elevation of Ntn-3 levels in DRGs significantly inhibited the intra-epidermal axon sprouting and alleviated DNP in diabetic mice. In conclusion, our studies identified Ntn-3 as an important regulator of DNP pathogenesis by gating the aberrant sprouting of sensory axons, indicating that Ntn-3 is a potential druggable target for DNP treatment.

Diabetes; Diabetic neuropathic pain; Netrin-3; Axon sprouting