| Autor: |
Xie, Ya-Kai, Luo, Hao, Zhang, Shan-Xin, Chen, Xiao-Ying, Guo, Ran, Qiu, Xiao-Yun, Liu, Shuai, Wu, Hui, Chen, Wen-Bo, Zhen, Xing-Hua, Ma, Qiang, Tian, Jin-Lan, Li, Shun, Chen, Xinzhong, Han, Qingjian, Duan, Shumin, Shen, Chengyong, Yang, Fan, Xu, Zhen-Zhong |
| Předmět: |
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| Zdroj: |
Science Translational Medicine; 4/6/2022, Vol. 14 Issue 639, p1-13, 13p |
| Abstrakt: |
Diabetic neuropathic pain (DNP) is a common and devastating complication in patients with diabetes. The mechanisms mediating DNP are not completely elucidated, and effective treatments are lacking. A-fiber sensory neurons have been shown to mediate the development of mechanical allodynia in neuropathic pain, yet the molecular basis underlying the contribution of A-fiber neurons is still unclear. Here, we report that the orphan G protein–coupled receptor 177 (GPR177) in A-fiber neurons drives DNP via WNT5a-mediated activation of transient receptor potential vanilloid receptor-1 (TRPV1) ion channel. GPR177 is mainly expressed in large-diameter A-fiber dorsal root ganglion (DRG) neurons and required for the development of DNP in mice. Mechanistically, we found that GPR177 mediated the secretion of WNT5a from A-fiber DRG neurons into cerebrospinal fluid (CSF), which was necessary for the maintenance of DNP. Extracellular perfusion of WNT5a induced rapid currents in both TRPV1-expressing heterologous cells and nociceptive DRG neurons. Computer simulations revealed that WNT5a has the potential to bind the residues at the extracellular S5-S6 loop of TRPV1. Using a peptide able to disrupt the predicted WNT5a/TRPV1 interaction suppressed DNP- and WNT5a-induced neuropathic pain symptoms in rodents. We confirmed GPR177/WNT5A coexpression in human DRG neurons and WNT5A secretion in CSF from patients with DNP. Thus, our results reveal a role for WNT5a as an endogenous and potent TRPV1 agonist, and the GPR177-WNT5a-TRPV1 axis as a driver of DNP pathogenesis in rodents. Our findings identified a potential analgesic target that might relieve neuropathic pain in patients with diabetes. A path toward diabetic pain relief: Individuals with diabetes often suffer from chronic diabetic neuropathic pain (DNP). The mechanisms mediating the development of DNP are not completely elucidated. Now, Xie et al. reported that the orphan G protein–coupled receptor GPR177 expressed in A-fiber dorsal root ganglion (DRG) neurons is required for the development of DNP in mice. Activation of GRP177 resulted in WNT5a release and subsequent activation of the TRPV1 ion channel. Pharmacological blockade of the interaction between WNT5a and TRPV1 eliminated DNP in rodents. In subjects with DNP, WNT5A secretion in CSF was increased compared with diabetic patients without DNP, suggesting that the GPR177-WNT5A-TRPV1 pathway could be a potential target for treating DNP in diabetic individuals. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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