Abstract
Post-amputation pain causes great suffering to amputees,but still no effective drugs are available due to its elusive mechanisms.Our previous clinical studies found that surgical removal or radiofrequency treatment of the neuroma at the axotomized nerve stump effectively relieves the phan-tom pain afflicting patients after amputation.This indicated an essential role of the residual nerve stump in the forma-tion of chronic post-amputation pain(CPAP).However,the molecular mechanism by which the residual nerve stump or neuroma is involved and regulates CPAP is still a mystery.In this study,we found that nociceptors expressed the mecha-nosensitive ion channel TMEM63A and macrophages infil-trated into the dorsal root ganglion(DRG)neurons worked synergistically to promote CPAP.Histology and qRT-PCR showed that TMEM63A was mainly expressed in mechani-cal pain-producing non-peptidergic nociceptors in the DRG,and the expression of TMEM63A increased significantly both in the neuroma from amputated patients and the DRG in a mouse model of tibial nerve transfer(TNT).Behavioral tests showed that the mechanical,heat,and cold sensitivity were not affected in the Tmem63a--/-mice in the naïve state,suggesting the basal pain was not affected.In the inflamma-tory and post-amputation state,the mechanical allodynia but not the heat hyperalgesia or cold allodynia was significantly decreased in Tmem63a-/-mice.Further study showed that there was severe neuronal injury and macrophage infiltration in the DRG,tibial nerve,residual stump,and the neuroma-like structure of the TNT mouse model,Consistent with this,expression of the pro-inflammatory cytokines TNF-α,IL-6,and IL-1 β all increased dramatically in the DRG.Interestingly,the deletion of Tmem63a significantly reduced the macrophage infiltration in the DRG but not in the tibial nerve stump.Furthermore,the ablation of macrophages significantly reduced both the expression of Tmem63a and the mechanical allodynia in the TNT mouse model,indicat-ing an interaction between nociceptors and macrophages,and that these two factors gang up together to regulate the formation of CPAP.This provides a new insight into the mechanisms underlying CPAP and potential drug targets its treatment.
基金项目
Ministry of Science and Technology of China(2021ZD0203201)
National Natural Science Foundation of China(81971034)
National Natural Science Foundation of China(81672237)
Innovative Research Team of Highlevel Local Universities in Shanghai()
Shanghai Pujiang Program(19PJ1401700)
Natural Science Foundation of Shanghai Municipality(22ZR1413800)
Program for Professor of Special Appointment(Eastern Scholar)at Shanghai Institutions of Higher Learning()
Shanghai Municipal Science and Technology Major Project(2018SHZDZX01)
ZJ Lab()
Shanghai Center for Brain Science and Brain-Inspired Technology()
Innovation Team and Talents Cultivation Program of the National Administration of Traditional Chinese Medicine(ZYYCXTD-C-202008)
维普
万方数据