Post-amputation pain causes great sufering to amputees,but still no efective drugs are available due to its elusive mechanisms.Our previous clinical studies found that surgical removal or radiofrequency treatment of t...Post-amputation pain causes great sufering to amputees,but still no efective 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 efectively relieves the phantom pain aficting patients after amputation.This indicated an essential role of the residual nerve stump in the formation 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 mechanosensitive ion channel TMEM63A and macrophages infltrated into the dorsal root ganglion(DRG)neurons worked synergistically to promote CPAP.Histology and qRT-PCR showed that TMEM63A was mainly expressed in mechanical pain-producing non-peptidergic nociceptors in the DRG,and the expression of TMEM63A increased signifcantly 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 afected in the Tmem63a-/-mice in the naïve state,suggesting the basal pain was not afected.In the infammatory and post-amputation state,the mechanical allodynia but not the heat hyperalgesia or cold allodynia was signifcantly decreased in Tmem63a-/-mice.Further study showed that there was severe neuronal injury and macrophage infltration in the DRG,tibial nerve,residual stump,and the neuromalike structure of the TNT mouse model,Consistent with this,expression of the pro-infammatory cytokines TNFα,IL-6,and IL-1βall increased dramatically in the DRG.Interestingly,the deletion of Tmem63a signifcantly reduced the macrophage infltration in the DRG but not in the tibial nerve stump.Furthermore,the ablation of macrophages signifcantly reduced both the expression of Tmem63a and the mechanical allodynia in the TNT mouse model,indicating 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.展开更多
Lower extremity amputation is increasingly prevalent in the United States,with growing numbers of patients suffering from diabetes and peripheral vascular disease.Amputation has significant functional sequelae as more...Lower extremity amputation is increasingly prevalent in the United States,with growing numbers of patients suffering from diabetes and peripheral vascular disease.Amputation has significant functional sequelae as more than half of patients are unable to ambulate at one year postoperatively.Improving mobility and decreasing chronic post-amputation pain can significantly improve the quality of life for these patients and reduce the cost burden on the healthcare system.Plastic and reconstructive surgery has been at the forefront of“reconstructive amputation”,in which nerve pedicles can be surgically guided to decrease painful neuroma formation as well as provide targets for myoelectric prosthesis use.We herein review post-amputation outcomes,epidemiology of chronic,post-amputation pain,and current treatments,including total muscle reinnervation and regenerative peripheral nerve interface,which are at the forefront of multidisciplinary treatment of lower extremity amputees.展开更多
基金supported by grants from the Ministry of Science and Technology of China(2021ZD0203201)the National Natural Science Foundation of China(81971034,81672237)+3 种基金The Innovative Research Team of High-level Local Universities in Shanghai,Shanghai Pujiang Program(19PJ1401700)the Natural Science Foundation of Shanghai Municipality(22ZR1413800)The Program for Professor of Special Appointment(Eastern Scholar)at Shanghai Institutions of Higher Learning,Shanghai Municipal Science and Technology Major Project(2018SHZDZX01)ZJ Lab,and 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).
文摘Post-amputation pain causes great sufering to amputees,but still no efective 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 efectively relieves the phantom pain aficting patients after amputation.This indicated an essential role of the residual nerve stump in the formation 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 mechanosensitive ion channel TMEM63A and macrophages infltrated into the dorsal root ganglion(DRG)neurons worked synergistically to promote CPAP.Histology and qRT-PCR showed that TMEM63A was mainly expressed in mechanical pain-producing non-peptidergic nociceptors in the DRG,and the expression of TMEM63A increased signifcantly 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 afected in the Tmem63a-/-mice in the naïve state,suggesting the basal pain was not afected.In the infammatory and post-amputation state,the mechanical allodynia but not the heat hyperalgesia or cold allodynia was signifcantly decreased in Tmem63a-/-mice.Further study showed that there was severe neuronal injury and macrophage infltration in the DRG,tibial nerve,residual stump,and the neuromalike structure of the TNT mouse model,Consistent with this,expression of the pro-infammatory cytokines TNFα,IL-6,and IL-1βall increased dramatically in the DRG.Interestingly,the deletion of Tmem63a signifcantly reduced the macrophage infltration in the DRG but not in the tibial nerve stump.Furthermore,the ablation of macrophages signifcantly reduced both the expression of Tmem63a and the mechanical allodynia in the TNT mouse model,indicating 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.
文摘Lower extremity amputation is increasingly prevalent in the United States,with growing numbers of patients suffering from diabetes and peripheral vascular disease.Amputation has significant functional sequelae as more than half of patients are unable to ambulate at one year postoperatively.Improving mobility and decreasing chronic post-amputation pain can significantly improve the quality of life for these patients and reduce the cost burden on the healthcare system.Plastic and reconstructive surgery has been at the forefront of“reconstructive amputation”,in which nerve pedicles can be surgically guided to decrease painful neuroma formation as well as provide targets for myoelectric prosthesis use.We herein review post-amputation outcomes,epidemiology of chronic,post-amputation pain,and current treatments,including total muscle reinnervation and regenerative peripheral nerve interface,which are at the forefront of multidisciplinary treatment of lower extremity amputees.
