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
The interactions between neural stem cells(NSCs)and their niche are essential for their maintenance,proliferation,differentiation,and migration,which contribute to brain plasticity,learning and memory,and cognition[1]...The interactions between neural stem cells(NSCs)and their niche are essential for their maintenance,proliferation,differentiation,and migration,which contribute to brain plasticity,learning and memory,and cognition[1].As one of the key components of the NSC niche,astrocytes are vital in regulating the processes underlying brain development such as neuro-/gliogenesis,angiogenesis,axonal outgrowth,synaptogenesis,and synaptic pruning[2].Chemical and electrical signals mediated by adhesion molecules,the extracellular matrix,paracrine secretion.展开更多
Abstract The voltage-gated Na+ channel subtype Nav1.7 is important for pain and itch in rodents and humans. We previously showed that a Nav1.7-targeting monoclonal antibody (SVmab) reduces Na+ currents and pain an...Abstract The voltage-gated Na+ channel subtype Nav1.7 is important for pain and itch in rodents and humans. We previously showed that a Nav1.7-targeting monoclonal antibody (SVmab) reduces Na+ currents and pain and itch responses in mice. Here, we investigated whether recom- binant SVmab (rSVmab) binds to and blocks Nav1.7 similar to SVmab. ELISA tests revealed that SVmab was capable of binding to Nav1.7-expressing HEK293 cells, mouse DRG neurons, human nerve tissue, and the voltagesensor domain II of Nav1.7. In contrast, rSVmab showed no or weak binding to Nav1.7 in these tests. Patch-clamp recordings showed that SVmab, but not rSVmab, markedly inhibited Na+ currents in Nav1.7-expressing HEK293 cells. Notably, electrical field stimulation increased the blocking activity of SVmab and rSVmab in Nav1.7- expressing HEK293 cells. SVmab was more effective than rSVmab in inhibiting paclitaxel-induced mechanical allodynia. SVmab also bound to human DRG neurons and inhibited their Na+ currents. Finally, potential reasons for the differential efficacy of SVmab and rSVmab and future directions are discussed.展开更多
Dear Editor,Cancer-associated itch can be described as pruritus associated with malignancy.Although intractable itch associated with specific types of cancer afflicts patients badly,few effective treatments are availa...Dear Editor,Cancer-associated itch can be described as pruritus associated with malignancy.Although intractable itch associated with specific types of cancer afflicts patients badly,few effective treatments are available due to limited knowledge about the mechanisms of such itch.Globally,cancer-associated itch is an uncommon symptomin malignancy.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.
基金AcknowledgementsThis research highlight was supported by STI 2030-Major Projects(2021ZD0203201),the National Natural Science Foundation of China(81971034,32271047),The Innovative Research Team of High-level Local Universities in Shanghai,Natural Science Foundation of Shanghai(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,Lingang Laboratory(LGQS-202203-12),Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(ZYYCXTDC-202008),and Shanghai Style of TCM for Inheritance and Innovation Team from Shanghai Municipal Health Commission(2021LPTD-007),Shanghai Artificial Intelligence Innovation and Development Project-Intelligent Dermatology Clinic Based on Modern TCM Diagnostic Technology,No.2020-RGZN-02038.
文摘The interactions between neural stem cells(NSCs)and their niche are essential for their maintenance,proliferation,differentiation,and migration,which contribute to brain plasticity,learning and memory,and cognition[1].As one of the key components of the NSC niche,astrocytes are vital in regulating the processes underlying brain development such as neuro-/gliogenesis,angiogenesis,axonal outgrowth,synaptogenesis,and synaptic pruning[2].Chemical and electrical signals mediated by adhesion molecules,the extracellular matrix,paracrine secretion.
基金supported by National Institutes of Health Grants R01NS89479,R01NS045594 and ROINS055860
文摘Abstract The voltage-gated Na+ channel subtype Nav1.7 is important for pain and itch in rodents and humans. We previously showed that a Nav1.7-targeting monoclonal antibody (SVmab) reduces Na+ currents and pain and itch responses in mice. Here, we investigated whether recom- binant SVmab (rSVmab) binds to and blocks Nav1.7 similar to SVmab. ELISA tests revealed that SVmab was capable of binding to Nav1.7-expressing HEK293 cells, mouse DRG neurons, human nerve tissue, and the voltagesensor domain II of Nav1.7. In contrast, rSVmab showed no or weak binding to Nav1.7 in these tests. Patch-clamp recordings showed that SVmab, but not rSVmab, markedly inhibited Na+ currents in Nav1.7-expressing HEK293 cells. Notably, electrical field stimulation increased the blocking activity of SVmab and rSVmab in Nav1.7- expressing HEK293 cells. SVmab was more effective than rSVmab in inhibiting paclitaxel-induced mechanical allodynia. SVmab also bound to human DRG neurons and inhibited their Na+ currents. Finally, potential reasons for the differential efficacy of SVmab and rSVmab and future directions are discussed.
基金supported by the National Natural Science Foundation of China(81971034)The Innovative Research Team of High-level Local Universities in Shanghai,Shanghai Pujiang Program(19PJ1401700)Building Project for Innovative team of National Traditional Chinese Medicine,and The Program for Professor of Special Appointment(Eastern Scholar)at Shanghai Institutions of Higher Learning,and the Priority Academic Program Development of Jiangsu High Education Institutions(PAPD).
文摘Dear Editor,Cancer-associated itch can be described as pruritus associated with malignancy.Although intractable itch associated with specific types of cancer afflicts patients badly,few effective treatments are available due to limited knowledge about the mechanisms of such itch.Globally,cancer-associated itch is an uncommon symptomin malignancy.