Related Publications
2576724
IXMHRBF6
pain
1
apa-cv
50
date
desc
1
1
4147
https://labsyspharm.org/wp-content/plugins/zotpress/
%7B%22status%22%3A%22success%22%2C%22updateneeded%22%3Afalse%2C%22instance%22%3Afalse%2C%22meta%22%3A%7B%22request_last%22%3A0%2C%22request_next%22%3A0%2C%22used_cache%22%3Atrue%7D%2C%22data%22%3A%5B%7B%22key%22%3A%22BZEF7GKE%22%2C%22library%22%3A%7B%22id%22%3A2576724%7D%2C%22meta%22%3A%7B%22lastModifiedByUser%22%3A%7B%22id%22%3A9036456%2C%22username%22%3A%22jtefft%22%2C%22name%22%3A%22%22%2C%22links%22%3A%7B%22alternate%22%3A%7B%22href%22%3A%22https%3A%5C%2F%5C%2Fwww.zotero.org%5C%2Fjtefft%22%2C%22type%22%3A%22text%5C%2Fhtml%22%7D%7D%7D%2C%22creatorSummary%22%3A%22Ma%20and%20Clardy%22%2C%22parsedDate%22%3A%222025-04-09%22%2C%22numChildren%22%3A1%7D%2C%22bib%22%3A%22%3Cdiv%20class%3D%5C%22csl-bib-body%5C%22%20style%3D%5C%22line-height%3A%202%3B%20padding-left%3A%201em%3B%20text-indent%3A-1em%3B%5C%22%3E%5Cn%20%20%3Cdiv%20class%3D%5C%22csl-entry%5C%22%3EMa%2C%20X.%20C.%2C%20%26amp%3B%20Clardy%2C%20J.%20%282025%29.%20Spontaneous%20Generation%20of%20an%20Endogenous%20ROR%26%23x3B3%3Bt%20Agonist.%20%3Ci%3EJournal%20of%20the%20American%20Chemical%20Society%3C%5C%2Fi%3E%2C%20%3Ci%3E147%3C%5C%2Fi%3E%2814%29%2C%2011688%26%23x2013%3B11692.%20%3Ca%20class%3D%27zp-DOIURL%27%20target%3D%27_blank%27%20href%3D%27https%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1021%5C%2Fjacs.5c02724%27%3Ehttps%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1021%5C%2Fjacs.5c02724%3C%5C%2Fa%3E%3C%5C%2Fdiv%3E%5Cn%3C%5C%2Fdiv%3E%22%2C%22data%22%3A%7B%22itemType%22%3A%22journalArticle%22%2C%22title%22%3A%22Spontaneous%20Generation%20of%20an%20Endogenous%20ROR%5Cu03b3t%20Agonist%22%2C%22creators%22%3A%5B%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Xiao%20Corey%22%2C%22lastName%22%3A%22Ma%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Jon%22%2C%22lastName%22%3A%22Clardy%22%7D%5D%2C%22abstractNote%22%3A%22The%20transcription%20factor%20ROR%5Cu03b3t%20regulates%20the%20development%20of%20Th17%20cells%20and%20their%20inflammatory%20cytokine%20IL-17%5Cu2500a%20pathway%20that%20can%20both%20clear%20bacterial%20pathogens%20and%20drive%20autoimmune%20diseases.%20An%20endogenous%20ROR%5Cu03b3t%20agonist%20with%20a%20noncanonical%20structure%2C%20a%20lysophosphatidylethanolamine%20%281-18%3A1-LPE%20or%201%29%2C%20was%20recently%20identified%2C%20and%20its%20identity%20both%20increases%20our%20understanding%20of%20immune%20regulation%20and%20creates%20options%20for%20therapeutic%20intervention.%20Compound%201%20could%20be%20formed%20directly%20through%20enzymatic%20cleavage%20of%20a%20suitable%20phosphatidylethanolamine%20%28PE%29%20by%20a%20phospholipase%20A2%20%28PLA2%29%20or%20by%20%5C%22triggering%5C%22%20of%20a%20suitable%20plasmalogen%20with%20accompanying%201%2C2-acyl%20migration%20from%20the%20sn-2%20to%20sn-1%20positions%20of%20glycerol.%20This%20study%20illustrates%20the%20plausibility%20of%20a%20plasmalogen-based%20pathway%20through%20synthesis%20of%20the%20plasmalogen%20precursor%20%282%29%20and%20triggering%20the%20plasmalogen%27s%20electron-rich%20vinyl%20ether%20with%20small%20electrophiles%20characteristic%20of%20inflammatory%20and%20tumor%20environments%20to%20create%201-18%3A1-LPE%20%281%29.%20The%20plasmalogen-based%20pathway%20is%20consistent%20with%20previous%20studies%20on%20the%20formation%20of%201%2C%20and%20it%20also%20conforms%20to%20Lands%20rules%20for%20acyl%20chain%20distribution%20and%20provides%20a%20mechanism%20for%20immune%20signaling%20with%20both%20spatial%20and%20temporal%20control.%22%2C%22date%22%3A%222025-04-09%22%2C%22language%22%3A%22eng%22%2C%22DOI%22%3A%2210.1021%5C%2Fjacs.5c02724%22%2C%22ISSN%22%3A%221520-5126%22%2C%22url%22%3A%22%22%2C%22collections%22%3A%5B%22IXMHRBF6%22%5D%2C%22dateModified%22%3A%222025-05-05T19%3A56%3A18Z%22%7D%7D%2C%7B%22key%22%3A%2237L7TMD8%22%2C%22library%22%3A%7B%22id%22%3A2576724%7D%2C%22meta%22%3A%7B%22lastModifiedByUser%22%3A%7B%22id%22%3A9036456%2C%22username%22%3A%22jtefft%22%2C%22name%22%3A%22%22%2C%22links%22%3A%7B%22alternate%22%3A%7B%22href%22%3A%22https%3A%5C%2F%5C%2Fwww.zotero.org%5C%2Fjtefft%22%2C%22type%22%3A%22text%5C%2Fhtml%22%7D%7D%7D%2C%22creatorSummary%22%3A%22Vaelli%20et%20al.%22%2C%22parsedDate%22%3A%222024-11-18%22%2C%22numChildren%22%3A1%7D%2C%22bib%22%3A%22%3Cdiv%20class%3D%5C%22csl-bib-body%5C%22%20style%3D%5C%22line-height%3A%202%3B%20padding-left%3A%201em%3B%20text-indent%3A-1em%3B%5C%22%3E%5Cn%20%20%3Cdiv%20class%3D%5C%22csl-entry%5C%22%3EVaelli%2C%20P.%2C%20Fujita%2C%20A.%2C%20Jo%2C%20S.%2C%20Zhang%2C%20H.-X.%20B.%2C%20Osorno%2C%20T.%2C%20Ma%2C%20X.%2C%20%26amp%3B%20Bean%2C%20B.%20P.%20%282024%29.%20State-Dependent%20Inhibition%20of%20Nav1.8%20Sodium%20Channels%20by%20VX-150%20and%20VX-548.%20%3Ci%3EMolecular%20Pharmacology%3C%5C%2Fi%3E%2C%20%3Ci%3E106%3C%5C%2Fi%3E%286%29%2C%20298%26%23x2013%3B308.%20%3Ca%20class%3D%27zp-DOIURL%27%20target%3D%27_blank%27%20href%3D%27https%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1124%5C%2Fmolpharm.124.000944%27%3Ehttps%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1124%5C%2Fmolpharm.124.000944%3C%5C%2Fa%3E%3C%5C%2Fdiv%3E%5Cn%3C%5C%2Fdiv%3E%22%2C%22data%22%3A%7B%22itemType%22%3A%22journalArticle%22%2C%22title%22%3A%22State-Dependent%20Inhibition%20of%20Nav1.8%20Sodium%20Channels%20by%20VX-150%20and%20VX-548%22%2C%22creators%22%3A%5B%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Patric%22%2C%22lastName%22%3A%22Vaelli%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Akie%22%2C%22lastName%22%3A%22Fujita%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Sooyeon%22%2C%22lastName%22%3A%22Jo%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Han-Xiong%20Bear%22%2C%22lastName%22%3A%22Zhang%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Tom%5Cu00e1s%22%2C%22lastName%22%3A%22Osorno%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Xiao%22%2C%22lastName%22%3A%22Ma%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Bruce%20P.%22%2C%22lastName%22%3A%22Bean%22%7D%5D%2C%22abstractNote%22%3A%22Nav1.8%20sodium%20channels%20%28Nav1.8%29%20are%20an%20attractive%20therapeutic%20target%20for%20pain%20because%20they%20are%20prominent%20in%20primary%20pain-sensing%20neurons%20with%20little%20expression%20in%20most%20other%20kinds%20of%20neurons.%20Recently%2C%20two%20Nav1.8-targeted%20compounds%2C%20VX-150%20and%20VX-548%2C%20have%20shown%20efficacy%20in%20clinical%20trials%20for%20reducing%20pain.%20We%20examined%20the%20characteristics%20of%20Nav1.8%20inhibition%20by%20these%20compounds.%20The%20active%20metabolite%20form%20of%20VX-150%20%28VX-150m%29%20inhibited%20human%20Nav1.8%20channels%20with%20an%20IC50%20of%2015%20nM.%20VX-548%20%28suzetrigine%29%20was%20even%20more%20potent%20%28IC50%200.27%20nM%29.%20Both%20VX-150m%20and%20VX-548%20had%20the%20unusual%20property%20of%20%5C%22reverse%20use-dependence%2C%5C%22%20whereby%20inhibition%20could%20be%20relieved%20by%20repetitive%20depolarizations%2C%20a%20property%20seen%20before%20with%20another%20Nav1.8%20inhibitor%2C%20A-887826.%20The%20relief%20of%20VX-548%20inhibition%20by%20large%20depolarizations%20occurred%20with%20a%20time%20constant%20of%20%5Cu223c40%20milliseconds%20that%20was%20not%20concentration-dependent.%20Reinhibition%20at%20negative%20voltages%20occurred%20with%20a%20rate%20that%20was%20nearly%20proportional%20to%20drug%20concentration%2C%20consistent%20with%20the%20idea%20that%20relief%20of%20inhibition%20reflects%20dissociation%20of%20drug%20from%20the%20channel%20and%20reinhibition%20reflects%20rebinding.%20The%20relief%20of%20inhibition%20by%20depolarization%20suggests%20a%20remarkably%20strong%20and%20unusual%20state-dependence%20for%20both%20VX-150m%20and%20VX-548%2C%20with%20very%20weak%20binding%20to%20channels%20with%20fully%20activated%20voltage%20sensors%20despite%20very%20tight%20binding%20to%20channels%20with%20voltage%20sensors%20in%20the%20resting%20state.%20SIGNIFICANCE%20STATEMENT%3A%20The%20Nav1.8%20sodium%20channel%20%28Nav1.8%29%20is%20a%20current%20target%20for%20new%20drugs%20for%20pain.%20This%20work%20describes%20the%20potency%2C%20selectivity%2C%20and%20state-dependent%20characteristics%20of%20inhibition%20of%20Nav1.8%20channels%20by%20VX-150%20and%20VX-548%2C%20compounds%20that%20have%20recently%20shown%20efficacy%20for%20relief%20of%20pain%20in%20clinical%20trials%20but%20whose%20mechanism%20of%20interaction%20with%20channels%20has%20not%20been%20described.%20The%20results%20show%20that%20the%20compounds%20share%20an%20unusual%20property%20whereby%20inhibition%20is%20relieved%20by%20depolarization%2C%20demonstrating%20a%20state-dependence%20different%20from%20most%20sodium%20channel%20inhibitors.%22%2C%22date%22%3A%222024-11-18%22%2C%22language%22%3A%22eng%22%2C%22DOI%22%3A%2210.1124%5C%2Fmolpharm.124.000944%22%2C%22ISSN%22%3A%221521-0111%22%2C%22url%22%3A%22%22%2C%22collections%22%3A%5B%22IXMHRBF6%22%5D%2C%22dateModified%22%3A%222025-04-30T14%3A11%3A13Z%22%7D%7D%2C%7B%22key%22%3A%22T3HXE4FL%22%2C%22library%22%3A%7B%22id%22%3A2576724%7D%2C%22meta%22%3A%7B%22creatorSummary%22%3A%22Jain%20et%20al.%22%2C%22parsedDate%22%3A%222024-05-28%22%2C%22numChildren%22%3A2%7D%2C%22bib%22%3A%22%3Cdiv%20class%3D%5C%22csl-bib-body%5C%22%20style%3D%5C%22line-height%3A%202%3B%20padding-left%3A%201em%3B%20text-indent%3A-1em%3B%5C%22%3E%5Cn%20%20%3Cdiv%20class%3D%5C%22csl-entry%5C%22%3EJain%2C%20A.%2C%20Gyori%2C%20B.%20M.%2C%20Hakim%2C%20S.%2C%20Jain%2C%20A.%2C%20Sun%2C%20L.%2C%20Petrova%2C%20V.%2C%20Bhuiyan%2C%20S.%20A.%2C%20Zhen%2C%20S.%2C%20Wang%2C%20Q.%2C%20Kawaguchi%2C%20R.%2C%20Bunga%2C%20S.%2C%20Taub%2C%20D.%20G.%2C%20Ruiz-Cantero%2C%20M.%20C.%2C%20Tong-Li%2C%20C.%2C%20Andrews%2C%20N.%2C%20Kotoda%2C%20M.%2C%20Renthal%2C%20W.%2C%20Sorger%2C%20P.%20K.%2C%20%26amp%3B%20Woolf%2C%20C.%20J.%20%282024%29.%20Nociceptor-immune%20interactomes%20reveal%20insult-specific%20immune%20signatures%20of%20pain.%20%3Ci%3ENature%20Immunology%3C%5C%2Fi%3E.%20%3Ca%20class%3D%27zp-DOIURL%27%20target%3D%27_blank%27%20href%3D%27https%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1038%5C%2Fs41590-024-01857-2%27%3Ehttps%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1038%5C%2Fs41590-024-01857-2%3C%5C%2Fa%3E%3C%5C%2Fdiv%3E%5Cn%3C%5C%2Fdiv%3E%22%2C%22data%22%3A%7B%22itemType%22%3A%22journalArticle%22%2C%22title%22%3A%22Nociceptor-immune%20interactomes%20reveal%20insult-specific%20immune%20signatures%20of%20pain%22%2C%22creators%22%3A%5B%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Aakanksha%22%2C%22lastName%22%3A%22Jain%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Benjamin%20M.%22%2C%22lastName%22%3A%22Gyori%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Sara%22%2C%22lastName%22%3A%22Hakim%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Ashish%22%2C%22lastName%22%3A%22Jain%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Liang%22%2C%22lastName%22%3A%22Sun%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Veselina%22%2C%22lastName%22%3A%22Petrova%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Shamsuddin%20A.%22%2C%22lastName%22%3A%22Bhuiyan%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Shannon%22%2C%22lastName%22%3A%22Zhen%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Qing%22%2C%22lastName%22%3A%22Wang%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Riki%22%2C%22lastName%22%3A%22Kawaguchi%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Samuel%22%2C%22lastName%22%3A%22Bunga%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Daniel%20G.%22%2C%22lastName%22%3A%22Taub%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22M.%20Carmen%22%2C%22lastName%22%3A%22Ruiz-Cantero%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Candace%22%2C%22lastName%22%3A%22Tong-Li%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Nicholas%22%2C%22lastName%22%3A%22Andrews%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Masakazu%22%2C%22lastName%22%3A%22Kotoda%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22William%22%2C%22lastName%22%3A%22Renthal%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Peter%20K.%22%2C%22lastName%22%3A%22Sorger%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Clifford%20J.%22%2C%22lastName%22%3A%22Woolf%22%7D%5D%2C%22abstractNote%22%3A%22Inflammatory%20pain%20results%20from%20the%20heightened%20sensitivity%20and%20reduced%20threshold%20of%20nociceptor%20sensory%20neurons%20due%20to%20exposure%20to%20inflammatory%20mediators.%20However%2C%20the%20cellular%20and%20transcriptional%20diversity%20of%20immune%20cell%20and%20sensory%20neuron%20types%20makes%20it%20challenging%20to%20decipher%20the%20immune%20mechanisms%20underlying%20pain.%20Here%20we%20used%20single-cell%20transcriptomics%20to%20determine%20the%20immune%20gene%20signatures%20associated%20with%20pain%20development%20in%20three%20skin%20inflammatory%20pain%20models%20in%20mice%3A%20zymosan%20injection%2C%20skin%20incision%20and%20ultraviolet%20burn.%20We%20found%20that%20macrophage%20and%20neutrophil%20recruitment%20closely%20mirrored%20the%20kinetics%20of%20pain%20development%20and%20identified%20cell-type-specific%20transcriptional%20programs%20associated%20with%20pain%20and%20its%20resolution.%20Using%20a%20comprehensive%20list%20of%20potential%20interactions%20mediated%20by%20receptors%2C%20ligands%2C%20ion%20channels%20and%20metabolites%20to%20generate%20injury-specific%20neuroimmune%20interactomes%2C%20we%20also%20uncovered%20that%20thrombospondin-1%20upregulated%20by%20immune%20cells%20upon%20injury%20inhibited%20nociceptor%20sensitization.%20This%20study%20lays%20the%20groundwork%20for%20identifying%20the%20neuroimmune%20axes%20that%20modulate%20pain%20in%20diverse%20disease%20contexts.%22%2C%22date%22%3A%222024-05-28%22%2C%22language%22%3A%22eng%22%2C%22DOI%22%3A%2210.1038%5C%2Fs41590-024-01857-2%22%2C%22ISSN%22%3A%221529-2916%22%2C%22url%22%3A%22%22%2C%22collections%22%3A%5B%22IXMHRBF6%22%5D%2C%22dateModified%22%3A%222025-04-29T18%3A26%3A37Z%22%7D%7D%2C%7B%22key%22%3A%22YVFWLS2C%22%2C%22library%22%3A%7B%22id%22%3A2576724%7D%2C%22meta%22%3A%7B%22lastModifiedByUser%22%3A%7B%22id%22%3A9036456%2C%22username%22%3A%22jtefft%22%2C%22name%22%3A%22%22%2C%22links%22%3A%7B%22alternate%22%3A%7B%22href%22%3A%22https%3A%5C%2F%5C%2Fwww.zotero.org%5C%2Fjtefft%22%2C%22type%22%3A%22text%5C%2Fhtml%22%7D%7D%7D%2C%22creatorSummary%22%3A%22Jayakar%20et%20al.%22%2C%22parsedDate%22%3A%222021-11-10%22%2C%22numChildren%22%3A2%7D%2C%22bib%22%3A%22%3Cdiv%20class%3D%5C%22csl-bib-body%5C%22%20style%3D%5C%22line-height%3A%202%3B%20padding-left%3A%201em%3B%20text-indent%3A-1em%3B%5C%22%3E%5Cn%20%20%3Cdiv%20class%3D%5C%22csl-entry%5C%22%3EJayakar%2C%20S.%2C%20Shim%2C%20J.%2C%20Jo%2C%20S.%2C%20Bean%2C%20B.%20P.%2C%20Singe%26%23xE7%3B%2C%20I.%2C%20%26amp%3B%20Woolf%2C%20C.%20J.%20%282021%29.%20Developing%20nociceptor-selective%20treatments%20for%20acute%20and%20chronic%20pain.%20%3Ci%3EScience%20Translational%20Medicine%3C%5C%2Fi%3E%2C%20%3Ci%3E13%3C%5C%2Fi%3E%28619%29%2C%20eabj9837.%20%3Ca%20class%3D%27zp-DOIURL%27%20target%3D%27_blank%27%20href%3D%27https%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1126%5C%2Fscitranslmed.abj9837%27%3Ehttps%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1126%5C%2Fscitranslmed.abj9837%3C%5C%2Fa%3E%3C%5C%2Fdiv%3E%5Cn%3C%5C%2Fdiv%3E%22%2C%22data%22%3A%7B%22itemType%22%3A%22journalArticle%22%2C%22title%22%3A%22Developing%20nociceptor-selective%20treatments%20for%20acute%20and%20chronic%20pain%22%2C%22creators%22%3A%5B%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Selwyn%22%2C%22lastName%22%3A%22Jayakar%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Jaehoon%22%2C%22lastName%22%3A%22Shim%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Sooyeon%22%2C%22lastName%22%3A%22Jo%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Bruce%20P.%22%2C%22lastName%22%3A%22Bean%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Ilyas%22%2C%22lastName%22%3A%22Singe%5Cu00e7%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Clifford%20J.%22%2C%22lastName%22%3A%22Woolf%22%7D%5D%2C%22abstractNote%22%3A%22Despite%20substantial%20efforts%20dedicated%20to%20the%20development%20of%20new%2C%20nonaddictive%20analgesics%2C%20success%20in%20treating%20pain%20has%20been%20limited.%20Clinically%20available%20analgesic%20agents%20generally%20lack%20efficacy%20and%20may%20have%20undesirable%20side%20effects.%20Traditional%20target-based%20drug%20discovery%20efforts%20that%20generate%20compounds%20with%20selectivity%20for%20single%20targets%20have%20a%20high%20rate%20of%20attrition%20because%20of%20their%20poor%20clinical%20efficacy.%20Here%2C%20we%20examine%20the%20challenges%20associated%20with%20the%20current%20analgesic%20drug%20discovery%20model%20and%20review%20evidence%20in%20favor%20of%20stem%20cell%5Cu2013derived%20neuronal-based%20screening%20approaches%20for%20the%20identification%20of%20analgesic%20targets%20and%20compounds%20for%20treating%20diverse%20forms%20of%20acute%20and%20chronic%20pain.%22%2C%22date%22%3A%222021-11-10%22%2C%22language%22%3A%22eng%22%2C%22DOI%22%3A%2210.1126%5C%2Fscitranslmed.abj9837%22%2C%22ISSN%22%3A%221946-6242%22%2C%22url%22%3A%22%22%2C%22collections%22%3A%5B%22IXMHRBF6%22%5D%2C%22dateModified%22%3A%222024-10-25T21%3A57%3A40Z%22%7D%7D%2C%7B%22key%22%3A%22QEF3PLDE%22%2C%22library%22%3A%7B%22id%22%3A2576724%7D%2C%22meta%22%3A%7B%22lastModifiedByUser%22%3A%7B%22id%22%3A9036456%2C%22username%22%3A%22jtefft%22%2C%22name%22%3A%22%22%2C%22links%22%3A%7B%22alternate%22%3A%7B%22href%22%3A%22https%3A%5C%2F%5C%2Fwww.zotero.org%5C%2Fjtefft%22%2C%22type%22%3A%22text%5C%2Fhtml%22%7D%7D%7D%2C%22creatorSummary%22%3A%22Lee%20et%20al.%22%2C%22parsedDate%22%3A%222019-11-25%22%2C%22numChildren%22%3A2%7D%2C%22bib%22%3A%22%3Cdiv%20class%3D%5C%22csl-bib-body%5C%22%20style%3D%5C%22line-height%3A%202%3B%20padding-left%3A%201em%3B%20text-indent%3A-1em%3B%5C%22%3E%5Cn%20%20%3Cdiv%20class%3D%5C%22csl-entry%5C%22%3ELee%2C%20S.%2C%20Jo%2C%20S.%2C%20Talbot%2C%20S.%2C%20Zhang%2C%20H.-X.%20B.%2C%20Kotoda%2C%20M.%2C%20Andrews%2C%20N.%20A.%2C%20Puopolo%2C%20M.%2C%20Liu%2C%20P.%20W.%2C%20Jacquemont%2C%20T.%2C%20Pascal%2C%20M.%2C%20Heckman%2C%20L.%20M.%2C%20Jain%2C%20A.%2C%20Lee%2C%20J.%2C%20Woolf%2C%20C.%20J.%2C%20%26amp%3B%20Bean%2C%20B.%20P.%20%282019%29.%20Novel%20charged%20sodium%20and%20calcium%20channel%20inhibitor%20active%20against%20neurogenic%20inflammation.%20%3Ci%3EELife%3C%5C%2Fi%3E%2C%20%3Ci%3E8%3C%5C%2Fi%3E.%20%3Ca%20class%3D%27zp-DOIURL%27%20target%3D%27_blank%27%20href%3D%27https%3A%5C%2F%5C%2Fdoi.org%5C%2F10.7554%5C%2FeLife.48118%27%3Ehttps%3A%5C%2F%5C%2Fdoi.org%5C%2F10.7554%5C%2FeLife.48118%3C%5C%2Fa%3E%3C%5C%2Fdiv%3E%5Cn%3C%5C%2Fdiv%3E%22%2C%22data%22%3A%7B%22itemType%22%3A%22journalArticle%22%2C%22title%22%3A%22Novel%20charged%20sodium%20and%20calcium%20channel%20inhibitor%20active%20against%20neurogenic%20inflammation%22%2C%22creators%22%3A%5B%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Seungkyu%22%2C%22lastName%22%3A%22Lee%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Sooyeon%22%2C%22lastName%22%3A%22Jo%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22S%5Cu00e9bastien%22%2C%22lastName%22%3A%22Talbot%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Han-Xiong%20Bear%22%2C%22lastName%22%3A%22Zhang%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Masakazu%22%2C%22lastName%22%3A%22Kotoda%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Nick%20A.%22%2C%22lastName%22%3A%22Andrews%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Michelino%22%2C%22lastName%22%3A%22Puopolo%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Pin%20W.%22%2C%22lastName%22%3A%22Liu%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Thomas%22%2C%22lastName%22%3A%22Jacquemont%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Maud%22%2C%22lastName%22%3A%22Pascal%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Laurel%20M.%22%2C%22lastName%22%3A%22Heckman%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Aakanksha%22%2C%22lastName%22%3A%22Jain%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Jinbo%22%2C%22lastName%22%3A%22Lee%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Clifford%20J.%22%2C%22lastName%22%3A%22Woolf%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Bruce%20P.%22%2C%22lastName%22%3A%22Bean%22%7D%5D%2C%22abstractNote%22%3A%22Voltage-dependent%20sodium%20and%20calcium%20channels%20in%20pain-initiating%20nociceptor%20neurons%20are%20attractive%20targets%20for%20new%20analgesics.%20We%20made%20a%20permanently%20charged%20cationic%20derivative%20of%20an%20N-type%20calcium%20channel-inhibitor.%20Unlike%20cationic%20derivatives%20of%20local%20anesthetic%20sodium%20channel%20blockers%20like%20QX-314%2C%20this%20cationic%20compound%20inhibited%20N-type%20calcium%20channels%20more%20effectively%20with%20extracellular%20than%20intracellular%20application.%20Surprisingly%2C%20the%20compound%20is%20also%20a%20highly%20effective%20sodium%20channel%20inhibitor%20when%20applied%20extracellularly%2C%20producing%20more%20potent%20inhibition%20than%20lidocaine%20or%20bupivacaine.%20The%20charged%20inhibitor%20produced%20potent%20and%20long-lasting%20analgesia%20in%20mouse%20models%20of%20incisional%20wound%20and%20inflammatory%20pain%2C%20inhibited%20release%20of%20the%20neuropeptide%20calcitonin%20gene-related%20peptide%20%28CGRP%29%20from%20dorsal%20root%20ganglion%20neurons%2C%20and%20reduced%20inflammation%20in%20a%20mouse%20model%20of%20allergic%20asthma%2C%20which%20has%20a%20strong%20neurogenic%20component.%20The%20results%20show%20that%20some%20cationic%20molecules%20applied%20extracellularly%20can%20powerfully%20inhibit%20both%20sodium%20channels%20and%20calcium%20channels%2C%20thereby%20blocking%20both%20nociceptor%20excitability%20and%20pro-inflammatory%20peptide%20release.%22%2C%22date%22%3A%222019-11-25%22%2C%22language%22%3A%22eng%22%2C%22DOI%22%3A%2210.7554%5C%2FeLife.48118%22%2C%22ISSN%22%3A%222050-084X%22%2C%22url%22%3A%22%22%2C%22collections%22%3A%5B%22IXMHRBF6%22%5D%2C%22dateModified%22%3A%222024-10-25T21%3A57%3A18Z%22%7D%7D%5D%7D
Ma, X. C., & Clardy, J. (2025). Spontaneous Generation of an Endogenous RORγt Agonist.
Journal of the American Chemical Society,
147(14), 11688–11692.
https://doi.org/10.1021/jacs.5c02724
Vaelli, P., Fujita, A., Jo, S., Zhang, H.-X. B., Osorno, T., Ma, X., & Bean, B. P. (2024). State-Dependent Inhibition of Nav1.8 Sodium Channels by VX-150 and VX-548.
Molecular Pharmacology,
106(6), 298–308.
https://doi.org/10.1124/molpharm.124.000944
Jain, A., Gyori, B. M., Hakim, S., Jain, A., Sun, L., Petrova, V., Bhuiyan, S. A., Zhen, S., Wang, Q., Kawaguchi, R., Bunga, S., Taub, D. G., Ruiz-Cantero, M. C., Tong-Li, C., Andrews, N., Kotoda, M., Renthal, W., Sorger, P. K., & Woolf, C. J. (2024). Nociceptor-immune interactomes reveal insult-specific immune signatures of pain.
Nature Immunology.
https://doi.org/10.1038/s41590-024-01857-2
Jayakar, S., Shim, J., Jo, S., Bean, B. P., Singeç, I., & Woolf, C. J. (2021). Developing nociceptor-selective treatments for acute and chronic pain.
Science Translational Medicine,
13(619), eabj9837.
https://doi.org/10.1126/scitranslmed.abj9837
Lee, S., Jo, S., Talbot, S., Zhang, H.-X. B., Kotoda, M., Andrews, N. A., Puopolo, M., Liu, P. W., Jacquemont, T., Pascal, M., Heckman, L. M., Jain, A., Lee, J., Woolf, C. J., & Bean, B. P. (2019). Novel charged sodium and calcium channel inhibitor active against neurogenic inflammation.
ELife,
8.
https://doi.org/10.7554/eLife.48118