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Highly specific σ2R/TMEM97 ligand alleviates neuropathic pain and inhibits the integrated stress response.
Yousuf, Muhammad Saad; Sahn, James J; Yang, Hongfen; David, Eric T; Shiers, Stephanie; Moreno, Marisol Mancilla; Iketem, Jonathan; Royer, Danielle M; Garcia, Chelsea D; Zhang, Jennifer; Hong, Veronica M; Mian, Subhaan M; Ahmad, Ayesha; Kolber, Benedict J; Liebl, Daniel J; Martin, Stephen F; Price, Theodore J.
Afiliación
  • Yousuf MS; Center for Advanced Pain Studies and Department of Neuroscience, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX 75080.
  • Sahn JJ; NuvoNuro, Austin, TX 78712.
  • Yang H; Department of Chemistry, University of Texas at Austin, Austin, TX 78712.
  • David ET; NuvoNuro, Austin, TX 78712.
  • Shiers S; Department of Chemistry, University of Texas at Austin, Austin, TX 78712.
  • Moreno MM; Center for Advanced Pain Studies and Department of Neuroscience, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX 75080.
  • Iketem J; Center for Advanced Pain Studies and Department of Neuroscience, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX 75080.
  • Royer DM; Center for Advanced Pain Studies and Department of Neuroscience, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX 75080.
  • Garcia CD; Center for Advanced Pain Studies and Department of Neuroscience, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX 75080.
  • Zhang J; Center for Advanced Pain Studies and Department of Neuroscience, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX 75080.
  • Hong VM; Center for Advanced Pain Studies and Department of Neuroscience, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX 75080.
  • Mian SM; Center for Advanced Pain Studies and Department of Neuroscience, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX 75080.
  • Ahmad A; Center for Advanced Pain Studies and Department of Neuroscience, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX 75080.
  • Kolber BJ; Center for Advanced Pain Studies and Department of Neuroscience, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX 75080.
  • Liebl DJ; Center for Advanced Pain Studies and Department of Neuroscience, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX 75080.
  • Martin SF; Center for Advanced Pain Studies and Department of Neuroscience, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX 75080.
  • Price TJ; University of Miami School of Medicine, Miami, FL.
bioRxiv ; 2023 Oct 17.
Article en En | MEDLINE | ID: mdl-37090527
The Sigma 2 receptor (σ2R) was described pharmacologically more than three decades ago, but its molecular identity remained obscure until recently when it was identified as transmembrane protein 97 (TMEM97). We and others have shown that σ2R/TMEM97 ligands alleviate mechanical hypersensitivity in mouse neuropathic pain models with a time course wherein maximal anti-nociceptive effect is approximately 24 hours following dosing. We sought to understand this unique anti-neuropathic pain effect by addressing two key questions: do these σ2R/TMEM97 compounds act selectively via the receptor, and what is their downstream mechanism on nociceptive neurons? Using male and female conventional knockout (KO) mice for Tmem97, we find that a new σ2R/TMEM97 binding compound, FEM-1689, requires the presence of the gene to produce anti-nociception in the spared nerve injury model in mice. Using primary mouse dorsal root ganglion (DRG) neurons, we demonstrate that FEM-1689 inhibits the integrated stress response (ISR) and promotes neurite outgrowth via a σ2R/TMEM97-specific action. We extend the clinical translational value of these findings by showing that FEM-1689 reduces ISR and p-eIF2α levels in human sensory neurons and that it alleviates the pathogenic engagement of ISR by methylglyoxal. We also demonstrate that σ2R/TMEM97 is expressed in human nociceptors and satellite glial cells. These results validate σ2R/TMEM97 as a promising target for further development for the treatment of neuropathic pain.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: BioRxiv Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: BioRxiv Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos