Validation of σ2R/TMEM97 as a neuropathic pain target: Specificity, human expression and mechanism of action

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 produce analgesia in mouse neuropathic pain models with a time course wherein analgesic onset is 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 novel σ2R/TMEM97 binding compound, FEM-1689, requires the presence of the gene to produce analgesia 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 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. Significance Statement Neuropathic pain is a major medical problem that is poorly treated with existing therapeutics. Our findings demonstrate that σ2R/TMEM97 targeting with modulators creates analgesia in a mouse model via a specific action on the receptor. We also identify a potential mechanism of action, ISR inhibition, that links the receptor to cellular signaling events that have preclinical and clinical validation for pain relief. Our work suggests that σ2R/TMEM97 can be selectively engaged by specific small molecules to produce ISR inhibition in a subset of cells that are critical for neuropathic pain. σ2R/TMEM97-targeted therapeutics thus have the potential to offer effective pain relief without the side effects associated with currently available neuropathic pain medicines. ### Competing Interest Statement The authors declare financial relationships. Drs. Martin and Sahn report being co-inventors on patents and pending patent applications related to work described in this article. MSY, JJS, SFM and TJP are co-founders of NuvoNuro, Inc.