Highly specific 2R/TMEM97 ligand FEM-1689 alleviates neuropathic pain and inhibits the integrated stress response

The sigma 2 receptor (a2R) 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 a2R/TMEM97 ligands alleviate mechanical hypersensitivity in mouse neuropathic pain models with a time course wherein maximal antinociceptive effect is approximately 24 h following dosing. We sought to understand this unique antineuropathic pain effect by addressing two key questions: do these a2R/TMEM97 compounds act selectively via the receptor, and what is their downstream mechanism on nociceptive neurons? Using male and female conventional knockout mice for Tmem97, we find that a a2R/TMEM97 binding compound, FEM-1689, requires the presence of the gene to produce antinociception in the spared nerve injury model in mice. Using primary mouse dorsal root ganglion neurons, we demonstrate that FEM-1689 inhibits the integrated stress response (ISR) and promotes neurite outgrowth via a a2R/TMEM97-specific action. We extend the clinical translational value of these findings by showing that FEM-1689 reduces ISR and p-eIF2 alpha levels in human sensory neurons and that it alleviates the pathogenic engage-ment of ISR by methylglyoxal. We also demonstrate that a2R/TMEM97 is expressed in human nociceptors and satellite glial cells. These results validate a2R/TMEM97 as a promising target for further development for the treatment of neuropathic pain. Significance Neuropathic pain is a major medical problem that is poorly treated with existing therapeutics. Our findings demonstrate that targeting a2R/TMEM97 with a modulator reduces pain hypersensitivity in a mouse model with exquisite selectivity. We also identify integrated stress response (ISR) inhibition as a potential mechanism of action that links the receptor to cellular signaling events that have preclinical and clinical validation for pain relief. Our work suggests that a2R/ TMEM97 can be selectively engaged by specific small molecules to produce ISR inhibition in a subset of cells that are critical for neuropathic pain. a2R/TMEM97- targeted therapeutics thus have the potential to offer effective pain relief without engagement of opioid receptors.