Loss of sigma-2 receptor/TMEM97 is associated with neuropathic injury-induced depression-like behaviors in female mice

Abstract

Previous studies have shown that ligands that bind to sigma-2 receptor/TMEM97 (σ₂R/TMEM97), a transmembrane protein, have anxiolytic/antidepressant-like properties and relieve neuropathic pain-like effects in rodents. Despite medical interest in σ₂R/TMEM97, little affective and pain behavioral characterization has been done using transgenic mice, which limits the development of σ₂R/TMEM97 as a viable therapeutic target. Using wild-type (WT) and global Tmem97 knockout (KO) mice, we sought to identify the contribution of Tmem97 in modulating affective and pain-like behaviors using a battery of affective and pain assays, including open field, light/dark preference, elevated plus maze, forced swim test, tail suspension test, and the mechanical sensitivity tests. Our results demonstrate that female Tmem97 KO mice show less anxiety-like and depressive-like behaviors in light/dark preference and tail suspension tests but not in an open field, elevated plus maze, and forced swim tests at baseline. We next performed spared nerve injury in WT and Tmem97 KO mice to assess the role of Tmem97 in neuropathic pain-induced anxiety and depression. WT mice, but not Tmem97 KO mice, developed a prolonged neuropathic pain-induced depressive-like phenotype when tested ten weeks after nerve injury in females. Our results show that Tmem97 plays a role in modulating anxiety-like and depressive-like behaviors in naïve animals with a significant change in the presence of nerve injury in female mice. Overall, these data demonstrate that Tmem97 could be a target to alleviate affective comorbidities of pain disorders.

Significance Statement Chronic pain comorbidities, including anxiety and depression, present a significant public health challenge. Pharmacological agents developed to target the sigma-2 receptor/TMEM97 (σ₂R/TMEM97) have demonstrated promising effects in alleviating anxiety, depression, and pain individually. Our work provides insight on the interaction between σ₂R/TMEM97 and neuropathic pain-induced affective behaviors using transgenic mice, suggesting its potential as a novel therapeutic target for addressing both the pain and psychiatric components in complex chronic pain disorders.