Loss of Sigma-2 Receptor/TMEM97 Is Associated with Neuropathic Injury-Induced Depression-Like Behaviors in Female Mice.

Previous studies have shown that ligands that bind to sigma-2 receptor/TMEM97 (sR/TMEM97), a transmembrane protein, have anxiolytic/antidepressant-like properties and relieve neuropathic pain-like effects in rodents. Despite medical interest in sR/TMEM97, little affective and pain behavioral characterization has been done using transgenic mice, which limits the development of sR/TMEM97 as a viable therapeutic target. Using wild-type (WT) and global knock-out (KO) mice, we sought to identify the contribution of 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 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 KO mice to assess the role of in neuropathic pain-induced anxiety and depression. WT mice, but not KO mice, developed a prolonged neuropathic pain-induced depressive-like phenotype when tested 10 weeks after nerve injury in females. Our results show that plays a role in modulating anxiety-like and depressive-like behaviors in naive animals with a significant change in the presence of nerve injury in female mice. Overall, these data demonstrate that could be a target to alleviate affective comorbidities of pain disorders.