Abstract
The Sigma-2 receptor (σ2/TMEM97), recently identified as Tmem97, is a transmembrane protein that is located in the endoplasmic reticulum (ER) and the plasma membrane. While the literature has highlighted ligands targeting Tmem97 for anti-neuropathic effects, its involvement in inflammatory pain-like responses remains understudied compared to neuropathic pain. Here, we aim to characterize Tmem97-associated inflammatory pain-like behaviors using global Tmem97 knockout (KO) and conditional Tmem97 knockout mice (cKO). Results indicate that Tmem97 KO mice exhibit a prolonged hypersensitivity to mechanical stimulation, but not to thermal stimulation, in a complete freud’s adjuvant (CFA)-induced inflammatory pain model (male and female, age 2-3 months). Similarly, Tmem97 floxed mice, crossed with Nav1.8-cre, show prolonged mechanical hypersensitivity but not thermal sensitivity (male and female, age 2-3 months). Three days post-CFA injection, a decrease in Tmem97 RNA expression in the dorsal root ganglion (DRG) is observed, which gradually returned to baseline in tandem with the resolution of inflammatory pain-like responses of wildtype mice. Loss of Tmem97, whether germline or specific to nociceptors, contributes to increased hypersensitivity in a sensory modality-dependent manner. The study’s outcomes provide critical insight into the peripheral role of σ2/TMEM97 in inflammatory pain modulation, suggesting that Tmem97 may be a promising therapeutic target for inflammation-associated pain. Future research aims to unravel the specific mechanisms, including Tmem97-associated cellular calcium response and/or signaling pathway, that may govern inflammatory pain-like responses. Funded by National Institutes of Health (F31NS129269).