The Sigma-2 receptor/TMEM97 (σ2/TMEM97) is a transmembrane protein located on the endoplasmic reticulum and plasma membrane and has emerged as a promising target for pain therapy. Although selective ligands, including FEM-1689 and CM-398, have shown anti-neuropathic activity in murine models, the role of σ2/TMEM97 in visceral pain has not been investigated. Given σ2/TMEM97’s role in inflammatory and neuropathic pain, this study aimed to determine the protein’s significance in modulating bladder-pain like changes in mice as a model for interstitial cystitis/bladder pain syndrome (IC/BPS). IC/BPS is a chronic bladder inflammatory condition characterized by urinary discomfort, pain and incontinence. We hypothesized that Tmem97 knockout (Tmem97 KO) female mice would exhibit increased pain-like behaviors compared to C57Bl/6J wildtype (WT) female mice in a cyclophosphamide (CYP)-induced IC/BPS model. Baseline results of pain-like behavior were taken prior to injection of CYP. After baseline testing, WT and global Tmem97 KO female mice of 8-12 weeks age were randomly administered either saline or CYP (20mg/mL) via intraperitoneal injection 3 times over 5 days. This formed four experimental groups: WT saline (n=12), WT CYP (n=10), KO saline (n=10), and KO CYP (n=11). 6-8 days after the first injection, pain-like responses were measured using the abdominal von Frey assay, real-time void spot assay, and urinary bladder distension-visceromotor response (UBD-VMR) assay. These different assays evaluated different aspects of bladder function. Mice were then sacrificed, and bladders were harvested and frozen for in situ hybridization and H&E staining. With in situ hybridization, we validated the absence of Tmem97 expression in Tmem97 KO bladder tissue. Results show minimal differences between Tmem97 KO and WT mice both at baseline and following peripheral bladder sensitization. Overall, these data suggest that σ2/TMEM97 signaling is not a major driver of visceral pain. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Jaiswal et al. (Fri,) studied this question.