Urinary bladder sigma-1 receptors: A new target for cystitis treatment González-Cano, Rafael Artacho Cordón, Antonia Romero Martínez, Lucía Tejada, Miguel Ángel Nieto López, Francisco Rafael Merlos, Manuel Cañizares García, Francisco Javier Cendán Martínez, Cruz Miguel Fernández Segura, Eduardo Baeyens Cabrera, José Manuel Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.phrs.2020.104724. No adequate treatment is available for painful urinary bladder disorders such as interstitial cystitis/bladder pain syndrome, and the identification of new urological therapeutic targets is an unmet need. The sigma-1 receptor (σ1-R) modulates somatic pain, but its role in painful urological disorders is unexplored. The urothelium expresses many receptors typical of primary sensory neurons (e.g. TRPV1, TRPA1 and P2X3) and high levels of σ1- R have been found in these neurons; we therefore hypothesized that σ1-R may also be expressed in the urothelium and may have functional relevance in this tissue. With western blotting and immunohistochemical methods, we detected σ1-R in the urinary bladder in wild-type (WT) but not in σ1-R-knockout (σ1-KO) mice. Interestingly, σ1-R was located in the bladder urothelium not only in mouse, but also in human bladder sections. The severity of histopathological (edema, hemorrhage and urothelial desquamation) and biochemical alterations (enhanced myeloperoxidase activity and phosphorylation of extracellular regulated kinases 1/2 [pERK1/2]) that characterize cyclophosphamide-induced cystitis was lower in σ1-KO than in WT mice. Moreover, cyclophosphamide-induced pain behaviors and referred mechanical hyperalgesia were dose-dependently reduced by σ1-R antagonists (BD-1063, NE-100 and S1RA) in WT but not in σ1-KO mice. In contrast, the analgesic effect of morphine was greater in σ1-KO than in WT mice. Together these findings suggest that σ1-R plays a functional role in the mechanisms underlying cyclophosphamide-induced cystitis, and modulates morphine analgesia against urological pain. Therefore, σ1-R may represent a new drug target for urinary bladder disorders. 2020-06-02T07:00:44Z 2020-06-02T07:00:44Z 2020-05 info:eu-repo/semantics/article R. González-Cano, et al. Urinary bladder sigma-1 receptors: A new target for cystitis treatment. Pharmacological Research 155 (2020) 104724 [https://doi.org/10.1016/j.phrs.2020.104724] http://hdl.handle.net/10481/62319 10.1016/j.phrs.2020.104724 eng http://creativecommons.org/licenses/by/3.0/es/ info:eu-repo/semantics/openAccess Atribución 3.0 España Elsevier