Abstract
Interstitial cystitis (IC)/bladder pain syndrome (BPS) is a chronic condition with severe pelvic pain and urinary symptoms significantly impairing quality of life. This study investigated the clinical relevance of the metabotropic glutamate receptor (mGluR) family in IC/BPS. Bladder biopsy samples were taken from 61 patients, including 42 Hunner-type IC, 11 non-Hunner type IC, and 8 controls without IC. Gene expression analysis revealed that mGluR2, mGluR3, and mGluR5 were significantly elevated in patients with IC/BPS compared to controls. Among these, mGluR5 showed the strongest association with pain severity, fibrosis, and lymphoplasmacytic infiltration. Patients with Hunner-type IC also exhibited increased expression of p65 and interleukin-1β, suggesting activation of inflammatory response modulation in IC/BPS. These findings suggest that mGluR5 may contribute to pain through immune response modulation in IC/BPS. Targeting mGluR5 could represent a promising therapeutic strategy to alleviate symptoms and improve patient quality of life.
Similar content being viewed by others
Data availability
All data generated or analysed during this study are included in this published article and its supplementary information files.
References
Kim, A. et al. Histopathological characteristics of interstitial cystitis/bladder pain syndrome without Hunner lesion. Histopathology 71, 415–424 (2017).
Schrepf, A. et al. Inflammation and inflammatory control in interstitial cystitis/bladder pain syndrome: Associations with painful symptoms. Pain 155, 1755–1761 (2014).
Whitmore, K. E. et al. Hunner lesion versus non‐Hunner lesion interstitial cystitis/bladder pain syndrome. Int. J. Urol. 26, 26–34 (2019).
Li, J., Yi, X. & Ai, J. Broaden horizons: The advancement of interstitial cystitis/bladder pain syndrome. Int. J. Mol. Sci. 23, 14594 (2022).
Hanno, P. M., Erickson, D., Moldwin, R. & Faraday, M. M. Diagnosis and treatment of interstitial cystitis/bladder pain syndrome: AUA guideline amendment. J. Urol. 193, 1545–1553 (2015).
Kennedy, J. D. Neuropathic pain: Molecular complexity underlies continuing unmet medical need. J. Med. Chem. 50, 2547–2556 (2007).
Lewis, G. N. & Rice, D. A. Chronic pain: We should not underestimate the contribution of neural plasticity. Crit. Rev. Phys. Rehabil. Med. https://doi.org/10.1615/critrevphysrehabilmed.2013010295 (2014).
Wozniak, M. K., Rojas, C., Wu, Y. & Slusher, S. B. The role of glutamate signaling in pain processes and its regulation by GCP II inhibition. Curr. Med. Chem. 19, 1323–1334 (2012).
Mazzitelli, M., Presto, P., Antenucci, N., Meltan, S. & Neugebauer, V. Recent advances in the modulation of pain by the metabotropic glutamate receptors. Cells 11, 2608 (2022).
Pereira, V. & Goudet, C. Emerging trends in pain modulation by metabotropic glutamate receptors. Front. Mol. Neurosci. 11, 464 (2019).
Carlton, S. M. & Neugebauer, V. Peripheral metabotropic glutamate receptors as drug targets for pain relief. Expert Opin. Ther. Targets 6, 349–361 (2002).
Chiechio, S. & Nicoletti, F. Metabotropic glutamate receptors and the control of chronic pain. Curr. Opin. Pharmacol. 12, 28–34 (2012).
Chiechio, S. Modulation of chronic pain by metabotropic glutamate receptors. Adv. Pharmacol. 75, 63–89 (2016).
Mazzitelli, M., Palazzo, E., Maione, S. & Neugebauer, V. Group II metabotropic glutamate receptors: Role in pain mechanisms and pain modulation. Front. Mol. Neurosci. 11, 383 (2018).
Neugebauer, V. Metabotropic glutamate receptors–Important modulators of nociception and pain behavior. Pain 98, 1–8 (2002).
Varney, M. & Gereau, I. Metabotropic glutamate receptor involvement in models of acute and persistent pain: Prospects for the development of novel analgesics. Curr. Drug. Targets. CNS. Neurol. Disord. 1, 283–296 (2002).
Crock, L. W. et al. Metabotropic glutamate receptor 5 (mGluR5) regulates bladder nociception. Mol. Pain 8, 1744-8069-1748-1720 (2012).
Golubeva, A. V., Zhdanov, A. V., Mallel, G., Dinan, T. G. & Cryan, J. F. The mouse cyclophosphamide model of bladder pain syndrome: Tissue characterization, immune profiling, and relationship to metabotropic glutamate receptors. Physiol. Rep. 2, e00260 (2014).
Simmons, R. M. A., Webster, A. A., Kalra, A. B. & Iyengar, S. Group II mGluR receptor agonists are effective in persistent and neuropathic pain models in rats. Pharmacol. Biochem. Behav. 73, 419–427 (2002).
Zhu, C. Z. et al. Role of central and peripheral mGluR5 receptors in post-operative pain in rats. Pain 114, 195–202 (2005).
Clemens, J. Q., Erickson, D. R., Varela, N. P. & Lai, H. H. Diagnosis and treatment of interstitial cystitis/bladder pain syndrome. J. Urol. 208, 34–42 (2022).
Karim, F., Wang, C.-C. & Gereau, R. W. Metabotropic glutamate receptor subtypes 1 and 5 are activators of extracellular signal-regulated kinase signaling required for inflammatory pain in mice. J. Neurosci. 21, 3771–3779 (2001).
Liu, F. et al. Metabotropic glutamate receptor 5 modulates calcium oscillation and innate immune response induced by lipopolysaccharide in microglial cell. Neuroscience 281, 24–34 (2014).
Shah, A., Silverstein, P. S., Singh, D. P. & Kumar, A. Involvement of metabotropic glutamate receptor 5, AKT/PI3K signaling and NF-κB pathway in methamphetamine-mediated increase in IL-6 and IL-8 expression in astrocytes. J. Neuroinflammation. 9, 1–10 (2012).
Acknowledgements
This work was supported by a research grant from the Konkuk University Medical Center (2022).
Funding
This work was supported by Konkuk University Medical Center Research Grant 2022.
Author information
Authors and Affiliations
Contributions
Y.K., M.L., and A.K. conceived and designed the study. Y.K., B.K., J.S., and M.L. performed data analysis and interpretation. Y.K., B.K., J.S., S.-G.C., S.K., and H.Y. were responsible for data acquisition. Y.K., J.S., M.L., and A.K. drafted the manuscript. Y.K., B.K., and M.L. conducted statistical analysis. Y.K., B.K., J.S., and A.K. processed the data. A.K. supervised the project. All authors reviewed and approved the final manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Ethical approval
The study was conducted in accordance with the principles of the Declaration of Helsinki. This study was approved by the Institutional Review Board of Konkuk Medical Center (KUMC 2020–12-052 and KUMC 2022–04-003). Informed consent was obtained from all participants prior to sample acquisition and retrieval of their health information.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
About this article
Cite this article
Kwak, Y., Kim, B., Seok, J. et al. Metabotropic glutamate receptor 5 expression associates with pain and inflammatory pathways in interstitial cystitis. Sci Rep (2026). https://doi.org/10.1038/s41598-026-43394-y
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41598-026-43394-y
