POL Scientific / Bladder / Volume 13 / Issue 1 / DOI: 10.14440/bladder.0407
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RESEARCH ARTICLE

Chronic pain without persistent inflammation in an LL-37–induced interstitial cystitis/painful bladder syndrome model: Analgesic effects of a sulfated glycosaminoglycan ether

Austin James Schults1,2 ,  Mark Martin Jensen2 ,  Wanjian Jia1 ,  Siam Oottamasathien1,3*
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1 Section of Pediatric Urology, Division of Urology, Department of Surgery, School of Medicine, University of Utah, Salt Lake City, Utah 84132, United States of America
2 Department of Urology, Massachusetts General Hospital, Harvard Medical School, Harvard University, Boston, Massachusetts 02114, United States of America
3 Department of Urology, Boston Children’s Hospital, Harvard Medical School, Harvard University, Boston, Massachusetts 02115, United States of America
Bladder 2026 , 13(1), e21200082; https://doi.org/10.14440/bladder.0407
Submitted: 26 November 2025 | Revised: 14 January 2026 | Accepted: 19 January 2026 | Published: 27 February 2026
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Background: Chronic bladder pain in interstitial cystitis often persists without overt inflammation, highlighting the need for physiologically relevant experimental models and effective non-opioid therapies. Objective: This study aims to evaluate the impact of persistent inflammation on bladder pain using an LL-37–induced murine model of interstitial cystitis/painful bladder syndrome (IC/PBS). We hypothesized that chronic pain could develop independently of ongoing inflammation and that a sulfated glycosaminoglycan ether (SAGE) compound could attenuate the pain and inflammation elicited by LL-37. Methods: Female C57BL/6 mouse bladders were instilled biweekly with 80 μM LL-37, a human antimicrobial peptide with immunomodulatory properties, for 1 h over four weeks. The analgesic efficacy of SAGE GM-0111, a sulfated hyaluronic acid derivative, was assessed by intravesical instillation immediately prior to LL-37 exposure. Pain responses were quantified using von Frey filaments (0.04–4.0 g). Inflammation and fibrosis were evaluated via myeloperoxidase and total collagen assays, gross examination, and histological analysis. Results: LL-37–treated animals exhibited significantly elevated pain responses (98.00 ± 0.42% positive response) compared to repeated saline controls (55.00 ± 3.80%; p < 0.001) and SAGE GM-0111–treated animals (54.17 ± 3.28%; p < 0.01). Despite pronounced hyperalgesia, no significant inflammation or fibrosis was detected by myeloperoxidase and collagen assays or histological evaluation. Conclusion: Repeated intravesical LL-37 administration induces a chronic pain phenotype that closely models human IC/PBS, wherein bladder pain occurs independently of overt inflammation. Furthermore, SAGE GM-0111 exerts significant analgesic effects in this model. This platform provides a valuable tool for elucidating mechanisms underlying bladder pain in IC/PBS, particularly in cases lacking evident inflammation or fibrosis.

Keywords
Cystitis
Bladder
Pain
Inflammation
Antimicrobial cationic peptides
Funding
This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) R01 grant from the National Institutes of Health (grant number: DK100868); the Primary Children’s Hospital Integrated Science Award; and the National Institutes of Health K12 grant (grant number: UL1RR025764).
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Conflict of interest
Siam Oottamasathien is an equity holder in GlycoMira Therapeutics. The other authors declare they have no competing interests or conflicts of interest to declare.
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Bladder, Electronic ISSN: 2327-2120 Print ISSN: TBA, Published by POL Scientific
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