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

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.