Interstitial cystitis/bladder pain syndrome (IC/BPS) is a refractory condition characterized by chronic pelvic pain accompanied by frequent urination (1). It suffers from high rates of missed diagnosis and inadequate treatment. Conventional stepwise therapeutic strategies primarily focus on ameliorating local bladder pathology but are limited by low levels of evidence and poor long-term efficacy (2). Currently, the mechanisms underlying the co-morbidity of pain and frequent urination in IC/BPS remain poorly understood, with existing research mostly confined to peripheral levels and lacking in-depth exploration of central integration mechanisms. This study aims to elucidate the central mechanisms governing the co-morbidity of pain and urination, thereby providing new theoretical foundations and intervention strategies for multimodal treatment of IC/BPS.

A mouse model of IC/BPS was established. A combination of techniques, including urodynamic assessment, neural tracing, tissue clearing and imaging, optogenetics, in vivo fiber photometry, ex vivo patch-clamp, immunofluorescence, and laser microdissection coupled with single-cell sequencing, was employed to systematically characterize the plasticity changes in the paraventricular hypothalamus nucleus(PVN) and its downstream brain regions during the progression of IC/BPS across structural, functional, electrophysiological, protein expression, and gene expression levels. Pain and urination behaviors were evaluated using hunchback scoring, Von-Frey filaments, urine spot assays, and urodynamic testing. This study was approved by the Institutional Animal Ethics Committee.

Functional magnetic resonance imaging and immunofluorescence results showed significant activation of glutamatergic neurons in the PVN of IC/BPS mice. Calcium signals in these neurons were markedly enhanced following pain and urination stimuli. Functional experiments confirmed that manipulating PVN activity simultaneously modulated both urination and pain behaviors. Optogenetic and chemogenetic activation of this brain region increased urination frequency, decreased bladder pressure, lowered pain thresholds, and increased hunchback scores; inhibition produced opposite effects. Furthermore, circuit tracing revealed that the PVN exerts its effects via projections to glutamatergic neurons in the periaqueductal gray (PAG). Modulation of this circuit concurrently ameliorated both pain and urination behaviors.

These findings systematically reveal, for the first time, the bidirectional regulatory role of PVN glutamatergic neurons in an IC/BPS mouse model. Intervening in this nucleus simultaneously affects both symptom domains, suggesting the PVN serves as a central integration node for pain-frequent urination co-morbidity. This discovery shifts the research perspective on IC/BPS from peripheral organ pathology to the level of central circuit integration.

A shared population of neurons within the PVN concurrently regulates pain and frequent urination in IC/BPS mice, achieving functional integration via the PVN-PAG glutamatergic neural circuit. This finding provides a novel central circuit basis for understanding the co-morbid mechanisms of IC/BPS and offers a theoretical foundation for developing multi-target intervention strategies.

1. Suskind AM, Berry SH, Ewing BA, Elliott MN, Suttorp MJ,Clemens JQ. The prevalence and overlap of interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic painsyndrome in men: results of the RAND interstitial cystitis epidemi-ology male study. J Urol. 2013;189(1):141-5.
2. Clemens JQ, Markossian T, Calhoun EA. Comparison of eco-nomic impact of chronic prostatitis/chronic pelvic pain syn-drome and interstitial cystitis/painful bladder syndrome.Urology. 2009;73(4):743-746

Continence 19S (2026) 102632
DOI: 10.1016/j.cont.2026.102632