Abstract: Chronic visceral pain disorders, such as interstitial cystitis/bladder pain syndrome (IC/BPS), are among the most difficult types of pain to treat, and response to treatment is often negligible. IC/BPS lacks a well-defined cause, is difficult to diagnose and to date, has no clear therapeutic target. Importantly, both psychological and oxidative stress have been shown to trigger a number of responses which can exacerbate such generalized pain syndromes and may do so by enhancing the effects of pro-nociceptive mediators and promoting oxidative damage. Chronic stress differs from acute or episodic stress as it leads to the persistent elevation of stress mediators that negatively impacts organ function in both animals and humans. Chronic stress increases the risk of disease/pathology and can itself result in hyperalgesia or pain in individuals predisposed to disease. More than half of patients with IC/BPS report daily or constant pain and urinary frequency, exacerbated by stressful circumstances- this exacerbation is termed a pain ‘flare’. While progress has been made to delineate the spinal circuits that gate pain signals emanating from the viscera, lack of a clear understanding of functional pain, their associated co-morbidities and a therapeutic target are a source of frustration for the clinician and patient. Because there are no effective treatments for IC/BPS, our research program is dedicated to discovering mechanisms mediating IC/BPS and applying that knowledge to target identification and validation. In this application, our plans for initial target identification and validation will use two distinct rodent models for IC/BPS which include a ‘bladder-centric’ model (cyclophosphamide-CYP) and a chronic stress model (water avoidance stress or WAS) model. While no available model attempts to mimic particular epidemiologic findings of IC/BPS patients, our findings in both models reveal similarities to human IC/BPS including changes in morphology and function of bladder neural and non-neuronal cells. In this regard, our newest preliminary experiments show that treatment of IC/BPS animals with a purine analog that increases uro-protective purines while simultaneously decreasing uro-damaging purines is effective at lowering pain sensitivity and reverses bladder dysfunction. Taken together, our research teams will use a multidisciplinary approach to validate a non-opioid-based target, namely purine nucleoside phosphorylase (PNPase), for the treatment of visceral pain disorders (e.g., IC/BPS). To achieve our objectives, in Aim 1, this project will determine validity of our target by assessing the role of PNPase in visceral pain using pharmacologic inhibitors in addition to using molecular approaches to knockdown PNPase and, in Aim 2, proof of concept for our target by measuring purines in exosomes isolated from IC/BPS and Hunner’s lesion patient samples to assess the role of PNPase as a contributor to visceral pain. Therapies that can protect mitochondria and reduce oxidative stress are likely to be important in terms of disease prevention. If successful, this therapy will challenge and shift current research and clinical practice paradigms.

Narrative (Relevance) Chronic visceral pain disorders, such as interstitial cystitis/bladder pain syndrome (IC/BPS), are among the most difficult types of pain to treat, and response to treatment is often negligible. Because there are no effective treatments that have shown significant clinical efficacy, our research program is dedicated to the validation of a non-opioid-based target, namely purine nucleoside phosphorylase (PNPase), and applying that knowledge to design and fast-track innovative therapies. Our expertise makes our research group uniquely suited to validate this non-opioid target for the treatment of IC/BPS.