The study hypothesized that Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) and its receptor PAC1 play a significant role in the pathophysiology of Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS), a chronic bladder condition characterized by pain, discomfort, and urinary dysfunction. The aims were to investigate the expression levels of PACAP in human IC/BPS tissues compared to controls, examine the regulatory role of PACAP/PAC1 in bladder inflammation and dysfunction using a rat model, and evaluate the potential of targeting the PACAP/PAC1 pathway as a novel therapeutic approach for managing IC/BPS symptoms.

This study employed a combined approach involving human bladder tissue samples from IC/BPS patients and a rat model of bladder inflammation to conduct quantitative analyses of PACAP expression. Methods included:
Ethical Approval and Informed Consent: Adherence to ethical standards and acquisition of informed consent from all participants.
Sample Collection: Collection of bladder tissue specimens from diagnosed IC/BPS patients and control subjects.
Transcriptomic Research Methods: Utilization of Trizol reagent kit for RNA extraction, quality assessment via Agilent 2100 Bioanalyzer, and subsequent RNA sequencing.
Animal Model Preparation: Induction of cystitis in Sprague-Dawley rats via cyclophosphamide injections, with assessments including Von Frey filament tests for nociceptive responses and urine spot assays for urination patterns.
Drug Treatments: Evaluation of the effects of PACAP6-38/saline intravesical and intrathecal instillation on bladder function and inflammation.

Upregulation of PACAP: Significant increase in PACAP expression in human IC/BPS tissues and correlation with increased bladder inflammation and hyperactivity in the rat model.
Inflammatory Pathway Involvement: Analysis showing PACAP and PAC1's role in the inflammatory pathways associated with IC/BPS.
Bladder Dysfunction Modulation: Intravesical and intrathecal administration of PACAP6-38 demonstrated effects on bladder function, reducing inflammation and improving bladder compliance and capacity in the rat model.

The results indicate that PACAP and PAC1 are involved in the pathogenesis of IC/BPS through their role in bladder inflammation and dysfunction. The significant upregulation of PACAP in IC/BPS tissues and its association with bladder hyperactivity suggest that PACAP not only contributes to the inflammatory response but also to the sensory regulation and neurotransmitter release affecting bladder function. The therapeutic effects observed with PACAP6-38 treatments in the rat model provide evidence supporting the potential of targeting the PACAP/PAC1 pathway in managing IC/BPS symptoms.

The study provides compelling evidence of PACAP and PAC1's crucial involvement in the pathophysiology of IC/BPS, underscoring their importance in bladder inflammation and dysfunction. The findings advocate for further research into the PACAP/PAC1 pathway as a promising target for developing novel therapeutic strategies for IC/BPS, aiming for better management and relief of symptoms for patients suffering from this challenging condition.