RT Journal Article SR Electronic T1 Urothelial Tight Junction Barrier Dysfunction Sensitizes Bladder Afferents JF eneuro JO eNeuro FD Society for Neuroscience SP ENEURO.0381-16.2017 DO 10.1523/ENEURO.0381-16.2017 A1 Nicolas Montalbetti A1 Anna C. Rued A1 Stefanie N. Taiclet A1 Lori A. Birder A1 F. Aura Kullmann A1 Marcelo D. Carattino YR 2017 UL http://www.eneuro.org/content/early/2017/05/15/ENEURO.0381-16.2017.abstract AB Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic voiding disorder that presents with pain in the urinary bladder and surrounding pelvic region. A growing body of evidence suggests that an increase in the permeability of the urothelium, the epithelial barrier that lines the interior of the bladder, contributes to the symptoms of IC/BPS. To examine the consequence of increased urothelial permeability on pelvic pain and afferent excitability, we overexpressed in the urothelium claudin 2 (Cldn2), a tight-junction associated protein whose message is significantly upregulated in biopsies of IC/BPS patients. Consistent with the presence of bladder-derived pain, rats overexpressing Cldn2 showed hypersensitivity to von Frey filaments applied to the pelvic region. Overexpression of Cldn2 increased the expression of c-Fos and promoted the activation of ERK1/2 in spinal cord segments receiving bladder input, which we conceive is the result of noxious stimulation of afferent pathways. To determine whether the mechanical allodynia observed in rats with reduced urothelial barrier function results from altered afferent activity, we examined the firing of acutely isolated bladder sensory neurons. In patch-clamp recordings, about 30% of the bladder sensory neurons from rats transduced with Cldn2, but not controls transduced with GFP, displayed spontaneous activity. Furthermore, bladder sensory neurons with tetrodotoxin-sensitive action potentials from rats transduced with Cldn2 showed hyperexcitability in response to suprathreshold electrical stimulation. These findings suggest that as a result of a leaky urothelium, the diffusion of urinary solutes through the urothelial barrier sensitizes bladders afferents, promoting voiding at low filling volumes and pain.Significance Statement Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic voiding disorder with symptoms that include urinary urgency, urinary frequency, and pain in the bladder and surrounding pelvic region, in the absence of proven urinary infection or other noticeable pathology. Although the exact cause of this disorder is unknown, numerous lines of evidence suggest that changes in the permeability of the epithelial cell layer that cover the internal surface of the urinary bladder contribute to the perpetuation of the symptoms. The present study examines the mechanisms that mediate lower urinary tract symptoms and pain in an animal model with reduced urothelial barrier function.