Project Summary The micturition reflex and normal sensation of bladder filling are mediated by non-nociceptive AG-fiber afferents in the pelvic nerve. While pelvic C-fiber afferents do not normally respond to bladder distension, bladder irritation/infection sensitizes these silent pelvic C-fibers to be responsive to bladder distension, causing urinary urgency, frequency and inducing bladder pain. In addition to the pelvic nerve, the hypogastric nerve (HGN) also innervates the bladder and hypogastric afferent fibers respond to bladder distention/irritation. Unfortunately, the role of these afferents in the control of micturition was discounted because bilateral transection of HGNs has no effect on normal physiological bladder voiding. Clinical observations have revealed, however, that HGN afferents contribute to visceral pain and bladder pain in humans. We have recently discovered that the HGN also contains “silent” fibers that are basally unresponsive to bladder distension under normal conditions but are sensitized to respond to these pressures after chemical irritation of the bladder. This suggests that these fibers may play a key role in pathological bladder disorders such as Overactive Bladder (OAB) or Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS), both of which present clinically as urinary urgency, frequency, and, with IC/BPS, bladder associated pain. At present, there is a gap in our understanding of the basic organization of the peripheral and central neural pathways controlling the lower urinary tract, especially in relation to the HGN. Preliminary data shows that electrical stimulation of HGN afferents can decrease bladder capacity in animals with chemically irritated bladders (0.25% acetic acid) but not non-irritated bladders, suggesting HGN nociceptors interact, either directly or indirectly, with the pelvic C-fiber pathways that drive bladder pathology. To further our understanding of the nociceptive pathways regulating bladder pathology, we hypothesize that hypogastric nerve nociceptors modulate bladder overactivity during bladder irritation through a convergence with pelvic nerve nociceptive pathways in the spinal cord and/or the brain. To test this concept, we will anatomically and functionally characterize the central projections of the nociceptive bladder afferent pathway in the HGN using anesthetized cats, electrophysiological methods, c-fos tracing and fMRI imaging. Completion of the proposed Research Plan will reveal the involvement of the HGN afferent pathway in the pathophysiological mechanisms underlying bladder dysfunction and potential new diagnostic and treatment strategies.