Characterization of Hypogastric Afferent Pathway Involved in Urinary Bladder Function and Dysfunction

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.

Grant Number: 5R01DK136505-03
NIH Institute/Center: NIH
Principal Investigator: JONATHAN BECKEL