Receptor-mediated dysfunction of satellite glia and uninjured sensory neurons as a novel link between referred neuropathic pain and bladder disease - PROJECT SUMMARY
Referred pain is both understudied in research and poorly understood in the clinic, particularly for patients with
bladder disease. Bladder pain can significantly lessen quality of life, which is amplified by unacknowledged or
improperly treated pain from the skin. Diagnosis of referred bladder or somatic pain is obfuscated by a lack of
obvious pathology, exacerbating the challenges of finding effective therapeutic approaches. Though the root
cause of such referred pain is unknown, it likely relies on visceral and skin afferent interactions, termed
viscerosomatic crosstalk. Mechanisms of referred pain attributed to the spinal cord fail to explain why patients
with pelvic pain have sensory innervation loss of the lower limb skin that is diagnostic for neuropathic pain.
Preliminary data shows that mechanical hypersensitivity in hind paws of mice with bladder inflammation closely
resembles nerve injury phenotypes and reflect patient experiences of lower limb sensitivity from bladder
inflammation or nerve damage. In the peripheral nervous system, dorsal root ganglia (DRG) neurons are
widely diverse in function and in innervating tissue, where injured and uninjured neurons, and their surrounding
satellite glia, undergo changes after injury that drive pain. Viscerosomatic crosstalk between uninjured bladder
or somatic neurons in DRG could be causing referred pain, but there is a dearth of information about bladder
neuron crosstalk in the DRG. Retrograde neuronal tracing studies confirming DRG can co-housing both
bladder and hind paw skin sensory neurons strongly support this possibility. The proposed research will test
the hypothesis that viscerosomatic crosstalk in DRG after injury results in hyperexcitable physiological
responses of the uninjured circuit, mediated by functional changes in their sensory neurons and
altered signaling with satellite glia. To do this, neurophysiology experiments will utilize intact DRGs to
maintain local communication between neurons and satellite glia, including a novel ex vivo preparation that
leaves the mouse sensory circuit from the hind paw skin to the spinal cord intact. Together with molecular
assays of protein expression, experiments will determine the mechanisms driving activation of tracer-labeled
uninjured neurons by probing activation of satellite glia and two key membrane receptors, transient potential
channel V member 1 (TRPV1), also known as the capsaicin receptor, and Purinocepter 3 (P2X3), a widely
studied adenosine triphosphate receptor, both of which are poorly understood in referred pain that results from
bladder inflammation or nerve injury. Aim 1 is designed to investigate how uninjured hind paw neurons are
physiologically altered after acrolein-induced cystitis, and the possibility that these alterations are mediated by
changes in TRPV1 or P2X3. Aim 2 will explore how uninjured bladder sensory neurons are affected by Spared
Nerve Injury, a robust model of lower limb neuropathic pain. Collectively, these data will help elucidate sensory
neuron crosstalk in DRG as a new biological mechanism underlying referred pain in patients with bladder
disease and provide a starting point for improved diagnosis and novel, effective therapeutic approaches.
