MP49-02: Modulation of sensory glia Gq-GPCR signaling in vivo affects spontaneous voiding and bladder function in an animal model of chronic pelvic pain

Alison Xiaoqiao Xie*, Randall Meacham, Anna Malykhina, Aurora, CO

Introduction: Chronic pelvic pain (CPP) is a bothersome and highly prevalent symptom present in many chronic disorders of the pelvis. Afferent hypersensitivity plays an important role in the generation and maintenance of CPP symptoms including visceral pain, urgency and urinary frequency. We previously showed that activation of Gq-G protein coupled receptors (Gq-GPCR) in satellite glial cells (SGCs) decreases lumbosacral nociceptive responses and alleviates visceral hypersensitivity in a mouse model of CPP. The objective of this study was to further investigate the modulatory capacity of satellite glial activation in regulation of spontaneous voiding and bladder function.

Methods: Intravesical instillation of vascular endothelial growth factor (VEGFA) induces sensory nerve remodeling in the urinary bladder, and increases nociceptive responses in the lumbosacral sensory ganglia associated with visceral hypersensitivity. Adult C57BL/6 mice were subjected to three intravesical instillations of VEGFA within a 2-week period. Selective activation of lumbosacral sensory glia was achieved by expressing Gq-coupled Designer Receptors Exclusively Activated by Designer Drugs (Gq-DREADD) in glial acidic fibrillary protein (GFAP+) expressing glia by using Gfap-Gq-DREADD transgenic mice or targeted adeno-associated viral vector (AAV) delivery. Gq-DREADD agonist, clozapine N-oxide (CNO), was used to selectively activate Gq-GPCR signaling in GFAP+ glia in vivo. Micturition patterns were recorded by performing a voiding spot assay (spontaneous voiding) and cystometry in unanesthetized animals (bladder function).

Results: Activation of lumbosacral SGCs significantly altered spontaneous voiding patterns and bladder function in vivo in VEGFA-treated mice. Higher urinary output, shorter intermicturition intervals, and fewer non-voiding contractions were observed in VEGFA-treated animals following activation of Gq-GPCR signaling. The observed glia-mediated neuromodulatory effects were long-lasting and dose-dependent.

Conclusions: Our data demonstrated that activation of sensory glia in the peripheral nervous system significantly regulate bladder functions. Targeting neuron-glia interactions in the sensory ganglia can be used to effectively alleviate visceral pain and regulate voiding function in vivo. Further studies are warranted to test a therapeutic potential of targeting glial cell signaling in treating hypersensitivity-related symptoms in CPP disorders.

Source of Funding: Colorado Pilot Program Mentored Award, CCTSI. "Beyond the neurons: the role of peripheral glia in neurogenic bladder dysfunction". 2019-2021

R01 DK129260-01. "Activating Peripheral Glia to Relieve Visceral Pain in Animal Models of Urological Chronic Pelvic Pain Syndrome (UCPPS)". 2021-2026