PD01-11 SENSORY GLIAL GQ-GPCR SIGNALING ALLEVIATES VISCERAL PAIN AND IMPROVES MICTURITION FUNCTION IN AN ANIMAL MODEL OF UROLOGICAL CHRONIC PELVIC PAIN SYNDROME

Abstract

You have accessJournal of UrologyInfections/Inflammation/Cystic Disease of the Genitourinary Tract: Interstitial Cystitis (PD01)1 Sep 2021PD01-11 SENSORY GLIAL GQ-GPCR SIGNALING ALLEVIATES VISCERAL PAIN AND IMPROVES MICTURITION FUNCTION IN AN ANIMAL MODEL OF UROLOGICAL CHRONIC PELVIC PAIN SYNDROME Alison Xie, Randall Meacham, and Anna Malykhina Alison XieAlison Xie More articles by this author , Randall MeachamRandall Meacham More articles by this author , and Anna MalykhinaAnna Malykhina More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001965.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Patients with urological chronic pelvic pain syndrome (UCPPS) experience chronic pelvic pain (CPP) and lower urinary tract symptoms (LUTS). Afferent hypersensitivity in bladder-projecting sensory neurons plays an important role in the generation and maintenance of UCPPS symptoms, especially visceral pain and urinary frequency. We found that Gq-GPCR activation in satellite glial cells (SGCs) in the sensory ganglia decreases afferent sensitivity in lumbar nociceptive pathways, and could be a promising and highly innovative approach to alleviate the symptoms of bladder overactivity and pain. In this study, we aimed to test if activation of lumbosacral sensory glial Gq-GPCR signaling alleviates visceral pain, and improves LUTS in UCPPS mouse models. METHODS: A mouse model of UCPPS was induced by intravesical instillation of recombinant mouse vascular endothelial growth factor (VEGFA). VEGF levels were associated with CPP in UCPPS patients, and in animal models of bladder overactivity. In mice, VEGFA induces sensory nerve remodeling in the urinary bladder, visceral mechanical hypersensitivity. Pharmacogenetic activation of spinal and sensory ganglionic glia was achieved by expressing Gq-coupled Designer Receptors Exclusively Activated by Designer Drugs (Gq-DREADD) in GFAP+ glia via Gfap-hM3Dq 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 and to decreases sensory neuronal excitability in vivo in awake animals. Afferent sensitivity and bladder function were evaluated by clinically-relevant visceral nociceptive assays and awake cystometry. RESULTS: Lumbosacral glial Gq-GPCR activation significantly attenuated VEGFA-induced visceral hypersensitivity, increased micturition efficiency, and shortened intermicturition intervals. The glia-mediated neuromodulatory effects were long-lasting and dose-dependent, suggesting broader implication of neuromodulation in treating pain and hypersensitivity in pelvic diseases. CONCLUSIONS: Our data demonstrated that sensory glial-mediated neuromodulation effectively alleviated visceral pain and regulated micturition in animal model of UCPPS by inhibiting afferent excitability in the lumbosacral spinal cord and respective sensory ganglia. These results suggest a strong therapeutic potential of targeting GFAP-expressing glia for the treatment of chronic pelvic pain and LUTS in UCPPS patients. Source of Funding: Colorado Pilot Program Mentored Award, CCTSI, PI: Alison Xiaoqiao XieR01 DK121506-01, PI: Anna Malykhina © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e35-e35 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Alison Xie More articles by this author Randall Meacham More articles by this author Anna Malykhina More articles by this author Expand All Advertisement Loading ...