title: Intravesical PAC1 Receptor Antagonist, PACAP(6-38), Reduces Urinary Bladder Frequency and Pelvic Sensitivity in NGF-OE Mice.
abstract: Chronic NGF overexpression (OE) in the urothelium, achieved through the use of a highly urothelium-specific uroplakin II promoter, stimulates neuronal sprouting in the urinary bladder, produces increased voiding frequency and non-voiding contractions, and referred somatic sensitivity. Additional NGF-mediated pleiotropic changes might contribute to increased voiding frequency and pelvic hypersensitivity in NGF-OE mice such as neuropeptide/receptor systems including PACAP(Adcyap1) and PAC1 receptor (Adcyap1r1). Given the presence of PAC1-immunoreactive fibers and the expression of PAC1 receptor expression in bladder tissues, and PACAP-facilitated detrusor contraction, whether PACAP/receptor signaling contributes to increased voiding frequency and somatic sensitivity was evaluated in NGF-OE mice. Intravesical administration of the PAC1 receptor antagonist, PACAP(6-38) (300 nM), significantly (p ≤ 0.01) increased intercontraction interval (2.0-fold) and void volume (2.5-fold) in NGF-OE mice. Intravesical instillation of PACAP(6-38) also decreased baseline bladder pressure in NGF-OE mice. PACAP(6-38) had no effects on bladder function in WT mice. Intravesical administration of PACAP(6-38) (300 nM) significantly (p ≤ 0.01) reduced pelvic sensitivity in NGF-OE mice but was without effect in WT mice. PACAP/receptor signaling contributes to the increased voiding frequency and pelvic sensitivity observed in NGF-OE mice.
authors.affiliation: Department of Neurological Sciences, College of Medicine, University of Vermont, D405A Given Research Building, Burlington, VT, 05405, USA.
authors.forename: Beatrice M
authors.initials: BM
authors.lastname: Girard
authors.affiliation: Department of Neurological Sciences, College of Medicine, University of Vermont, D405A Given Research Building, Burlington, VT, 05405, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Malley
authors.affiliation: Department of Neurological Sciences, College of Medicine, University of Vermont, D405A Given Research Building, Burlington, VT, 05405, USA.
authors.forename: Morgan M
authors.initials: MM
authors.lastname: Mathews
authors.affiliation: Department of Neurological Sciences, College of Medicine, University of Vermont, D405A Given Research Building, Burlington, VT, 05405, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: May
authors.affiliation: Department of Neurological Sciences, College of Medicine, University of Vermont, D405A Given Research Building, Burlington, VT, 05405, USA. margaret.vizzard@uvm.edu.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Vizzard
mesh_terms: D000818:Animals; D051379:Mice; D008810:Mice, Inbred C57BL; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000008:administration & dosage / Q000494:pharmacology*; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D014554:Urination
chemical_list: D010446:Peptide Fragments; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; C075647:pituitary adenylate-cyclase-activating-peptide (6-38); D020932:Nerve Growth Factor
keywords: Bladder pain syndrome; Cystometry; Interstitial cystitis; Neuropeptides; Pelvic pain; Urinary bladder