Intravesical PAC1 Receptor Antagonist, PACAP(6–38), Reduces Urinary Bladder Frequency and Pelvic Sensitivity in NGF-OE Mice

• Published in: Journal of molecular neuroscience 2016-06, Vol.59 (2), p.290-299
• Main Authors: Girard, Beatrice M., Malley, Susan E., Mathews, Morgan M., May, Victor, Vizzard, Margaret A.
• Format: Article
• Language: English
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Bladder; Cell Biology; Inflammation; Mice; Mice, Inbred C57BL; Nerve Growth Factor - genetics; Nerve Growth Factor - metabolism; Neurochemistry; Neurology; Neuropeptides; Neurosciences; Pain; Peptide Fragments - administration & dosage; Peptide Fragments - pharmacology; Pituitary Adenylate Cyclase-Activating Polypeptide - administration & dosage; Pituitary Adenylate Cyclase-Activating Polypeptide - pharmacology; Proteomics; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide - antagonists & inhibitors; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide - genetics; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide - metabolism; Signal transduction; Smooth muscle; Transgenic animals; Urinary Bladder - drug effects; Urinary Bladder - metabolism; Urinary Bladder - physiology; Urination
• ISSN: 0895-8696; 1559-1166
• DOI: 10.1007/s12031-016-0764-1

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.