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

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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.

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  1. Department of Neurological Sciences, College of Medicine, University of Vermont, D405A Given Research Building, Burlington, VT, 05405, USA

    Beatrice M. Girard, Susan E. Malley, Morgan M. Mathews, Victor May & Margaret A. Vizzard

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  1. Beatrice M. Girard
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  2. Susan E. Malley
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  3. Morgan M. Mathews
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  4. Victor May
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  5. Margaret A. Vizzard
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Correspondence to Margaret A. Vizzard.

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This work was funded by National Institutes of Health (NIH) grants DK051369 (MAV), DK060481 (MAV), and DK065989 (MAV). This publication was also supported by grants from the National Center for Research Resources (5 P30 RR 032135) and the National Institute of General Medical Sciences (8 P30 GM 103498) from the NIH.

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Girard, B.M., Malley, S.E., Mathews, M.M. et al. Intravesical PAC1 Receptor Antagonist, PACAP(6–38), Reduces Urinary Bladder Frequency and Pelvic Sensitivity in NGF-OE Mice. J Mol Neurosci 59, 290–299 (2016). https://doi.org/10.1007/s12031-016-0764-1

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