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Intrabladder PAC1 Receptor Antagonist, PACAP(6-38), Reduces Urinary Bladder Frequency and Pelvic Sensitivity in Mice Exposed to Repeated Variate Stress (RVS)

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Abstract

Stress causes symptom exacerbation in functional disorders of the urinary bladder. However, the potential mediators and underlying mechanisms of stress effects on micturition reflex function are unknown. We have characterized PACAP (Adcyap1) and PAC1 receptor (Adcyap1r1) signaling in stress-induced urinary bladder dysfunction in mice. We determined PACAP and PAC1 transcripts and protein expressions in the urinary bladder and lumbosacral dorsal root ganglia (DRG) and spinal cord in repeated variate stress (RVS) or control mouse (handling only) groups. RVS in mice significantly (p ≤ 0.01) increased serum corticosterone and urinary bladder NGF content and decreased weight gain. PACAP and PAC1 mRNA and protein were differentially regulated in lower urinary tract tissues with changes observed in lumbosacral DRG and spinal cord but not in urinary bladder. RVS exposure in mice significantly (p ≤ 0.01) increased (2.5-fold) voiding frequency as determined using conscious cystometry. Intrabladder administration of the PAC1 receptor antagonist, PACAP(6-38) (300 nM), significantly (p ≤ 0.01) increased infused volume (1.5–2.7-fold) to elicit a micturition event and increased the intercontraction interval (i.e., decreased voiding frequency) in mice exposed to RVS and in control mice, but changes were smaller in magnitude in control mice. We also evaluated the effect of PAC1 blockade at the level of the urinary bladder on pelvic sensitivity in RVS or control mouse groups using von Frey filament testing. Intrabladder administration of PACAP(6-38) (300 nM) significantly (p ≤ 0.01) reduced pelvic sensitivity following RVS. PACAP/receptor signaling in the CNS and PNS contributes to increased voiding frequency and pelvic sensitivity following RVS and may represent a potential target for therapeutic intervention.

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Acknowledgments

The authors thank Dr. James A. Waschek for his generous gift of transgenic PACAP-EGFP mice breeding pairs. The authors also gratefully acknowledge the research efforts of summer undergraduate research students, some of whom were supported by a NINDS Summer Research Experience in Neuroscience for Undergraduates (R25 NS090623) through the Summer Undergraduate Neuroscience Fellowship Program at UVM. Student researchers included William (Trey) Walker, Michelle Hernandez, Hina Rattu, Neysharie Sánchez-Torres, Jenna McQuesten, Morgan Mathews, Diana Grinberg, Phat (Tony) Chan, Eric Hauke, and Gabrielle Krumgalz.

Funding

This work was funded by National Institutes of Health (NIH) grants DK051369 (MAV), DK060481 (MAV), DK065989 (MAV), and DK120108 (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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Authors and Affiliations

  1. Department of Neurological Sciences, Larner College of Medicine at The University of Vermont, Burlington, VT, 05405, USA

    Beatrice M. Girard, Susan E. Campbell, Katharine I. Beca, Megan Perkins, Harrison Hsiang, Victor May & Margaret A. Vizzard

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  1. Beatrice M. Girard
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  2. Susan E. Campbell
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  3. Katharine I. Beca
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  4. Megan Perkins
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  5. Harrison Hsiang
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  6. Victor May
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  7. Margaret A. Vizzard
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Corresponding author

Correspondence to Margaret A. Vizzard.

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The UVM Institutional Animal Care and Use Committee approved all experimental protocols involving animal (IACUC #08-085, #13-030, #X9-020). The UVM Office of Animal Care Management oversaw all animal use in accordance with AAALAC and NIH guidelines.

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The authors declare that they have no conflict of interest.

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The funding entity, NIH, had no role in the studies described including the following: design, data collection and analysis of studies performed in the Vizzard laboratory, decision to publish, or the preparation of the manuscript. The contents are solely the responsibility of the authors and do not necessarily represent the official views of NIH.

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Girard, B.M., Campbell, S.E., Beca, K.I. et al. Intrabladder PAC1 Receptor Antagonist, PACAP(6-38), Reduces Urinary Bladder Frequency and Pelvic Sensitivity in Mice Exposed to Repeated Variate Stress (RVS). J Mol Neurosci 71, 1575–1588 (2021). https://doi.org/10.1007/s12031-020-01649-x

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