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PACAP/PAC1 Expression and Function in Micturition Pathways

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Abstract

Neural injury, inflammation, or diseases commonly and adversely affect micturition reflex function that is organized by neural circuits in the CNS and PNS. One neuropeptide receptor system, pituitary adenylate cyclase-activating polypeptide (PACAP; Adcyap1), and its cognate receptor, PAC1 (Adcyap1r1), have tissue-specific distributions in the lower urinary tract. PACAP and associated receptors are expressed in the LUT and exhibit changes in expression, distribution, and function in preclinical animal models of bladder pain syndrome (BPS)/interstitial cystitis (IC), a chronic, visceral pain syndrome characterized by pain, and LUT dysfunction. Blockade of the PACAP/PAC1 receptor system reduces voiding frequency and somatic (e.g., hindpaw, pelvic) sensitivity in preclinical animal models and a transgenic mouse model that mirrors some clinical symptoms of BPS/IC. The PACAP/receptor system in micturition pathways may represent a potential target for therapeutic intervention to reduce LUT dysfunction following urinary bladder inflammation.

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Abbreviations

ATP:

Adenosine triphosphate

BOO:

Bladder outlet obstruction

BPS:

Bladder pain syndrome

CGRP:

Calcitonin-gene related peptide

CNS:

Central nervous system

CYP:

Cyclophosphamide

DO:

Detrusor overactivity

DRG:

Dorsal root ganglion

GPCR:

G protein-coupled receptor

HPA:

Hypothalamic-pituitary-adrenal

IC:

Interstitial cystitis

LUT:

Lower urinary tract

NGF:

Nerve growth factor

NGF-OE:

Nerve growth factor overexpression

NVC:

Non-voiding bladder contraction

PAC1:

PACAP type I receptor

PACAP:

Pituitary adenylate cyclase-activating polypeptide

PAG:

Periaqueductal gray

PC:

Pheochromocytoma

PMC:

Pontine micturition center

PNS:

Peripheral nervous system

Sub-P:

Substance P

TrkA:

Receptor tyrosine kinase A, tropomyosin-related kinase A

TrkB:

Receptor tyrosine kinase B, tropomyosin-related kinase B

TrkC:

Receptor tyrosine kinase C, tropomyosin-related kinase C

VIP:

Vasoactive intestinal polypeptide

VPAC1:

VIP receptor 1

VPAC2:

VIP receptor 2

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Funding

Research described herein was funded by the National Institutes of Health (NIH) Grants RO1-DK051369 (MAV) and RO1-DK060481 (MAV). This publication was also made possible by NIH Grants: 5 P30 RR032135 from the COBRE Program of the National Center for Research Resources and 8 P30 GM103498 from the National Institute of General Medical Sciences.

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Authors and Affiliations

  1. Department of Neurological Sciences, The Robert Larner, M.D. College of Medicine at The University of Vermont, Given Building, D405A, Burlington, VT, 05405, USA

    Jacqueline Ojala, Katharine Tooke, Harrison Hsiang, Beatrice M. Girard, Victor May & Margaret A. Vizzard

Authors
  1. Jacqueline Ojala
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  2. Katharine Tooke
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  3. Harrison Hsiang
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  4. Beatrice M. Girard
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  5. Victor May
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  6. Margaret A. Vizzard
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Contributions

K.T., J.O., B.G., H.H., V.M., and M.V. conceived, discussed, and outlined the review. K.T., J.O., B.G., H.H., V.M., and M.V. drafted and revised the paper.

Corresponding author

Correspondence to Margaret A. Vizzard.

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Studies Involving Animal Research

The studies described from the Vizzard laboratory were performed in accordance with institutional and national guidelines and regulations. The University of Vermont Institutional Animal Care and Use Committee approved all experimental protocols involving animal use. Animal care was under the supervision of the University of Vermont’s Office of Animal Care Management in accordance with the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) and National Institutes of Health guidelines. All efforts were made to minimize the potential for animal pain, stress, or distress.

Conflicts of Interest

The authors declare that the research described from the Vizzard laboratory were conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The funding entity, NIH, had no role in the studies described including: design, data collection, and analysis of studies performed in the Vizzard laboratory, decision to publish, or preparation of the review. The contents are solely the responsibility of the authors and do not necessarily represent the official views of NIH.

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Ojala, J., Tooke, K., Hsiang, H. et al. PACAP/PAC1 Expression and Function in Micturition Pathways. J Mol Neurosci 68, 357–367 (2019). https://doi.org/10.1007/s12031-018-1170-7

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  • DOI: https://doi.org/10.1007/s12031-018-1170-7

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