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Effects of CYP-Induced Cystitis on PACAP/VIP and Receptor Expression in Micturition Pathways and Bladder Function in Mice with Overexpression of NGF in Urothelium

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Abstract

We have previously demonstrated nerve growth factor (NGF) regulation of pituitary adenylate cyclase-activating polypeptide (PACAP)/receptors in bladder reflex pathways using a transgenic mouse model of chronic NGF overexpression in the bladder using the urothelial-specific uroplakin II promoter. We have now explored the contribution of target-derived NGF in combination with cyclophosphamide (CYP)-induced cystitis to determine whether additional changes in neuropeptides/receptors are observed in micturition reflex pathways due to the presence of additional inflammatory mediators in the urinary bladder. Quantitative PCR was used to determine PACAP/vasoactive intestinal polypeptide (VIP), substance P, galanin, and receptor transcript expression in the urinary bladder (urothelium, detrusor) in mice with overexpression of NGF in the urothelium (NGF-OE) and wild-type (WT) mice with CYP-induced cystitis (4 h, 48 h, and chronic). With CYP-induced cystitis (4 h), WT and NGF-OE mice exhibited similar changes in galanin transcript expression in the urothelium (30-fold increase) and detrusor (threefold increase). In contrast, PACAP, VIP, and substance P transcripts exhibited differential changes in WT and NGF-OE with CYP-induced cystitis. PAC1, VPAC1, and VPAC2 transcript expression also exhibited differential responses in NGF-OE mice that were tissue (urothelium vs. detrusor) and CYP-induced cystitis duration-dependent. Using conscious cystometry, NGF-OE mice treated with CYP exhibited significant (p ≤ 0.01) increases in voiding frequency above that observed in control NGF-OE mice. In addition, no changes in the electrical properties of the major pelvic ganglia neurons of NGF-OE mice were detected using intracellular recording, suggesting that the urinary bladder phenotype in NGF-OE mice is not influenced by changes in the efferent limb of the micturition reflex. These studies are consistent with target-derived NGF and other inflammatory mediators affecting neurochemical plasticity and the reflex function of micturition pathways.

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Acknowledgments

The authors thank Dr. Debra Cockayne, Roche Palo Alto, for the generous gift of NGF-OE mouse breeders used in the present study. The authors acknowledge the technical support of Abbey Peterson in the conduct of these studies. The authors gratefully acknowledge the technical expertise and support provided by the VT Cancer Center DNA Analysis Facility. This work was funded by National Institutes of Health (NIH) grants DK051369 (MAV), DK060481 (MAV), DK065989 (MAV), and DK081444 (JDT). 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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  1. Department of Anatomy and Neurobiology, University of Vermont, Burlington, VT, 05405, USA

    Beatrice M. Girard, John D. Tompkins, Rodney L. Parsons, Victor May & Margaret A. Vizzard

  2. Department of Neurology, University of Vermont College of Medicine, D415A Given Research Building, Burlington, VT, 05405, USA

    Margaret A. Vizzard

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  1. Beatrice M. Girard
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  2. John D. Tompkins
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Correspondence to Margaret A. Vizzard.

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Girard, B.M., Tompkins, J.D., Parsons, R.L. et al. Effects of CYP-Induced Cystitis on PACAP/VIP and Receptor Expression in Micturition Pathways and Bladder Function in Mice with Overexpression of NGF in Urothelium. J Mol Neurosci 48, 730–743 (2012). https://doi.org/10.1007/s12031-012-9834-1

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