Interstitial cystitis (IC) is a chronic inflammatory bladder disease syndrome characterized by urinary frequency, urgency, suprapubic and pelvic pain. The working hypothesis for this proposal is that urinary bladder hyperreflexia and altered sensation that accompany IC are due to an alteration in the primary afferent limb of the micturition reflex and, in part, to an alteration in interneuronal mechanisms in the spinal cord. Urinary bladder hyperreflexia after cystitis may also be due to an alteration in the efferent limb of the micturition reflex. The combination of these changes facilitates a spinal reflex pathway to the urinary bladder by altering various types of synaptic transmission at the interneuronal level in the spinal cord and by altering synaptic transmission to the pelvic ganglia. The following aims address these hypotheses: 1). Previous studies have demonstrated significant increases in urinary bladder neurotrophic factor (NTF) mRNA/protein after chronic cyclophosphamide (CYP)-induced cystitis. Thus, the role that NTFs (eq., nerve growth factor, NGF; brain derived neurotrophic factor, BDNF) play in mediating, functional, neurochemical and organizational plasticity of bladder reflexes after cystitis will be examined by chronic administration of NTFs in vivo. The companion studies will examine the effects of administration of NTF neutralizing antibodies on this plasticity after cystitis. 2). Previous studies have demonstrated dramatic upregulation of the peptide, pituitary adenylate cyciase-activating polypeptide, (PACAP) in bladder afferent and spinal pathways after cystitis. We will extend these observations by examining the functional significance of this upregulation. Thus, the influence of PACAP antagonists on bladder reflexes will be determined. Furthermore, the role of PACAP in cystitis-induced bladder hyperreflexia will be examined in PACAP knockout mice. 3). In the current proposal, we will take a new approach by examining changes in the properties of an efferent component of micturition reflexes. Thus, the electrical and pharmacological properties of bladder postganglionic neurons after CYP-induced cystitis will be examined. These studies will involve, in vitro, intracellular recordings from the cell body of the postganglionic neuron located in the major pelvic ganglion. Axons of these neurons terminate in the inflamed urinary bladder and these cells are also likely to be influenced by the inflammatory milieu.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK051369-08
Application #
6915010
Study Section
Special Emphasis Panel (ZRG1-UROL (01))
Program Officer
Mullins, Christopher V
Project Start
1996-07-29
Project End
2008-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
8
Fiscal Year
2005
Total Cost
$316,588
Indirect Cost
Name
University of Vermont & St Agric College
Department
Neurology
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
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Heppner, Thomas J; Hennig, Grant W; Nelson, Mark T et al. (2018) PACAP38-Mediated Bladder Afferent Nerve Activity Hyperexcitability and Ca2+ Activity in Urothelial Cells from Mice. J Mol Neurosci :
Girard, Beatrice M; Tooke, Katharine; Vizzard, Margaret A (2017) PACAP/Receptor System in Urinary Bladder Dysfunction and Pelvic Pain Following Urinary Bladder Inflammation or Stress. Front Syst Neurosci 11:90
Heppner, Thomas J; Hennig, Grant W; Nelson, Mark T et al. (2017) Rhythmic Calcium Events in the Lamina Propria Network of the Urinary Bladder of Rat Pups. Front Syst Neurosci 11:87
Missig, Galen; Mei, Linda; Vizzard, Margaret A et al. (2017) Parabrachial Pituitary Adenylate Cyclase-Activating Polypeptide Activation of Amygdala Endosomal Extracellular Signal-Regulated Kinase Signaling Regulates the Emotional Component of Pain. Biol Psychiatry 81:671-682
Girard, Beatrice; Peterson, Abbey; Malley, Susan et al. (2016) Accelerated onset of the vesicovesical reflex in postnatal NGF-OE mice and the role of neuropeptides. Exp Neurol 285:110-125
Girard, Beatrice M; Malley, Susan E; Mathews, Morgan M et al. (2016) Intravesical PAC1 Receptor Antagonist, PACAP(6-38), Reduces Urinary Bladder Frequency and Pelvic Sensitivity in NGF-OE Mice. J Mol Neurosci 59:290-9
Bishop, James H; Fox, James R; Maple, Rhonda et al. (2016) Ultrasound Evaluation of the Combined Effects of Thoracolumbar Fascia Injury and Movement Restriction in a Porcine Model. PLoS One 11:e0147393
Gonzalez, Eric J; Heppner, Thomas J; Nelson, Mark T et al. (2016) Purinergic signalling underlies transforming growth factor-?-mediated bladder afferent nerve hyperexcitability. J Physiol 594:3575-88

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