Our previous research in rats has shown that exposure to bladder inflammation during the neonatal period of development markedly enhances the degree of bladder hyperalgesia that occurs in response to a second exposure to bladder inflammation as an adult. Neonatal bladder inflammation also significantly increases micturition frequency and significantly decreases the threshold for micturition reflexes in adulthood. These outcomes are consistent with the primary symptoms of painful bladder syndrome (PBS) / interstitial cystitis (IC) and suggest that neonatal bladder inflammation may be a contributing factor to bladder disorders. The general hypothesis of the present proposal is that neonatal bladder inflammation predisposes an organism to adult bladder pain by impairing the development and/or function of an opioid inhibitory system that normally serves to suppress bladder pain. The specific hypotheses that refine and develop this general hypothesis are tested in the following specific aims:
Specific Aim 1 will test the hypothesis that the estrous cycle influences the magnitude of the endogenous opioid inhibitory response evoked by bladder inflammation in the adult rat.
Specific Aim 2 will test the hypothesis that neonatal bladder inflammation predisposes an organism to adult bladder pain by impairing a descending inhibitory system originating from neurons located in the rostroventral medulla (RVM).
Specific Aim 3 will test the hypothesis that neonatal bladder inflammation predisposes an organism to adult bladder pain by altering <-, :- and/or 4-opioid receptor expression in the spinal cord.
Specific Aim 4 will test the hypothesis that neonatal bladder inflammation predisposes an organism to adult bladder pain by altering spinal cord opioid peptide content.
Specific Aim 5 will test the hypothesis that neonatal bladder inflammation predisposes an organism to adult bladder pain by reducing opioid inhibition of spinal dorsal horn neurons We believe these systematic studies, based on an innovative hypothesis, will lay the groundwork for potential novel therapeutic modalities for the treatment of urinary bladder pain by identifying opposing substrates underlying the development of bladder pain. Translation to the treatment of painful bladder syndromes would be highly probable because we will be able to identify key loci for targeted interventions.

Public Health Relevance

We believe these systematic studies, based on an innovative hypothesis, will lay the groundwork for potential novel therapeutic modalities for the treatment of urinary bladder pain associated with painful bladder syndrome (PBS) / interstitial cystitis (IC) by identifying opposing substrates underlying the development of bladder pain. Translation to the treatment of PBS/IC would be highly probable because we will be able to identify key developmental factors that give rise to the disorders, underlying mechanisms responsible for the disorders, and loci for targeted interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK078655-02S1
Application #
8011777
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Mullins, Christopher V
Project Start
2010-01-20
Project End
2011-01-19
Budget Start
2010-01-20
Budget End
2011-01-19
Support Year
2
Fiscal Year
2010
Total Cost
$45,727
Indirect Cost
Name
University of Alabama Birmingham
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Shaffer, Amber D; Ness, Timothy J; Robbins, Meredith T et al. (2013) Early in life bladder inflammation alters opioid peptide content in the spinal cord and bladder of adult female rats. J Urol 189:352-8
Shaffer, Amber D; Ness, Timothy J; Randich, Alan (2013) Early-in-life bladder inflammation alters U50,488H but not morphine-induced inhibition of visceromotor responses to urinary bladder distension. Neurosci Lett 534:150-4
Shaffer, Amber D; Ball, Chelsea L; Robbins, Meredith T et al. (2011) Effects of acute adult and early-in-life bladder inflammation on bladder neuropeptides in adult female rats. BMC Urol 11:18
Robbins, Meredith T; Deberry, Jennifer; Randich, Alan et al. (2011) Footshock stress differentially affects responses of two subpopulations of spinal dorsal horn neurons to urinary bladder distension in rats. Brain Res 1386:118-26
Ness, T J; Randich, A (2010) Neonatal bladder inflammation alters activity of adult rat spinal visceral nociceptive neurons. Neurosci Lett 472:210-4
DeBerry, Jennifer; Randich, Alan; Shaffer, Amber D et al. (2010) Neonatal bladder inflammation produces functional changes and alters neuropeptide content in bladders of adult female rats. J Pain 11:247-55
Ball, Chelsea L; Ness, Timothy J; Randich, Alan (2010) Opioid blockade and inflammation reveal estrous cycle effects on visceromotor reflexes evoked by bladder distention. J Urol 184:1529-35
Randich, Alan; Mebane, Hannah; Ness, Timothy J (2009) Ice water testing reveals hypersensitivity in adult rats that experienced neonatal bladder inflammation: implications for painful bladder syndrome/interstitial cystitis. J Urol 182:337-42
Ness, T J; Castroman, P J; Randich, A (2009) Acute bladder inflammation differentially affects rat spinal visceral nociceptive neurons. Neurosci Lett 467:150-4
Wesselmann, Ursula; Baranowski, Andrew P; Börjesson, Mats et al. (2009) EMERGING THERAPIES AND NOVEL APPROACHES TO VISCERAL PAIN. Drug Discov Today Ther Strateg 6:89-95

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