Because of current, limited options for treating painful disorders in the lower urinary tract (LUT) such as interstitial cystitis (1C) or chronic pelvic pain syndrome (CPPS), there is a great demand for the development of new treatment strategy. Supported by NIH grant """"""""Afferent plasticity underlying urethral and pelvic pain"""""""" R01 DK57267, 09/01/1999- 08/31/2003, we found that;(1) there is a considerable heterogeneity in afferent fiber populations in visceral neural pathways to the bladder/proximal urethra and somatic neural pathways to the external urethral sphincter (EUS)/pelvic floor, and (2) tissue inflammation of bladder/urethra and nerve injury of somatic pudendal nerves can induce bladder/urethral hyperactivity associated with C-fiber afferent hyperexcitability due to a reduction in different types of voltage-gated K+ currents. Thus, the goals of this proposed project are to further identify the mechanismsinducing afferent hyperexcitability related to LUT pain, especially focusing on the role and neurotrophic factor-dependent regulation of C-fiber afferents (i.e., peptidergic and non-peptidergic populations). We will first examine the effects of the ribosome-inactivating toxin saporin conjugated with isolectin B4, which can theoretically suppress afferent transmission via IB4-binding, non-peptidergic C-fiber afferent pathways. This will allow us to identify the functional role of non-peptidergic C-fiber afferents in pain conditions arising from different regions of the LUT. Secondly, we will explore the regulatory role of two different neurotrophic factors (NGF and GDNF) in the emergence of C-fiber hyperexcitability involved in LUT pain since these two factors reportedly modulate the functional properties of peptidergic and non-peptidergic C-fiber afferent pathways, respectively. Thirdly, we will seek to elucidate molecular identities of voltage-gated K+ (Kv) channels responsible for C-fiber hyperexcitability since altered expression of Kv channels was shown to contribute to C-fiber hyperexcitability in LUT pain conditions in our previous study.
The Specific Aims of this proposal using animals models of urethral or pelvic pain are: I) to investigate the effects of targeting non-peptidergic C-fiber afferent pathways on LUT pain conditions using saporin conjugates;II) to investigate the effects of NGF/GDNF and their antibodies on LUT pain conditions;and III) to identify the changes in expression of Kv channel subunits in LUT afferent neurons and the correlation with a reduction of K+ current subtypes and C-fiber afferent neuron hyperexcitability. The long-term objectives of the research program are to identify the detailed mechanisms and new, effective therapeutic targets for pain conditions in the LUT. This is recognized as a high priority in the urologic care of patients with IC/CPPS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK057267-08
Application #
7740215
Study Section
Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
Program Officer
Mullins, Christopher V
Project Start
1999-09-30
Project End
2011-11-30
Budget Start
2009-12-01
Budget End
2011-11-30
Support Year
8
Fiscal Year
2010
Total Cost
$257,173
Indirect Cost
Name
University of Pittsburgh
Department
Urology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Yoshimura, Naoki; Miyazato, Minoru; Kitta, Takeya et al. (2014) Central nervous targets for the treatment of bladder dysfunction. Neurourol Urodyn 33:59-66
Kashyap, Mahendra; Kawamorita, Naoki; Tyagi, Vikas et al. (2013) Down-regulation of nerve growth factor expression in the bladder by antisense oligonucleotides as new treatment for overactive bladder. J Urol 190:757-64
Honda, Masashi; Yoshimura, Naoki; Hikita, Katsuya et al. (2013) Supraspinal and spinal effects of L-trans-PDC, an inhibitor of glutamate transporter, on the micturition reflex in rats. Neurourol Urodyn 32:1026-30
Takahashi, Ryosuke; Yoshizawa, Tsuyoshi; Yunoki, Takakazu et al. (2013) Hyperexcitability of bladder afferent neurons associated with reduction of Kv1.4 ?-subunit in rats with spinal cord injury. J Urol 190:2296-304
Miyazato, Minoru; Oshiro, Takuma; Chancellor, Michael B et al. (2013) An alpha1-adrenoceptor blocker terazosin improves urine storage function in the spinal cord in spinal cord injured rats. Life Sci 92:125-30
Honda, Masashi; Yoshimura, Naoki; Inoue, Seiya et al. (2013) Inhibitory role of the spinal galanin system in the control of micturition. Urology 82:1188.e9-13
Corcoran, Anthony T; Yoshimura, Naoki; Tyagi, Vikas et al. (2013) Mapping the cytokine profile of painful bladder syndrome/interstitial cystitis in human bladder and urine specimens. World J Urol 31:241-6
Funahashi, Yasuhito; Oguchi, Tomohiko; Goins, William F et al. (2013) Herpes simplex virus vector mediated gene therapy of tumor necrosis factor-? blockade for bladder overactivity and nociception in rats. J Urol 189:366-73
Yoshimura, Naoki; Miyazato, Minoru; Sasaki, Katsumi et al. (2013) Gene therapy for lower urinary tract dysfunction. Int J Urol 20:56-63
Oguchi, T; Funahashi, Y; Yokoyama, H et al. (2013) Effect of herpes simplex virus vector-mediated interleukin-4 gene therapy on bladder overactivity and nociception. Gene Ther 20:194-200

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