Persons with chronic abdominal and pelvic pain disorders comprise a large proportion of patients seeking relief from gastroenterologists, urologists and gynecologists. Two common pelvic disorders, painful bladder syndrome (PBS) and irritable bowel syndrome (IBS), are characterized by altered bladder/bowel habits (e.g., urge, frequency and, in IBS, stool consistency), pain and hypersensitivity. These patients typically exhibit significantly lower response thresholds to provocative stimuli (e.g., cystometry, rectal distension), complain of increased sensitivity during normal organ function, and exhibit increased tenderness in areas of somatic referral which, in addition, are expanded in size. Interestingly, PBS and IBS exist in the absence of an apparent pathobiological cause and are thus characterized as 'functional.'It is widely assumed that functional disorders reflect altered CNS processing, but considerable evidence suggests that persistent afferent drive contributes significantly to the recurrent, unexplained pain and hypersensitivity that characterize them. The objective of this proposal is to determine the mechanisms by which pain and hypersensitivity arise and is maintained as a necessary step in developing better informed and more successful management strategies.
The Aims i nclude:
7 Aim 1 : characterize the proportions of mechano-sensitive and insensitive afferents in electrophysiological experiments in the both the lumbar splanchnic and pelvic nerve innervations of the bladder and colorectum.
7 Aim 2 : evaluate organ hypersensitivity in behavioral experiments, after which the proportions of bladder and colorectal mechanically insensitive afferents (MIAs) will be determined in bladder and colorectum removed from hypersensitive mice. We hypothesize the proportions of MIAs will be significantly reduced in organs from hypersensitive mice relative to normal controls.
7 Aim 3 : identify the 'chemotypes'of mechano-sensitive and insensitive bladder and colorectal dorsal root ganglion neurons in both the lumbar splanchnic and pelvic nerve pathways. We hypothesize that there are significant differences in chemotype between MIAs and mechanosensitive afferents as well as between different mechanosensitive afferents and, further, between organs.

Public Health Relevance

Painful bladder syndrome and irritable bowel syndrome are chronic, debilitating visceral disorders, more common in women, in which pain and hypersensitivity are the most troubling symptoms. These disorders are notoriously difficult to manage. The objective of this research is to determine the mechanisms by which organ pain and hypersensitivity arises and is maintained as a necessary step in developing better informed and more successful management strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK093525-02
Application #
8335201
Study Section
Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
Program Officer
Bavendam, Tamara G
Project Start
2011-09-19
Project End
2015-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$581,292
Indirect Cost
$196,787
Name
University of Pittsburgh
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Schwartz, Erica S; La, Jun-Ho; Young, Erin E et al. (2016) Chronic Prostatitis Induces Bladder Hypersensitivity and Sensitizes Bladder Afferents in the Mouse. J Urol 196:892-901
Brumovsky, Pablo R (2016) Dorsal root ganglion neurons and tyrosine hydroxylase--an intriguing association with implications for sensation and pain. Pain 157:314-20
La, Jun-Ho; Feng, Bin; Kaji, Kaori et al. (2016) Roles of isolectin B4-binding afferents in colorectal mechanical nociception. Pain 157:348-54
Shaffer, Amber D; Feng, Bin; La, Jun-Ho et al. (2015) A novel role for follistatin in hypersensitivity following cystitis. Neurourol Urodyn :
Schwartz, Erica S; Xie, Amy; La, Jun-Ho et al. (2015) Nociceptive and inflammatory mediator upregulation in a mouse model of chronic prostatitis. Pain 156:1537-44
Malet, Mariana; Brumovsky, Pablo R (2015) VGLUTs and Glutamate Synthesis-Focus on DRG Neurons and Pain. Biomolecules 5:3416-37
Feng, Bin; Gebhart, G F (2015) In vitro functional characterization of mouse colorectal afferent endings. J Vis Exp :52310
Zhu, Yi; Feng, Bin; Schwartz, Erica S et al. (2015) Novel method to assess axonal excitability using channelrhodopsin-based photoactivation. J Neurophysiol 113:2242-9
Feng, Bin; Zhu, Yi; La, Jun-Ho et al. (2015) Experimental and computational evidence for an essential role of NaV1.6 in spike initiation at stretch-sensitive colorectal afferent endings. J Neurophysiol 113:2618-34
La, J-H; Gebhart, G F (2014) Condition-specific role of colonic inflammatory molecules in persistent functional colorectal hypersensitivity in the mouse. Neurogastroenterol Motil 26:1730-42

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