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 #
5R01DK093525-03
Application #
8531919
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
2013-08-01
Budget End
2014-07-31
Support Year
3
Fiscal Year
2013
Total Cost
$565,010
Indirect Cost
$192,678
Name
University of Pittsburgh
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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
Brumovsky, Pablo R; La, Jun-Ho; Gebhart, Gerald F (2014) Distribution across tissue layers of extrinsic nerves innervating the mouse colorectum - an in vitro anterograde tracing study. Neurogastroenterol Motil 26:1494-507
Brumovsky, Pablo R; Seal, Rebecca P; Lundgren, Kerstin H et al. (2013) Expression of vesicular glutamate transporters in sensory and autonomic neurons innervating the mouse bladder. J Urol 189:2342-9
Kiyatkin, Michael E; Feng, Bin; Schwartz, Erica S et al. (2013) Combined genetic and pharmacological inhibition of TRPV1 and P2X3 attenuates colorectal hypersensitivity and afferent sensitization. Am J Physiol Gastrointest Liver Physiol 305:G638-48
Schwartz, Erica S; La, Jun-Ho; Scheff, Nicole N et al. (2013) TRPV1 and TRPA1 antagonists prevent the transition of acute to chronic inflammation and pain in chronic pancreatitis. J Neurosci 33:5603-11
Feng, Bin; Kiyatkin, Michael E; La, Jun-Ho et al. (2013) Activation of guanylate cyclase-C attenuates stretch responses and sensitization of mouse colorectal afferents. J Neurosci 33:9831-9
Malet, M; Vieytes, C A; Lundgren, K H et al. (2013) Transcript expression of vesicular glutamate transporters in lumbar dorsal root ganglia and the spinal cord of mice - Effects of peripheral axotomy or hindpaw inflammation. Neuroscience 248C:95-111
Feng, Bin; La, Jun Ho; Schwartz, Erica S et al. (2012) Irritable bowel syndrome: methods, mechanisms, and pathophysiology. Neural and neuro-immune mechanisms of visceral hypersensitivity in irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol 302:G1085-98
Feng, Bin; La, Jun-Ho; Schwartz, Erica S et al. (2012) Long-term sensitization of mechanosensitive and -insensitive afferents in mice with persistent colorectal hypersensitivity. Am J Physiol Gastrointest Liver Physiol 302:G676-83