Functional gastrointestinal disorders such as irritable bowel syndrome (IBS) are characterized by pain and discomfort and enhanced sensitivity to gastrointestinal stimuli in the absence of a demonstrable organic cause (i.e., there are no mechanical, biochemical or inflammatory conditions to explain the symptoms). Visceral hypersensitivity thus differs from somatic hyperalgesia, which is commonly associated with tissue injury and inflammation. Because the anatomical organization of visceral afferent innervation and adequate noxious stimuli for viscera significantly differ from the innervation and adequate stimuli in the somatic realm, peripheral mechanisms of visceral hypersensitivity differ from those of somatic hyperalgesia and are not well understood. The long term objective of this research program is to understand peripheral mechanisms of visceral hypersensitivity. The current application proposes to continue to establish behavioral relevance of stimuli and treatments before subsequent examination of peripheral contributions to the development of visceral hypersensitivity. The peripheral receptors to be examined for contributions to colon hypersensitivity include ASIC3, TRPV1, P2X2-3, and PAR2, all of which have been implicated in visceral hypersensitivity. For each of these receptors: 1) Their contribution to baseline and enhanced responses (hypersensitivity) to colon distension 1-14 days after colon insult (intracolonic zymosan) will be examined in awake, behaving mice, 2) Mechano-and chemo-sensitivity of pelvic nerve and lumbar splanchnic nerve fiber terminals in the colon will be studied using an in vitro colon-nerve preparation, and 3) Whole cell currents and excitability of colon sensory neurons, identified by content of retrograde tracer will be studied. The overall hypothesis is that these 4 ligand-gated ion channels contribute to mechano-transduction in the colon. We also hypothesize that protons and/or endogenous mediators (e.g., ATP, mast cell tryptase, serotonin) contribute to visceral hypersensitivity and can do so in the absence of frank tissue damage, which is relevant to IBS and other functional gastrointestinal disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS019912-23
Application #
6929393
Study Section
Special Emphasis Panel (ZRG1-IFCN-K (02))
Program Officer
Porter, Linda L
Project Start
1983-07-01
Project End
2006-04-30
Budget Start
2005-07-01
Budget End
2006-04-30
Support Year
23
Fiscal Year
2005
Total Cost
$284,636
Indirect Cost
Name
University of Iowa
Department
Pharmacology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Malet, Mariana; Brumovsky, Pablo R (2015) VGLUTs and Glutamate Synthesis-Focus on DRG Neurons and Pain. Biomolecules 5:3416-37
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
La, J H; Schwartz, E S; Gebhart, G F (2011) Differences in the expression of transient receptor potential channel V1, transient receptor potential channel A1 and mechanosensitive two pore-domain K+ channels between the lumbar splanchnic and pelvic nerve innervations of mouse urinary bladder and col Neuroscience 186:179-87
Brumovsky, Pablo R; Seroogy, Kim B; Lundgren, Kerstin H et al. (2011) Some lumbar sympathetic neurons develop a glutamatergic phenotype after peripheral axotomy with a note on VGLUT?-positive perineuronal baskets. Exp Neurol 230:258-72
Brumovsky, Pablo R; Robinson, David R; La, Jun-Ho et al. (2011) Expression of vesicular glutamate transporters type 1 and 2 in sensory and autonomic neurons innervating the mouse colorectum. J Comp Neurol 519:3346-66
Tanaka, T; Shinoda, M; Feng, B et al. (2011) Modulation of visceral hypersensitivity by glial cell line-derived neurotrophic factor family receptor α-3 in colorectal afferents. Am J Physiol Gastrointest Liver Physiol 300:G418-24
Schwartz, Erica S; Christianson, Julie A; Chen, Xiaowei et al. (2011) Synergistic role of TRPV1 and TRPA1 in pancreatic pain and inflammation. Gastroenterology 140:1283-1291.e1-2
Feng, Bin; Gebhart, G F (2011) Characterization of silent afferents in the pelvic and splanchnic innervations of the mouse colorectum. Am J Physiol Gastrointest Liver Physiol 300:G170-80
La, Jun-Ho; Gebhart, G F (2011) Colitis decreases mechanosensitive K2P channel expression and function in mouse colon sensory neurons. Am J Physiol Gastrointest Liver Physiol 301:G165-74
Feng, Bin; Brumovsky, Pablo R; Gebhart, Gerald F (2010) Differential roles of stretch-sensitive pelvic nerve afferents innervating mouse distal colon and rectum. Am J Physiol Gastrointest Liver Physiol 298:G402-9

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