Chronic visceral hypersensitivity is a common feature of a number of debilitating human syndromes, often occurring following inflammation. This hypersensitivity has been proposed to develop due to interactions between inflamed tissues and the primary sensory neurons that innervate these structures. In the previous funding period we found that visceral organs (colon, bladder, pancreas and stomach) are densely innervated by afferents expressing TRPV1 and/or TRPA1, two channels that have been shown to be required for development of inflammatory hyperalgesia. We also found that all members of the GDNF family of growth factors could, like NGF, sensitize primary sensory neurons and that these growth factors produced greater potentiation at lower doses than NGF. Preliminary data generated for this application show that inflammation of cutaneous or visceral structures induces significant increases in mRNA for GDNF family members. Using our ex vivo physiological preparation we found that the colon is innervated by at least two functionally discrete populations of neurons and that TRPV1 was exclusively expressed in a population that had previously been identified as mechanically sensitive, high threshold, nociceptors. Thus, the general hypothesis of the proposed studies is that visceral hyperalgesia is initiated by increased sensitivity selectively in the TRPV1/TRPA1- expressing population of visceral nociceptors and that this is regulated, at least in part, by changes in growth factors in the inflamed tissues. Our general hypothesis will be tested in three Specific Aims: SA1: Test the hypothesis that hypersensitivity of colon and bladder are accompanied by upregulation of the GDNF family of growth factors and that these growth factors can sensitize identified, dissociated, visceral afferents. Real-time PCR and Western analysis will be used to confirm changes in growth factor expression in colon and bladder following inflammatory insult. Spinal sensory ganglia will be assayed for changes in TRPV1, TRPA1, trkA, ret and GFR11-3. Calcium imaging will be used to determine how GDNF family members affect response properties of identified, dissociated colonic and bladder afferents in neurons isolated from naove mice and mice with inflamed organs. SA2: Test the hypothesis that neonatal or adult inflammation produces hypersensitivity specifically in TRPV1-positive afferents. We have developed a novel ex vivo preparation that allows intracellular recordings from intact visceral afferents. We will use this paradigm to study naive and inflamed colon and bladder afferents. We will determine if inflammation of one organ produces hypersensitivity in another, and whether neonatal injury produces long-term changes in adult neurons. SA3: Test the hypothesis that artemin responsive afferents are required for induction of visceral hypersensitivity in vivo. One of the most exciting findings from our lab is that there is a significant population of visceral nociceptors that express a combination of GFR13, trkA, TRPV1 and TRPA1. We will use a cell toxin that specifically targets these neurons to determine if it can be used to ablate these neurons to prevent or reverse chronic visceral pain.

Public Health Relevance

Abdominal, thoracic and pelvic organ pain is the number one reason for patient visits to doctor's offices in the US. These organs are innervated by different types of sensory neurons. The goal of these studies is to determine if a specific type of neuron is responsible for persistent pain sensations and whether these can be ablated without affecting normal organ function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS050758-08
Application #
8238365
Study Section
Special Emphasis Panel (ZRG1-IFCN-E (02))
Program Officer
Babcock, Debra J
Project Start
2005-01-15
Project End
2013-10-28
Budget Start
2012-03-01
Budget End
2013-10-28
Support Year
8
Fiscal Year
2012
Total Cost
$324,778
Indirect Cost
$110,403
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
DeBerry, Jennifer J; Schwartz, Erica S; Davis, Brian M (2014) TRPA1 mediates bladder hyperalgesia in a mouse model of cystitis. Pain 155:1280-7
Stopczynski, Rachelle E; Normolle, Daniel P; Hartman, Douglas J et al. (2014) Neuroplastic changes occur early in the development of pancreatic ductal adenocarcinoma. Cancer Res 74:1718-27
Malin, Sacha; Molliver, Derek; Christianson, Julie A et al. (2011) TRPV1 and TRPA1 function and modulation are target tissue dependent. J Neurosci 31:10516-28
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
Stucky, Cheryl L; Dubin, Adrienne E; Jeske, Nathaniel A et al. (2009) Roles of transient receptor potential channels in pain. Brain Res Rev 60:2-23
Christianson, Julie A; Bielefeldt, Klaus; Altier, Christophe et al. (2009) Development, plasticity and modulation of visceral afferents. Brain Res Rev 60:171-86
Malin, Sacha A; Christianson, Julie A; Bielefeldt, Klaus et al. (2009) TPRV1 expression defines functionally distinct pelvic colon afferents. J Neurosci 29:743-52
Bielefeldt, Klaus; Davis, Brian; Binion, David G (2009) Pain and inflammatory bowel disease. Inflamm Bowel Dis 15:778-88
McIlwrath, S L; Davis, B M; Bielefeldt, K (2009) Deletion of P2X3 receptors blunts gastro-oesophageal sensation in mice. Neurogastroenterol Motil 21:890-e66
Malin, Sacha A; Davis, Brian M (2008) Postnatal roles of glial cell line-derived neurotrophic factor family members in nociceptors plasticity. Sheng Li Xue Bao 60:571-8

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