irritable bowel syndrome (IBS) is the leading digestive disease diagnosis among gastroenterologists and affect 15-20% of the US population. The predominant complaint of IBS patients is RECURRENT ABDOMINAL PAIN with disturbed bowel movements.Central sensitization mediated by the NMDA receptor activation is implicated in these disorders. In this collaborative project between a laboratory that studies glutamate transporters (Lin C.G-Co-PI) and one that studies pain and gastrointestinal function (Stephens, R.L.-PI) the study of the role of plasticity related to glutamate transporter function in mediating visceral pain has been initiated. Dysfunction of glutamate transporter function is an emerging theme in the pathophysiology of chronic and persistant pain. Transgenic mice overexpressinghuman EAAT2 glutamate transporter, the quantitatively dominant glutamate transporter responsible for controlling extracellular glutamate, were markedly protected in the murine writhing model of visceral pain. Experiments are proposed to confirm and extend these findings to gain insight into mechanisms mediating visceral hyperalgesia. Two hypotheses are proposed; 1)to assess other murine models of visceral nociceptions for protective effect in EAAT2 overexpressingtransgenic animals and 2) to correlate augmented glutamate uptake at knownsites of visceral nociceptive neurotransmission with protective effects produced by transgenic animals. Validation of the transgenic approach of EAAT2 overexpression has marked implications for potential pharmacogenetic avenues of therapy of chronic visceral pain. Subsequent subclinical approaches would be to produce targeted gene transfer of EAAT2 in rat models of neonatal noxious exposure which produces visceral hypersensitivity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
3R21DK071839-02S1
Application #
7617329
Study Section
Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
Program Officer
Hamilton, Frank A
Project Start
2008-06-01
Project End
2010-02-28
Budget Start
2008-06-01
Budget End
2010-02-28
Support Year
2
Fiscal Year
2008
Total Cost
$5,796
Indirect Cost
Name
Ohio State University
Department
Physiology
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Roman, K; Yang, M; Stephens Jr, Robert L (2013) Characterization of the Visceral Antinociceptive Effect of Glial Glutamate Transporter GLT-1 Upregulation by Ceftriaxone. ISRN Pain 2013:726891
Yang, M; Roman, K; Chen, D-F et al. (2011) GLT-1 overexpression attenuates bladder nociception and local/cross-organ sensitization of bladder nociception. Am J Physiol Renal Physiol 300:F1353-9
Stephens Jr, Robert L (2011) Glutamate transporter activators as anti-nociceptive agents. Eurasian J Med 43:182-5
Lin, Yuan; Tian, Guilian; Roman, Kenny et al. (2009) Increased glial glutamate transporter EAAT2 expression reduces visceral nociceptive response in mice. Am J Physiol Gastrointest Liver Physiol 296:G129-34