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-Principal Investigator) and one that studies pain and gastrointestinal function (Stephens, R.L.-Principal Investigator) 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 overexpressing human 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 overexpressing transgenic animals and 2) to correlate augmented glutamate uptake at known sites 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. ? ? ?
| 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 |
