GLIAL GLUTAMATE TRANSPORTER EAAT2 AND VISCERAL PAIN

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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.