GLIAL GLUTAMATE TRANSPORTER EAAT2 AND VISCERAL PAIN

肠易激综合征（IBS）是胃肠病学家诊断的主要消化系统疾病， 影响了15-20%的美国人口。IBS患者的主要主诉是复发 腹痛伴排便障碍：由NMDA受体介导的中枢敏感化 激活与这些疾病有关。在这个合作项目中， 谷氨酸转运蛋白（LinC.G-Co-PI）和一种研究疼痛和胃肠功能的转运蛋白（Stephens， R.L.- PI）与谷氨酸转运蛋白功能相关的可塑性在介导内脏疼痛中的作用研究 已经开始了。谷氨酸转运蛋白功能障碍是一个新兴的主题， 慢性和持续性疼痛的病理生理学。人EAAT 2谷氨酸转基因小鼠 谷氨酸转运蛋白，数量上占优势的谷氨酸转运蛋白，负责控制细胞外 谷氨酸盐在内脏痛的小鼠扭体模型中得到显著保护。实验提出了 证实并扩展这些发现，以深入了解内脏痛觉过敏的介导机制。两 提出了以下假设：1）评估内脏伤害感受的其他小鼠模型在以下方面的保护作用： EAAT 2过表达转基因动物和2）与已知位点的谷氨酸摄取增加相关 内脏伤害性神经传递与转基因动物产生的保护作用。验证 EAAT 2过表达的转基因方法对潜在的药物遗传学具有显著的意义， 慢性内脏痛的治疗途径。随后的亚临床方法将产生 EAAT 2基因在新生大鼠伤害性暴露模型中的靶向转移， 超敏反应

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.