GLIAL GLUTAMATE TRANSPORTER EAAT2 AND VISCERAL PAIN

描述（由申请人提供）：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15-20%的美国人口。IBS患者的主要主诉是反复腹痛伴排便紊乱。NMDA受体激活介导的中枢致敏作用与这些疾病有关。在一个研究谷氨酸转运蛋白的实验室（Lin C.G-Co-首席研究员）和一个研究疼痛和胃肠道功能的实验室（Stephens，R.L.主要研究者）已经启动了与谷氨酸转运体功能相关的可塑性在介导内脏疼痛中的作用的研究。谷氨酸转运体功能障碍是慢性和持续性疼痛病理生理学中的一个新兴主题。过表达人EAAT 2谷氨酸转运蛋白（负责控制细胞外谷氨酸的定量显性谷氨酸转运蛋白）的转基因小鼠在内脏痛的小鼠扭体模型中受到显著保护。实验拟证实和扩展这些发现，以深入了解介导内脏痛觉过敏的机制。提出了两个假设; 1）评估其他内脏伤害感受的鼠模型在EAAT 2过表达转基因动物中的保护作用，2）将已知内脏伤害感受神经传递位点的谷氨酸摄取增加与转基因动物产生的保护作用相关联。EAAT 2过表达的转基因方法的验证对慢性内脏痛治疗的潜在药物遗传学途径具有显著意义。随后的亚临床方法将是在新生儿有害暴露的大鼠模型中产生EAAT 2的靶向基因转移，该模型产生内脏高敏感性。

DESCRIPTION (provided by applicant): 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.