Visceral hypersensitivity is the leading complaint of functional bowel disorders. Central sensitization mediated by glutamate receptor activation is implicated in pathophysiology of visceral pain. The glial glutamate transporter EAAT2 is the principal mediator of glutamate clearance to terminate glutamate-mediated responses. Transgenic mice over-expressing human EAAT2 (EAAT2 mice), which exhibited a 2-fold enhanced glutamate uptake, showed 39% less writhing response to intraperitoneal acetic acid than non-transgenic littermates. Moreover, EAAT2 transgenic mice showed a 53-64% reduction in visceromotor response (VMR) to colo-rectal distension (CRD) when assessing the response to graded increase in pressures. Corroborating the involvement of enhanced glutamate uptake, wild-type mice treated for 1 week with ceftriaxone an EAAT2 expression activator, showed a 49-70% reduction in VMR to CRD. Moreover, systemic pretreatment with the selective EAAT2 transporter blocker dihydrokainate reversed the ceftriaxone-blunted nociceptive response to CRD. However, the enhanced VMR to CRD produced by intracolonic ethanol was not significantly attenuated by 1-week ceftriaxone pre-treatment. The data suggests that enhanced glutamate uptake provides protective effects against colonic distension-induced nociception, and represents an exciting new mechanistic approach leading to better therapeutic options to visceral pain disorders.