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Am J Physiol Gastrointest Liver Physiol 296: G129-G134, 2009. First published November 20, 2008; doi:10.1152/ajpgi.90556.2008
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HORMONES AND SIGNALING

Increased glial glutamate transporter EAAT2 expression reduces visceral nociceptive response in mice

Yuan Lin,1 Guilian Tian,1 Kenny Roman,2 Chalonda Handy,2 Joseph B. Travers,3 Chien-liang Glenn Lin,1 and Robert L. Stephens, Jr.2

Departments of 1Neuroscience, 2Physiology and Cell Biology, and 3Oral Biology, The Ohio State University, Columbus, Ohio

Submitted 12 September 2008 ; accepted in final form 14 November 2008

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 overexpressing human EAAT2 (EAAT2 mice), which exhibited a twofold enhanced glutamate uptake, showed 39% less writhing response to intraperitoneal acetic acid than nontransgenic littermates. Moreover, EAAT2 transgenic mice showed a 53–64% reduction in visceromotor response (VMR) to colorectal distension (CRD) in assessments of the response to graded increase in pressures. Corroborating the involvement of enhanced glutamate uptake, wild-type mice treated for 1 wk 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-wk ceftriaxone pretreatment. The data suggest 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.

colon; pain; gastrointestinal; excitatory amino acids


Address for reprint requests and other correspondence: R. L. Stephens Jr., The Ohio State Univ., Depts. of Physiology and Cell Biology, 304 Hamilton Hall, 1645 Neil Ave., Columbus, OH 43210 (e-mail: stephens.6{at}osu.edu) or C. G. Lin, The Ohio State Univ., Dept. of Neuroscience, 4198 Graves Hall, 333 West 10th Ave., Columbus, OH 43210 (e-mail: lin.492{at}osu.edu)






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