title: GLT-1 overexpression attenuates bladder nociception and local/cross-organ sensitization of bladder nociception.
abstract: Glutamatergic pathways mediate transmission of pain. Strategies to reduce glutamatergic neurotransmission may have beneficial effects to mitigate nociception. Recent work revealed that overexpression of the astrocytic glutamate transporter (GLT-1) by transgenic or pharmacologic approaches produced a diminished visceral nociceptive response to colonic distension. The purpose of this study was to determine the effect of GLT-1 overexpression on the visceromotor response to bladder distension. Increased glutamate uptake activity produced by 1-wk ceftriaxone (CTX) treatment attenuated 60-64% the visceromotor response to graded bladder distension compared with vehicle-treated mice. One-hour pretreatment with selective GLT-1 antagonist dihydrokainate reversed the blunted visceromotor response to bladder distension produced by 1-wk CTX, suggesting that GLT-1 overexpression mediated the analgesic effect of CTX. Moreover, sensitization of the visceromotor response to bladder distension produced by local bladder irritation (acrolein) was also attenuated by 1-wk CTX treatment. A model of cross-organ sensitization of bladder visceromotor response to distension was next studied to determine whether increased expression of GLT-1 can mitigate colon to bladder sensitization. Intracolonic trinitrobenzene sulfonic acid (TNBS) administered 1 h before eliciting the visceromotor response to graded bladder distension produced a 75-138% increase in visceromotor response compared with animals receiving intracolonic vehicle. In marked contrast, animals treated with 1-wk CTX + intracolonic TNBS showed no enhanced visceromotor response compared with the 1-wk vehicle + intracolonic vehicle group. The study suggests that GLT-1 overexpression attenuates the visceromotor response to bladder distension and both local irritant-induced and cross-organ-sensitized visceromotor response to bladder distension.
authors.affiliation: Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: M
authors.initials: M
authors.lastname: Yang
authors.forename: K
authors.initials: K
authors.lastname: Roman
authors.forename: D-F
authors.initials: DF
authors.lastname: Chen
authors.forename: Z-G
authors.initials: ZG
authors.lastname: Wang
authors.forename: Y
authors.initials: Y
authors.lastname: Lin
authors.forename: R L
authors.initials: RL
authors.lastname: Stephens
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002443:Ceftriaxone / Q000494:pharmacology; D003106:Colon / Q000187:drug effects / Q000503:physiopathology*; D004576:Electromyography; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism*; D005260:Female; D007608:Kainic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D010146:Pain / Q000503:physiopathology*; D058748:Pain Perception / Q000187:drug effects / Q000502:physiology*; D001743:Urinary Bladder / Q000187:drug effects / Q000503:physiopathology*
chemical_list: D027342:Excitatory Amino Acid Transporter 2; C020889:dihydrokainic acid; D002443:Ceftriaxone; D007608:Kainic Acid