GLT‐1 over‐expression attenuates bladder nociception and cross‐organ sensitization

Glutamate is a major excitatory neurotransmitter released by pain‐transmitting afferent neurons; strategies to decrease glutamate availability may have utility in pain management. Recent data in our laboratory suggests that animals over‐expressing the glutamate transporter GLT‐1, responsible for glutamate removal, show a 53%–64% reduction in the visceromotor response (VMR) produced by colon distension. Thus, this study examined nociception associated with urinary bladder distension (UBD) in mice. The data show that the VMR to UBD was inhibited 57–64% by enhanced GLT‐1 expression induced by 7 day ceftriaxone treatment. Pretreatment with dihydrokainate, a selective GLT‐1 blocker, reversed this response. To study cross‐organ sensitization, the irritant TNBS was administered into the distal colon (ic) 1 hour before UBD; a 75–138% increase in VMR compared to controls resulted. Pharmacologic GLT‐1 over‐expression before ic TNBS attenuated the VMR response. Finally, irritation of the bladder, by intravesicular acrolein, increased the VMR produced by UBD 55–74%, and the response was attenuated by GLT‐1 over‐expression. This study suggests that GLT‐1 over‐expression blunts bladder nociception due to UBD, cross‐organ sensitization and bladder irritation; and thus represents a potential therapeutic approach. Supported by NIH DK 071839 (RLS).