GLT‐1 over‐expression mitigates chronic bladder inflammation and GLuR1 trafficking

Abstract

Strategies to attenuate glutamate induced changes in synaptic activity may lead to better options in visceral pain management. Previous data in our laboratory showed that animals over‐expressing the glutamate transporter GLT‐1, crucial for glutamate removal, had a visceromotor response (VMR) to urinary bladder distension (UBD) that was inhibited 57–64%. The current study showed that intrathecal pretreatment with dihydrokainate (DHK; 0.03mM), a selective GLT‐1 blocker, reversed this response and intracisternal administration of DHK was not effective. Also, a chronic bladder inflammation model was established via intraperitoneal treatment of cyclophosphamide (80mg/kg; day 0, 2, 4, and 6) and measured the VMR associated with urinary bladder distension in mice. The data showed that cyclophosphamide treatment significantly increased VMR (66%–120% at 0.15 and 0.2mL) and the effect was diminished by GLT‐1 over‐expression. To study trafficking of the GLuR1 subunit from the cytosol to the membrane in the lumbosacral spinal region of animals with chronic bladder inflammation, cyclophosphamide was administered as previously described, and the results showed a 33% increase in total GluR1 and a 27% increase in membrane GLuR1 compared to controls. A small increase was recorded in the cytosol (<10%). GLT‐1 over‐expression attenuated the increased total (9%) and membrane (11%) GLuR1expression. Overall, this study suggests that GLT‐1 over‐expression mitigates visceral nociception due to chronic bladder inflammation and trafficking of GLuR1 to the membrane may be involved. Supported by NIH DK 071839 (RLS) and APS Porter Fellowship (KR).