Characterization of the Visceral Antinociceptive Effect of Glial Glutamate Transporter GLT-1 Upregulation by Ceftriaxone

Recent studies demonstrate that glial glutamate transporter-1 (GLT-1) upregulation attenuates visceral nociception. The present work further characterized the effect of ceftriaxone- (CTX-) mediated GLT-1 upregulation on visceral hyperalgesia. Intrathecal pretreatment with dihydrokainate, a selective GLT-1 antagonist, produced a reversal of the antinociceptive response to bladder distension produced by CTX. The hyperalgesic response to urinary bladder distension caused by intravesicular acrolein was also attenuated by CTX treatment as was the enhanced time spent licking of abdominal area due to intravesicular acrolein. Bladder inflammation via cyclophosphamide injections enhanced the nociceptive to bladder distension; cohorts administered CTX and concomitant cyclophosphamide showed reduced hyperalgesic response. Cyclophosphamide-induced bladder hyperalgesia correlated with a significant 22% increase in GluR1 AMPA receptor subunit expression in the membrane fraction of the lumbosacral spinal cord, which was attenuated by CTX coadministration. Finally, neonatal colon insult-induced hyperalgesia caused by intracolonic mustard oil (2%) administration at P9 and P11 was attenuated by CTX. These studies suggest that GLT-1 upregulation (1) attenuates the hyperalgesia caused by bladder irritation/inflammation or by neonatal colonic insult, (2) acts at a spinal site, and (3) may produce antinociceptive effects by attenuating GluR1 membrane trafficking. These findings support further consideration of this FDA-approved drug to treat chronic pelvic pain syndromes. 1. Introduction Interstitial cystitis/painful bladder syndrome (IC/PBS) is associated with several symptoms that include changes in bladder function and pain hypersensitivity that can develop spontaneously or be iatrogenically induced [1]. For example, the prolonged use of the chemotherapeutic drug cyclophosphamide leads to the induction of interstitial cystitis due to its breakdown in the liver to acrolein that is stored in the bladder and disrupts urothelial cell homeostasis [2]. Overall, therapeutic options for visceral pain disorders are limited largely to symptomatic relief [3]. Pain-transmitting afferent neurons utilize glutamate as the principle neurotransmitter to signal nociception related to the visceral organs [4]. Therefore, strategies to decrease spinal extracellular glutamate may be a viable option in pain management. Glutamate transporters are essential for maintaining homeostatic levels of extracellular glutamate [5]. Previous studies show that inhibition of glutamate transporter activity in