Effect of intrathecal ACEA-1021 in a rat model for postoperative pain

Drugs antagonizing glycine at the N-methyl-D-aspartate (NMDA) receptor have been developed to improve efficacy, increase specificity, and, perhaps, reduce side effects. The purpose of this study was to examine the effect of intrathecally (IT) administered ACEA-1021, a glycine receptor antagonist at the NMDA receptor complex, in a rat model of postoperative pain. Rats with IT catheters were anesthetized and underwent a plantar incision. Two hours later, withdrawal threshold to punctate stimulation was determined by applying calibrated von Prey filaments adjacent to the wound. In another group, the response frequency to a plastic disk, a blunt, nonpunctate mechanical stimulus applied directly on the incision also was measured. In unincised rats, NMDA, alpha -amino-3-hydroxy-5methyl-4-isoxazole-propionic acid (AMPA), or kainate (KA) was administered IT 30 minutes after ACEA-1021 or vehicle. Spontaneous nociceptive behaviors (SNB) caused by IT excitatory amino acids (EAAs) were counted. In the vehicle-treated group, the median withdrawal threshold for punctate stimulation decreased from 522 mN before incision to 61 mN or less for 4 hours after incision. In 3 separate groups, the median withdrawal threshold increased to 61, 118, and 332 mN 30 minutes after IT administration of 10, 30, and 60 nmol of ACEA-1021, respectively. In 3 other groups, IT administration of 10, 30, and 60 nmol of ACEA-1021 decreased the response frequency to the blunt mechanical stimulus from 95 +/- 13 or greater to 78 +/- 40%, 67 +/- 37%, and 22 +/- 27% 30 minutes after drug injection, respectively. Sixty nmol of ACEA-1021 inhibited SNBs caused by IT NMDA, KA, and AMPA. IT administration of ACEA-1021 decreased incision-induced pain behaviors in this rat model. ACEA-1021 blocked SNB by NMDA, KA, and AMPA. These data, coupled with previous studies, suggest that inhibition of pain behaviors by IT ACEA-1021 is produced by blockade of spinal non-NMDA receptors.