Prevention of N-Methyl-d-Aspartate-Induced Mechanical Nociception by Intrathecal Administration of Ketoprofen and Ketamine in Sheep

Abstract

Nonsteroidal antiinflammatory drugs and N-methyl-D-aspartate (NMDA) receptor antagonists reduce pain hypersensitivity when given by the intrathecal (i.t.) route, but their combined effects have hardly been studied. We assessed the effects of the nonsteroidal antiinflammatory drug ketoprofen and the NMDA receptor channel blocker ketamine, given alone and in combination, on mechanical nociceptive thresholds in sheep implanted with indwelling cervical i.t. catheters. Sheep were given, by i.t. catheter, ketoprofen (200-3200 microM; 100 microL) and ketamine (25-400 microM; 100 microL) alone or in combination (837.95-3350.78 microM; 100 microL; 0.955:0.045 proportion). They also received NMDA (2 mM; 100 microL) preceded by the highest concentration of ketoprofen and ketamine alone or in combination. Saline solution (0.9%; 100 microL) and xylazine (1.95 mM; 100 microL) were used as negative and positive controls, respectively. Xylazine significantly increased the area under the nociceptive threshold versus time curve values (AUC) for 30, 60, and 180 min posttreatment. Ketoprofen and ketamine, alone and in combination, produced no significant effect on AUC values. NMDA alone decreased the AUC value for 30 min posttreatment. This pain hypersensitivity was prevented by preadministering ketoprofen and ketamine alone and in combination. In sheep, i.t. administration of ketoprofen and ketamine, alone or together, produced no hypoalgesia; however, they prevented NMDA-induced mechanical hypersensitivity. Ketoprofen and ketamine may have therapeutic potential in conditions associated with persistent pain.