Synergistic depression of NMDA receptor‐mediated transmission by ketamine, ketoprofen and L‐NAME combinations in neonatal rat spinal cords in vitro

Abstract

Spinal N-methyl-D-aspartate (NMDA) receptor/cyclooxygenase (COX) and nitric oxide synthase (NOS) pathways play a major role in nociceptive processing, and influencing them simultaneously may induce synergistic analgesia. This study determined the spinal antinociceptive interactions between ketamine (NMDA receptor channel blocker), ketoprofen (COX inhibitor) and L-NAME (NOS inhibitor) combinations. Using an in vitro neonatal rat spinal cord preparation, two A-fibre-mediated reflexes, the monosynaptic reflex (MSR) and the low-intensity excitatory postsynaptic potential (epsp), and one C-fibre-mediated reflex, the high-intensity epsp, were evoked electrically. The effect of drugs and drug combinations on these reflexes was assessed and the type of interaction determined by isobolographic analysis. Infusion of ketamine alone decreased all three reflexes. That of ketoprofen decreased both the low and the high-intensity epsp only. Infusion of L-NAME alone produced no significant effects. Co-infusion of fixed ratios of IC(40) fractions of both (ketamine+ketoprofen) and (ketamine+L-NAME) were synergistic for depressing the low and the high-intensity epsps. The interaction was sub-additive for both combinations on the MSR. The only significant effect for the (ketoprofen+L-NAME) combination was synergism on the high-intensity epsp. All three combinations synergistically depressed nociceptive spinal transmission, and both ketamine and ketoprofen and ketamine and L-NAME combinations did so with potentially decreased motor side effects. If such combination profiles also occur in vivo, the present findings raise the possibility of ultimate therapeutic exploitation of increased analgesia with fewer side effects.