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

Abstract

Background and purpose: 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. Experimental approach: 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. Key results: Infusion of ketamine alone decreased all three reflexes. That of ketoprofen decreased both the low and the highintensity epsp only. Infusion of L-NAME alone produced no significant effects. Co-infusion of fixed ratios of IC 40 fractions of both (ketamine þ ketoprofen) and (ketamine þ 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 þ L-NAME) combination was synergism on the high-intensity epsp. Conclusions and implications: 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.

Spinal Reflexes and Windup In Vitro: Effects of Analgesics and Anesthetics

“…Ketoprofen inhibits both COX‐1 and COX‐2 isoforms. It has been shown to depress responses to low‐ and high‐intensity stimuli to the same extent and with similar EC 50 with only a minor reduction in the MSR .…”

L-Arginine-No System Participates in the Analgesic Effect of Flunixin Meglumine in the Rat

“…administration of acetic acid), Morgan et al demonstrated synergistic interaction between L-NAME and fl urbiprofen/indomethacin [16]. Ketoprofen and L-NAME co-infused in vitro, signifi cantly inhibited the production of a highly-sensitive excitatory postsynaptic potential, which is obtained by electrical stimulation of the isolated spinal cord of neonatal rats [28]. However, there are literature data that show the opposite effect, i.e.…”