Enkephalinase Inhibition Prevented Tolerance to Nitrous Oxide Analgesia in Rats

Abstract

Tolerance to nitrous oxide (N₂O) antinociception was studied in rats in accordance with the Randall-Selitto pressure nociception test. Both N₂O (70% in 30% O₂) and the relatively selective enkephalinase inhibitor phosphoramidon (350 μg i.c.v.), which blocks the biotransformation of enkephalins, were administered. They both induced a significant analgesic effect which vanished within 45 min. The rapidly developed tolerance to N₂O analgesia does not affect the anaesthetic state since the animals remained motionless for the duration of exposure lasting 3 h. In the animals treated with the enkephalinase inhibitor phosphoramidon, no development of tolerance to N₂O-antinociception occurred during the exposure lasting 3 h. The results indicate that tolerance to N₂O analgesia can be abolished by activation of the enkephalinergic system, which might suggest a possible insufficiency of this system during tolerance to N₂O.