The effects of ketamine and its enantiomers on the morphine- or dexmedetomidine-induced antinociception after intrathecal administration in rats

Background: The spinal administration of some N-methyl-d-aspartate receptor antagonists results in antinociception and potentiates the effects of opio ids and alpha(2)-adrenoceptor agonists, but Ketamine and its enantiomers ha ve not been examined. The present study investigated the interactions of ra cemic ketamine, R(-)-ketamine and S(+)-ketamine with morphine and with dexm edetomidine. Methods: Intrathecal catheters were implanted into male Wistar rats. Three days later, the acute nociceptive sensitivity was assessed using the tail-f lick test. Analgesic latencies were converted to the percentage maximum pos sible effect. The dose that yielded 50% of the maximum possible effect (ED5 0) and dose-response and time-course curves were determined for the ketamin es (30-300 mu g), morphine (0.1-3.0 mu g), dexmedetomidine (0.3-10.0 mu g), and mixtures of two doses of ketamines (30 or 100 mu g) with different dos es of morphine or dexmedetomidine for fixed-dose analysis. Results: Neither racemic ketamine nor its enantiomers alone had a significa nt effect on the tail-flick test, with the exception of the highest dose of racemic ketamine, which caused motor impairment. Morphine and dexmedetomid ine each produced dose-dependent antinociception, with ED50 of 1.7 mu g (95 % confidence interval: 1.04-2.32) and 4.85 mu g (3.96-5.79), respectively. A low dose (30 mu g) of racemic ketamine or its enantiomers did not influen ce the ED50 of morphine significantly. Coadministration of 100 pg racemic k etamine or S(+)-ketamine, but not R(-)-ketamine, significantly enhanced and prolonged the antinociceptive effect of morphine. Both doses of racemic ke tamine or its isomers significantly decreased the ED50 value for dexmedetom idine, although the higher dose of racemic or S(+)-ketamine had the highest potency. One-hundred micrograms of racemic ketamine or S(+)-ketamine also prolonged the effects of dexmedetomidine. Conclusions: These data indicate that racemic ketamine and S(+)-ketamine, b ut not R(-)-ketamine, exhibit similar effectiveness in potentiating the ant inociceptive effects of both morphine and dexmedetomidine.