Interaction between sufentanil and U-50488H with respect to antinociception and respiratory depression in rats

Background: Opiate receptors have been argued to differentially regulate analgesia and respiratory depression. In order to validate possible interactions between the opiate mu-and kappa-receptors, interactions between sufentanil and U-50488H were studied in rats. Methods: Rats equipped with an arterial catheter were tested in the tail flick latency (TFL) test after intravenous treatment with sufentanil (a mu-agonist), U-50488H (a kappa-agonist) or fixed ratio combinations of both drugs. Simultaneously, respiratory changes were monitored by blood gas analysis. Results: The ED(50)s of sufentanil for a TFL >6.0 and greater than or equal to 10.0 s were 0.0002 and 0.00059 mg/kg. For U-50488H the corresponding values were 1.53 and 8.11 mg/kg. Using a fixed dose ratio of 1/10 000, an additivity was demonstrated between sufentanil and U-50488H in terms of antinociception. With regard to respiratory parameters, PaCO2 significantly increased after all doses of sufentanil early after treatment. At the higher doses tested, there was also a decrease in PaO2 and O-2 saturation. For U-50488H only the highest doses resulted in an early and small shift in PaCO2. The combination of sufentanil/U-50488H resulted in only a small increase in PaCO2 at the highest dose regimen tested. Conclusion: The results presented here demonstrate that drug mixtures of sufentanil and U-50488H can be additive with respect to antinociception with additionally less risk for respiratory side-effects, as compared with sufentanil alone. Therefore, a combination of mu-and kappa-opiate receptor agonists might be more beneficial than each agent alone.