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

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.

Rats equipped with an arterial catheter were tested in the tail flick latency (TFL) test after intravenous treatment with sulentanil (a mu-agonist), U-50488H (a kappa-agonist) or fixed ratio combinations of both drugs. Simultaneously, respiratory changes were monitored by blood gas analysis.

The ED50s of sufentanil for a TFL > 6.0 and > or = 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 O2 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.

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.