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

Acta Anaesthesiol Scand. 1997 Aug;41(7):895-902. doi: 10.1111/j.1399-6576.1997.tb04806.x.


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 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.

Results: 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.

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.

MeSH terms

  • 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer
  • Analgesics / pharmacology*
  • Animals
  • Carbon Dioxide / blood
  • Drug Synergism
  • Male
  • Oxygen / blood
  • Pyrrolidines / pharmacology*
  • Pyrrolidines / toxicity
  • Rats
  • Rats, Wistar
  • Respiration / drug effects*
  • Respiratory Insufficiency / chemically induced
  • Respiratory Insufficiency / physiopathology
  • Sufentanil / pharmacology*
  • Sufentanil / toxicity


  • Analgesics
  • Pyrrolidines
  • Carbon Dioxide
  • 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer
  • Sufentanil
  • Oxygen