TIME-COURSE CHARACTERISTICS OF ACUTE TOLERANCE DEVELOPMENT TO CONTINUOUSLY INFUSED ALFENTANIL IN RATS

The time course of the development of acute tolerance to alfentanil wa s characterized in rat experiments using various algorithms of continu ous infusion of the drug. To maintain analgesia ata constant level (ta il compression test), alfentanil use was steadily increased: Time to 5 0% increase in alfentanil use was 255 +/- 98 min with analgesia mainta ined at a level of 50% increase in the pressure threshold, and 203 +/- 116 min with analgesia maintained at a level of 200% increase. With t he use of the alfentanil infusion regimen designed to rapidly achieve and maintain the constant alfentanil plasma concentration (120 ng/mL), the rate of development of acute tolerance, measured in terms of time to 50% recovery during continuing infusion, was 81 +/- 26 min with th e compression test and 88 +/- 38 min with the hot-plate test, but 374 +/- 46 min with the rotarod test (P < 0.0001). Thus we demonstrated ra pid development of acute tolerance to continuously infused alfentanil with different methods of tolerance assessment. The results also indic ate that the time course of tolerance development does not depend on t he type of noxious stimulation (mechanical versus thermal) if the resp onse is organized predominantly supraspinally, and that acute toleranc e to the direct effect of alfentanil on motor functions does not mask the rapid development of tolerance to its analgesic effect.