Tolerance to respiratory actions of sufentanil: functional tolerance and route-dependent differential tolerance

The work was aimed at 1) characterizing the development of chronic tolerance to the respiratory effects of sufentanil in anesthetized and awake rats and 2) analyzing the influence that routes of administration of opiates can exert on tolerance development and expression. Tolerance was developed by infusing sufentanil s.c. with osmotic minipumps for 7 days; it was evaluated by injecting acute sufentanil while the minipumps were still maintained. When maximal depression attained was considered, dose-response curves were displaced to the right, the tolerance indexes being 7.3 and 2.6 in awake and anesthetized rats, respectively. No displacement was observed when acute sufentanil was injected i.c.v. and i.v., indicating lack of tolerance. However, several signs of tolerance were detected when the areas under the time-course curve of the effects were considered: faster and more complete recovery of the depression and flattening of the slope of the dose-area under the curve responses, even after i.c.v. and i.v. administration. The results indicate the need for distinguishing between development and expression of tolerance. Differential tolerance can be explained by considering tolerance expression as a deferred phenomenon. In addition, functional compensation stands as a factor of tolerance and as a mechanism responsible for dose-response curve flattening in tolerant subjects.