Quantification of effect delay and acute tolerance development to morphine in the rat.

In this study the effect delay and the development of acute tolerance to morphine's antinociceptive effect were investigated in the rat. The antinociceptive response induced after three different short infusions of morphine was measured by using the electrical stimulation vocalization method. Three treatment groups received morphine hydrochloride over 10, 60 and 180 min, targeting maximal plasma concentrations of 25 microM at the end of the infusion. The maximal concentrations of morphine obtained for the three groups were 29.4 +/- 3.7, 26.7 +/- 4.7 and 28.9 +/- 7.3 microM, respectively. Both an effect delay and acute tolerance were observed. For each group, the peak effects were 248 +/- 82, 337 +/- 116 and 303 +/- 49% above base line, at 35, 65 and 90 min after the start of the infusions. A pharmacokinetic-pharmacodynamic model with separate effect and tolerance compartments (the ET-model) well described the antinociceptive response over time. The antinociceptive effect was best described by using a linear model, whereas acute tolerance was best described by using an Emax model. The rates of drug equilibration between the plasma and the effect compartment (ke0) and the plasma and the tolerance compartment (kt0), expressed as half-lives, were 34 +/- 2 and 48 +/- 4 min, respectively. High concentrations were required for the acute tolerance to develop (TC50 of 17 microM).