Pharmacodynamics and tolerance development during multiple intravenous bolus morphine administration in rats

Limited information is available about how the time course of the development of tolerance to morphine-induced antinociception is related to the kinetics of drug administration and disposition. The objectives of the present experiment were to characterize the rate and extent of tolerance development during the administration of multiple increasing i.v. bolus doses of morphine to rats, and to construct a pharmacokinetic-pharmacodynamic model of morphine tolerance. Morphine was administered according to two different treatment (TXT) regimens: a 12-hr TXT, in which a total morphine exposure of 24 mg/kg was administered in seven escalating doses, and a 13-day TXT, in which escalating doses of morphine were administered daily up to a maximum of 6 mg/kg. Analgesic effect, expressed as the percent of maximum possible response, was assessed with the hot water-induced tail flick. Serum samples were collected for determination of morphine concentrations by HPLC. Concentration-normalized peak effects, measured after each morphine dose, remained constant throughout the 12-hr study period, which suggests that there was little or no tolerance development during the 12-hr TXT. In contrast, tolerance appeared more significant during administration of the 13-day TXT; a large decrease in normalized peak effect occurred between days 1 and 8. Effect remained constant thereafter, with administration of the maximum dose of morphine for the remainder of the treatment period. A pharmacokinetic-pharmacodynamic model describing the development of tolerance during the 13-day TXT was constructed. The applicability of this model of tolerance to morphine-induced antinociception with different modes of administration is discussed.