A pharmacokinetic-pharmacodynamic model of tolerance to morphine analgesia during infusion in rats

Abstract

A pharmacokinetic-pharmacodynamic (PK-PD) model was constructed to describe the kinetics of tolerance development to morphine-induced antinociception. Tail-flick latencies in response to hot water (50 degrees C) were assessed in male Sprague-Dawley rats exposed to a 12-hr iv infusion of either morphine (1.4 to 3.0 mg/kg per hr) or saline. Morphine-induced antinociception, expressed as the percentage of maximum possible response (% MPR), peaked after 120 min of infusion and decreased thereafter despite sustained systemic morphine concentrations. Both the rate and extent of tolerance development increased with increasing concentrations; an overall residual effect of approximately 24% MPR was observed at the end of the infusion regardless of the steady-state morphine concentration. The kinetics of tolerance offset were examined in a separate experiment by assessing tail-flick latency 15 min after morphine iv bolus (2 mg/kg) in tolerant and control rats. Recovery of response neared completion 18.5 days after a 12-hr exposure to morphine (2.0 mg/kg per hr). A PK-PD model was constructed to account for the delay in onset of antinociceptive effect and tolerance development relative to the blood concentration-time profile. According to this model, both the extent and the rate of tolerance development were modulated by the kinetics of the drug in the central compartment. Accumulation of a hypothetical "inhibitor" acting either as a reverse agonist, a competitive or noncompetitive antagonist, or a partial agonist could potentially account for the loss of pharmacologic effect in the presence of an agonist. The rate of tolerance development predicted from the PK-PD model varied widely (28-fold) depending on the type of pharmacologic interaction selected to account for the loss of effect. Using the rate of tolerance offset to discriminate between the different models (t1/2 offset 5.4 days), onset and offset of tolerance was described accurately by postulating that the inhibitor behaves as a partial agonist with low intrinsic activity (5.5% MPR) and high binding affinity for the receptor (IC50 15.0 ng/ml).

Aspects on Tail‐Flick, Hot‐Plate and Electrical Stimulation Tests for Morphine Antinociception

“…In the tail-flick group the response latency increased more rapidly to the cut-off 50 f fusion rate was administered in three different studies. The tail-flick response approached the cut-off latency (Ouellet & Pollack 1995;Smith & Smith 1995), while for electrical stimulation vocalisation observations the maximum response was much below the cut-off response (Ekblom ef al. 1993b).…”

“…2, which is the most commonly applied transformation, the effect increase is described as the fraction of the difference between the cut-off limit and the baseline observation (Ouellet & Pollack 1995). The maximum value will always be 100%, which equals the cut-off value.…”

Pharmacokinetic‐pharmacodynamic modelling of the EEG effect of alfentanil in rats: assessment of rapid functional adaptation

“…This explanation would be in line with numerous in‐vivo and in‐vitro studies which have shown that upon exposure to opioid agonists the efficacy of the μ‐opioid receptor system may be attenuated by several molecular‐ and cellular mechanisms (for reviews see Johnson & Fleming, 1989; Collin & Cesselin, 1991). More recently there have been attempts to characterize quantitatively the rate and extent of functional tolerance development to opiates using more traditional measures of analgesic response (Ekblom et al , 1993; Gardmark et al , 1993; Ouellet & Pollack, 1995). In all these studies however morphine has been used as a model drug.…”

Antagonism ofN-Methyl-d-aspartate Receptors Reduces the Vulnerability of the Immune System to Stress after Chronic Morphine

“…This hallmark of tolerance is observed for many other effects of acute morphine (Donovan et al, 1977;Mucha et al, 1978;Milne et al, 1989;Detweiler et al, 1995;Ouellet and Pollack, 1995;Kest and Hopkins, 2001;Bardin et al, 2003). As previously shown, a dose of morphine (10 mg/kg s.c.) that significantly suppresses mitogen-activated lymphocyte proliferation in naïve animals had no such effect in chronic morphine-treated animals (Bayer et al, 1996;Mellon et al, 2001).…”