Nociceptive stimulus modality-related difference in pharmacokinetic–pharmacodynamic modeling of morphine in the rat

Shang, Gang-Wei; Liu, Dan-Na; Yan, Lai-Hong; Cui, Xiuyu; Zhang, Kui-Ping; Qi, Chao

doi:10.1016/j.pbb.2006.09.016

Cited by 15 publications

(16 citation statements)

References 37 publications

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“…Nonetheless, these routes give very similar absorption rates: analgesia peaks 15–30 minutes after administration of morphine to mice by either i.p. [37] or s.c. routes [38]. The striking correspondence between plasma concentrations and μ antagonism in Figure 5 suggests that the same is true of nor-BNI.…”

Section: Discussionmentioning

confidence: 99%

Long-acting κ opioid antagonists nor-BNI, GNTI and JDTic: pharmacokinetics in mice and lipophilicity

et al. 2012

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BackgroundNor-BNI, GNTI and JDTic induce κ opioid antagonism that is delayed by hours and can persist for months. Other effects are transient. It has been proposed that these drugs may be slowly absorbed or distributed, and may dissolve in cell membranes, thus slowing elimination and prolonging their effects. Recent evidence suggests, instead, that they induce prolonged desensitization of the κ opioid receptor.MethodsTo evaluate these hypotheses, we measured relevant physicochemical properties of nor-BNI, GNTI and JDTic, and the timecourse of brain and plasma concentrations in mice after intraperitoneal administration (using LC-MS-MS).ResultsIn each case, plasma levels were maximal within 30 min and declined by >80% within four hours, correlating well with previously reported transient effects. A strong negative correlation was observed between plasma levels and the delayed, prolonged timecourse of κ antagonism. Brain levels of nor-BNI and JDTic peaked within 30 min, but while nor-BNI was largely eliminated within hours, JDTic declined gradually over a week. Brain uptake of GNTI was too low to measure accurately, and higher doses proved lethal. None of the drugs were highly lipophilic, showing high water solubility (> 45 mM) and low distribution into octanol (log D7.4 < 2). Brain homogenate binding was within the range of many shorter-acting drugs (>7% unbound). JDTic showed P-gp-mediated efflux; nor- BNI and GNTI did not, but their low unbound brain uptake suggests efflux by another mechanism.ConclusionsThe negative plasma concentration-effect relationship we observed is difficult to reconcile with simple competitive antagonism, but is consistent with desensitization. The very slow elimination of JDTic from brain is surprising given that it undergoes active efflux, has modest affinity for homogenate, and has a shorter duration of action than nor-BNI under these conditions. We propose that this persistence may result from entrapment in cellular compartments such as lysosomes.

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Section: Discussionmentioning

confidence: 99%

Long-acting κ opioid antagonists nor-BNI, GNTI and JDTic: pharmacokinetics in mice and lipophilicity

et al. 2012

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“…It was proposed that the fast and short-lasting anti-thermal pain effect of unconjugated and conjugated morphine was due to tolerance [59]. Morphine administered as an IV bolus to rats caused less tolerance than IV infusions at two different rates, with tolerance stronger for the higher infusion rate [156].…”

Section: Clockwise Hysteresismentioning

confidence: 99%

Understanding the Hysteresis Loop Conundrum in Pharmacokinetic / Pharmacodynamic Relationships

et al. 2014

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Hysteresis loops are phenomena that sometimes are encountered in the analysis of pharmacokinetic and pharmacodynamic relationships spanning from pre-clinical to clinical studies. When hysteresis occurs it provides insight into the complexity of drug action and disposition that can be encountered. Hysteresis loops suggest that the relationship between drug concentration and the effect being measured is not a simple direct relationship, but may have an inherent time delay and disequilibrium, which may be the result of metabolites, the consequence of changes in pharmacodynamics or the use of a non-specific assay or may involve an indirect relationship. Counter-clockwise hysteresis has been generally defined as the process in which effect can increase with time for a given drug concentration, while in the case of clockwise hysteresis the measured effect decreases with time for a given drug concentration. Hysteresis loops can occur as a consequence of a number of different pharmacokinetic and pharmacodynamic mechanisms including tolerance, distributional delay, feedback regulation, input and output rate changes, agonistic or antagonistic active metabolites, uptake into active site, slow receptor kinetics, delayed or modified activity, time-dependent protein binding and the use of racemic drugs among other factors. In this review, each of these various causes of hysteresis loops are discussed, with incorporation of relevant examples of drugs demonstrating these relationships for illustrative purposes. Furthermore, the effect that pharmaceutical formulation has on the occurrence and potential change in direction of the hysteresis loop, and the major pharmacokinetic / pharmacodynamic modeling approaches utilized to collapse and model hysteresis are detailed.

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“…However, several pieces of evidence argue against this interpretation. First, M3G levels in plasma and CSF are higher at 2 hr after injection of 10-15 mg/kg of morphine (Barjavel et al, 1995;Shang et al, 2006) than they are at 4 hr post-injection, yet the anxiolytic-like effects observed after acute administration of 10 mg/kg morphine peaked at 4 hr, and were absent at 2 hr. Second, the lower dose of morphine (5.6 mg/kg) produces anxiolytic-like effects at 2 hr post-treatment where the higher dose of 10 mg/kg is without effect, yet plasma levels of M3G at 2 hr post-injection are significantly higher with 10 mg/kg than 5.6 mg/kg of morphine (Barjavel et al, 1995;Zheng et al, 1998).…”

mentioning

confidence: 97%

“…As shown in Figure 1, both 5.6 and 10 mg/kg morphine produced time-dependent anxiolyticlike effects after acute treatment, with peak effects at 2 hr following 5.6 mg/kg morphine and at 4 hr following 10 mg/kg morphine. One possible interpretation of the delay in onset of anxiolytic-like effect is that it is mediated by a build-up of morphine metabolites, which in the rat consist primarily of morphine-3-glucuronide (M3G; Christrup, 1997;Shang et al, 2006;Zheng et al, 1998). However, several pieces of evidence argue against this interpretation.…”

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confidence: 99%

Withdrawal from acute morphine dependence is accompanied by increased anxiety-like behavior in the elevated plus maze

Zhang

Schulteis

2008

Pharmacology Biochemistry and Behavior

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Pretreatment with a single moderate dose of morphine (e.g. 5.6-10 mg/kg) 4-24 hr prior to challenge with an opioid antagonist such as naloxone results in reliable expression of behaviors that resemble aversive or emotional consequences of withdrawal from chronic opioid exposure, including suppression of operant responding, elevations in brain reward thresholds, and conditioned place aversion. Repeated daily or weekly treatment with these same morphine doses results in a progressive increase in naloxone potency to elicit these withdrawal signs. The current study sought to determine whether increased anxiety-like behavior during withdrawal from chronic opioid dependence is also seen after acute morphine exposure, and progresses with repeated intermittent treatment. Male Wistar rats were handled and injected with either vehicle or morphine for 4 consecutive days. Three injection regimens were employed: Morphine Naive (4 vehicle injections), Acute Morphine (3 vehicle injections, 4th injection 5.6 or 10 mg/kg morphine), or Repeat Morphine (all 4 injections with 5.6 or 10 mg/kg morphine). Acute pretreatment with 5.6 mg/kg or 10 mg/kg morphine resulted in timedependent increases in exploration of the open arms of the plus maze in naloxone-naive rats when rats were tested at 2, 4 or 8 hr after the final pretreatment injection, with the effects at the higher dose appearing later (4 hr) than after the lower dose (2 hr). This pattern of results, in combination with a separate study which confirmed a significant anxiolytic-like effect of a low dose of morphine (0.56 mg/kg) administered 15 min prior to test, suggested that low residual morphine levels in the plasma remaining at 2-4 hr after 5.6 and 10 mg/kg morphine may be sufficient to elicit anxiolytic-like effects. Repeat treatment with either dose of morphine resulted in a further increase in the magnitude and duration of this anxiolytic-like effect. These effects had dissipated by 8 hr post-morphine, and therefore precipitation of withdrawal by one of several doses of naloxone (0.10-3.3 mg/kg) was assessed in separate cohorts of rats 8 hr after the final pretreatment under Morphine Naïve, Acute Morphine, or Repeat Morphine conditions. Naloxone resulted in a significant dose-dependent expression of anxiety-like behavior with no effects on general activity after Acute Morphine pretreatment at either 5.6 or 10 mg/kg morphine. A further significant shift in naloxone potency was observed after Repeat Morphine pretreatment at the 10 mg/kg but not the 5.6 mg/kg dose. Thus, anxiety-like behavior is a prominent feature of the negative emotional consequences of naloxoneprecipitated withdrawal from acute opioid dependence.

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Nociceptive stimulus modality-related difference in pharmacokinetic–pharmacodynamic modeling of morphine in the rat

Cited by 15 publications

References 37 publications

Long-acting κ opioid antagonists nor-BNI, GNTI and JDTic: pharmacokinetics in mice and lipophilicity

Long-acting κ opioid antagonists nor-BNI, GNTI and JDTic: pharmacokinetics in mice and lipophilicity

Understanding the Hysteresis Loop Conundrum in Pharmacokinetic / Pharmacodynamic Relationships

Withdrawal from acute morphine dependence is accompanied by increased anxiety-like behavior in the elevated plus maze

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