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Comparative Study
. 2005 Aug;145(7):975-83.
doi: 10.1038/sj.bjp.0706247.

Opioid antagonists differ according to negative intrinsic efficacy in a mouse model of acute dependence

Ellen A Walker  1 , Steven N Sterious
Affiliations
Comparative Study

Opioid antagonists differ according to negative intrinsic efficacy in a mouse model of acute dependence

Ellen A Walker et al. Br J Pharmacol. 2005 Aug.

Abstract

The purpose of the present study is to compare the capacity of opioid antagonists to elicit withdrawal jumping in mice following two acute pretreatment doses of the opioid agonist morphine. Antagonists that precipitate vigorous withdrawal jumping across both morphine treatment doses are hypothesized to be strong inverse agonists at the mu-opioid receptor, whereas antagonists that elicit withdrawal jumping in mice treated with the high but not the low dose of morphine are hypothesized to be weak inverse agonists. Male, Swiss-Webster mice (15-30 g) were acutely treated with 56 or 180 mg kg(-1) morphine 4 h prior to injection with naloxone, naltrexone, diprenorphine, nalorphine, or naloxonazine. Vertical jumping, paw tremors, and weight loss were recorded. Naloxone, naltrexone, and diprenorphine produced withdrawal jumping after 56 and 180 mg kg(-1)morphine pretreatment. Nalorphine and naloxonazine produced moderate withdrawal jumping after 180 mg kg(-1) morphine pretreatment, but failed to elicit significant withdrawal jumping after 56 mg kg(-1) morphine pretreatment. Nalorphine and naloxonazine blocked the withdrawal jumping produced by naloxone. All antagonists produced paw tremors and weight loss although these effects were generally not dose-dependent. Taken together, these findings reveal a rank order of negative intrinsic efficacy for these opioid antagonists as follows: naloxone=naltrexone> or =diprenorphine>nalorphine=naloxonazine. Furthermore, the observation that nalorphine and naloxonazine blocked the naloxone-induced withdrawal jumping provides additional evidence that nalorphine and naloxonazine are weaker inverse agonists than naloxone.

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Figures

Figure 1
Figure 1
Effects of naloxone, naltrexone, and diprenorphine on withdrawal jumping in mice pretreated 4 h earlier with either 56 or 180 mg kg−1 morphine. Each point on the dose–response curve represents 1–3 experiments consisting of 7–11 mice each. Ordinate: % of mice exhibiting withdrawal jumping. Abscissa: dose of antagonist, in mg kg−1. Vertical bars represent the s.e.m. across experiments.
Figure 2
Figure 2
Effects of nalorphine and naloxonazine on withdrawal jumping in mice pretreated 4 h earlier with either 56 or 180 mg kg−1 morphine. Each point on the dose–response curve represents 1–4 experiments consisting of 7–11 mice each. See Figure 1 for other details.
Figure 3
Figure 3
Effects of 1.0 or 10 mg kg−1 naltrexone pretreatments on naloxone–precipitated withdrawal jumping in mice pretreated 4 h earlier with either 56 (open bars) or 100 mg kg−1 (striped bars) morphine. Naltrexone was administered 20 min prior to naloxone. Bars above 0 represent control naloxone-precipitated jumping from Figure 1. Variance is expressed as s.t.d. Combination naltrexone and naloxone bars represent a single experiment in 10 mice. Ordinate: % of mice exhibiting withdrawal jumping. Abscissa: dose of naltrexone pretreatment, in mg kg−1.
Figure 4
Figure 4
Effects of nalorphine and naloxonazine pretreatments on naloxone-precipitated withdrawal jumping in mice pretreated 4 h earlier with either 56 or 100 mg kg−1 morphine. Nalorphine and naloxonazine were administered 20 min prior to naloxone. Control naloxone data from Figure 1. Each point in the combination experiment represents 1–3 experiments consisting of 7–11 mice. Points above NLR and NLZ represent the effects of nalorphine (N=30) and naloxonazine (N=30–44) alone in the combination experiments. See Figure 1 for other details.
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