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. 2006 Dec;149(8):1071-82.
doi: 10.1038/sj.bjp.0706946. Epub 2006 Oct 30.

In vivo pharmacological resultant analysis reveals noncompetitive interactions between opioid antagonists in the rat tail-withdrawal assay

E A Walker  1
Affiliations

In vivo pharmacological resultant analysis reveals noncompetitive interactions between opioid antagonists in the rat tail-withdrawal assay

E A Walker. Br J Pharmacol. 2006 Dec.

Abstract

Background and purpose: Pharmacological resultant analysis is a technique that can detect secondary effects of competitive antagonists in vitro. The utility of pharmacological resultant analysis as a potential tool for the investigation of antagonist interactions in vivo was examined in the present study using two opioid antagonists, naltrexone and CTAP.

Experimental approach: Using the experimental design of pharmacological resultant analysis, the well-characterized opioid antagonist naltrexone was examined in the presence of multiple doses of CTAP to block the antinociceptive effects of morphine in the rat warm-water (55(o)C), tail-withdrawal assay.

Key results: Alone, all doses of naltrexone, CTAP, and CTOP examined blocked the antinociceptive effects of morphine. In the presence of fixed doses of 1 or 10 microg CTAP, increasing doses of naltrexone produced dose-dependent shifts to the right in the morphine dose-response curve. However, a lower dose of naltrexone in combination with 1 or 10 mug CTAP failed to alter the morphine dose-response curve. In the presence of a fixed dose of 0.1 mg kg(-1) naltrexone, CTAP doses produced irregular shifts to the right in the morphine dose-response curves.

Conclusions and implications: Resultant analysis was applied and an apparent pK(C) value for CTAP was found to be one log unit higher than the apparent pA(2) value for CTAP, evidence that CTAP may have secondary actions or that a signal transducer function may be altered by the combinations of these antagonists. Taken together, these data suggest pharmacological resultant analysis can reveal novel interactions between antagonists in vivo.

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Figures

Figure 1
Figure 1
Naltrexone s.c. or i.c.v., CTAP i.c.v. and CTOP i.c.v. antagonism of the antinociceptive effects of morphine-induced antinociception in the warm-water (55°C) tail-withdrawal assay. Ordinate: latency measures converted to % maximum effect. Abscissa: cumulative dose of morphine in mg kg−1. Each point represents the mean of one observation in 6–8 rats. All antagonist doses were administered 25 min before the determination of the morphine-dose–response curve. Points above N or C are the effects of naltrexone, CTAP or CTOP alone.
Figure 2
Figure 2
Effects of naltrexone s.c. in the presence of a fixed dose of CTAP i.c.v. (left and middle panels) or naltrexone i.c.v. (right panel), respectively. Naltrexone s.c., CTAP i.c.v. or naltrexone i.c.v. were coadministered 25 min before determination of the morphine dose–response curve. Ordinate: latency measures converted to % maximum effect. Abscissa: cumulative dose of morphine in mg kg−1. Each point represents the mean of one observation in 6–8 rats. Points above N are the effects of naltrexone alone or the effects of naltrexone in combination with CTAP or naltrexone alone.
Figure 3
Figure 3
Effects of CTAP i.c.v. in the presence of a fixed dose of 0.1 mg kg−1 naltrexone s.c. Naltrexone s.c. and CTAP i.c.v. were coadministered 25 min before determination of the morphine dose–response curve. Points above C are the effects of CTAP alone or the effects of CTAP in combination with naltrexone alone. Each point represents the mean of one observation in 6–8 rats. Other details as in Figure 1.
Figure 4
Figure 4
Secondary Schild plots for naltrexone (left panel) or CTAP (right panel) as antagonists of the antinociceptive effects of morphine. Left panel: Schild plots for naltrexone alone and in the presence of 1 or 10 μg CTAP i.c.v. Individual potency estimate for naltrexone in the presence of a single dose of 1 μg naltrexone (open squares). Slopes of the regression lines were not significantly different so regressions lines were drawn with a common slope calculated to be −0.87 (for details see ‘Data Analysis'). Right panel: Schild plots of CTAP alone and in the presence of 0.1 mg kg−1 naltrexone. Ordinate: logarithm of the quantity [(N+C (A50 of the agonist in the presence of a constant dose of CTAP and increasing dose of naltrexone) divided by C (A50 of the agonist plus a constant dose of CTAP)]-1). A50 values are determined from Figures 2, 3. Abscissa: negative logarithm of molar doses of naltrexone (left panel) or CTAP (right panel). Inset: resultant plot for CTAP. Ordinate: logarithm of the quantity (y−1), where y is the equal dose ratio for naltrexone in the presence of 1.0 or 10 μg CTAP. Abscissa: negative logarithm of molar doses of CTAP.
Figure 5
Figure 5
Effects of CTOP i.c.v. in the presence of a fixed dose of 0.18 mg kg−1 naltrexone s.c. and 1 μg CTAP i.c.v. CTOP i.c.v., naltrexone s.c. or CTAP i.c.v. were administered alone or in combination 25 min before determination of the morphine dose–response curve. Points above A are the effects of the antagonist or antagonist combination alone. Each point represents the mean of one observation in 6–8 rats. Other details as in Figure 1.
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