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Comparative Study
. 2008 Mar 31;583(1):48-55.
doi: 10.1016/j.ejphar.2008.01.004. Epub 2008 Jan 24.

Comparison of the opioid receptor antagonist properties of naltrexone and 6 beta-naltrexol in morphine-naïve and morphine-dependent mice

Mary F Divin  1 , M C Holden Ko, John R Traynor
Affiliations
Comparative Study

Comparison of the opioid receptor antagonist properties of naltrexone and 6 beta-naltrexol in morphine-naïve and morphine-dependent mice

Mary F Divin et al. Eur J Pharmacol. .

Abstract

It has been proposed that on chronic morphine treatment the micro-opioid receptor becomes constitutively active, and as a consequence, the opioid withdrawal response arises from a reduction in the level of this constitutively active receptor. In support of this, the putative micro-opioid receptor inverse agonist naltrexone has been shown to precipitate more severe withdrawal behavior in mice than the putative neutral receptor antagonist 6 beta-naltrexol. In the present study naltrexone and 6 beta-naltrexol were compared in NIH Swiss mice to test the hypothesis that their differential ability to precipitate withdrawal is due to differences in their in vivo opioid receptor antagonist potencies caused by differential access to micro-opioid receptors in the central nervous system and not necessarily by intrinsic differences in their opioid receptor activity. In naïve mice both compounds had similar potencies to antagonize morphine-induced antinociception in the hot plate and warm-water tail-withdrawal assays when measured under equilibrium conditions and afforded similar calculated apparent in vivo micro-opioid receptor affinities. In morphine-dependent mice both compounds precipitated withdrawal jumping but naltrexone was between 10- and 100-fold more potent than 6 beta-naltrexol. A similar potency difference was seen for other withdrawal behaviors. Both naltrexone and 6 beta-naltrexol at 1 mg/kg reversed antinociception induced by the long-lasting micro-opioid receptor agonist BU72 in the warm-water tail-withdrawal assay, but antagonism by naltrexone was 6-fold more rapid in onset at equal doses. Since the compounds have similar affinity for the micro-opioid receptor in vivo, the results suggest that the differences observed between the ability of naltrexone and 6 beta-naltrexol to precipitate withdrawal in the mouse may be explained by differential onset of receptor antagonist action.

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Figures

Fig. 1
Fig. 1
Morphine-induced antinociception in NIH Swiss mice in (a) the 55°C hot plate assay in the presence or absence of 10 mg/kg naltrexone or 6β-naltrexol, or (b) the 50°C warm-water tail-withdrawal assay. While 1, 3, and 10 mg/kg naltrexone or 6β-naltrexol were examined in the warm-water tail-withdrawal assay for the Schild analysis presented in Fig. 1c, only one antagonist dose (10 mg/kg) is shown for clarity. Mice received vehicle, 6β-naltrexol, or naltrexone s.c. 30 min prior to cumulative doses of morphine s.c. in 30 min intervals. Data are expressed as % MPE versus dose of morphine on a logarithmic scale and represent means ± S.E.M. for five-six mice in each group. (c) Schild plots for naltrexone and 6β-naltrexol generated using three doses of each compound (1, 3, and 10 mg/kg) to antagonize morphine in the warm-water tail-withdrawal assay with slopes constrained to unity.
Fig. 2
Fig. 2
Withdrawal jumping behavior in morphine-dependent mice. Mice were implanted with a 75 mg morphine pellet. After 72 h withdrawal was precipitated with s.c. injection of vehicle, 6β-naltrexol (1 or 10 mg/kg), or naltrexone (0.1 mg/kg). Jumping behavior was measured in 5 min periods for 20 min immediately following antagonist injection. Data are expressed as the number of jumps in each 5 min period and represent mean ± S.E.M. for eight-nine mice in each group.
Fig. 3
Fig. 3
Behavioral responses in morphine pellet-implanted dependent mice. Mice were implanted with a 75 mg morphine pellet and 72 h later withdrawal was precipitated by s.c. injection of vehicle, 6β-naltrexol (1 or 10 mg/kg), or naltrexone (0.1 mg/kg). Total jumping, wet dog shakes, paw tremors, grooming, scratching, and head washing behaviors were measured for 20 min immediately following antagonist injection. Data are expressed as the total number of responses in a 20 min period and represent mean ± S.E.M. for eight-nine mice in each group. *P<0.05 compared to vehicle injection.
Fig. 4
Fig. 4
Behavioral responses in morphine-dependent mice that received five s.c. morphine 30 mg/kg injections 12 h apart as described in Methods. Withdrawal was precipitated by s.c. injection of vehicle, 6β-naltrexol (1 or 10 mg/kg), or naltrexone (0.1 mg/kg). Total jumping, wet dog shakes, paw tremors, grooming, scratching, and head washing behaviors were measured for 20 min immediately following antagonist injection. Data are expressed as the total number of responses in a 20 min period and represent mean ± S.E.M. for eight-nine mice in each group.*P<0.05 compared to vehicle injection.
Fig. 5
Fig. 5
Withdrawal jumping behavior in morphine-dependent mice implanted with a 75 mg morphine pellet for 72 h. Withdrawal was precipitated by s.c. naltrexone injection (0.1 mg/kg) co-administered with vehicle, co-administered with 6β-naltrexol (1 mg/kg), or following a 90 min pretreatment (PT) with 6β-naltrexol (1 mg/kg). Jumping behavior was measured in 5 min periods for 20 min immediately following naltrexone injection. Data are expressed as the number of jumps per 5 min and represent mean ± S.E.M. for eight-nine mice in each group.
Fig. 6
Fig. 6
Time course of s.c. 6β-naltrexol (1 or 10 mg/kg) or s.c. naltrexone (1 mg/kg) to antagonize 0.32 mg/kg BU72-induced antinociception in the warm-water tail-withdrawal assay at 50°C in NIH Swiss mice. Mice received BU72 s.c. 1 h prior to injection of vehicle, 6β-naltrexol, or naltrexone (time 0). The ability of 6β-naltrexol or naltrexone to antagonize BU72-induced antinociception in the warm-water tail-withdrawal assay was measured at various time points following receptor antagonist injection. Data are expressed as % MPE and represent mean ± S.E.M. for five mice in each group.
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References

    1. Aceto MD. Characterization of prototypical opioid antagonists, agonist-antagonists, and agonists in the morphine-dependent rhesus monkey. Neuropeptides. 1984;5:15–18. - PubMed
    1. Arunlakshana O, Schild HO. Some quantitative uses of drug antagonists. Brit. J. Pharmacol. Chemother. 1959;14:48–58. - PMC - PubMed
    1. Blasig J, Herz A, Reinhold K, Zieglgansberger S. Development of physical dependence on morphine in respect to time and dosage and quantification of the precipitated withdrawal syndrome in rats. Psychopharmacologia (Berl) 1973;33:19–38. - PubMed
    1. Blumberg H, Ikeda C. Comparison of naltrexone and 6β-naltrexol in rats and mice. Fed. Proc. 1976;35:469.
    1. Bullingham R,E, McQuay HJ, Moore RA. Clinical pharmacokinetics of narcotic agonist-antagonist drugs. Clin. Pharmacokinetics. 1983;8:332–343. - PubMed

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