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

It has been proposed that on chronic morphine treatment the µ-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 µ-opioid receptor inverse agonist naltrexone has been shown to precipitate more severe withdrawal behavior in mice than the putative neutral receptor antagonist 6β-naltrexol. In the present study naltrexone and 6β-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 µ-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 µ-opioid receptor affinities. In morphine-dependent mice both compounds precipitated withdrawal jumping but naltrexone was between 10- and 100-fold more potent than 6β-naltrexol. A similar potency difference was seen for other withdrawal behaviors. Both naltrexone and 6β-naltrexol at 1 mg/kg reversed antinociception induced by the long-lasting µ-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 µ-opioid receptor in vivo, the results suggest that the differences observed between the ability of naltrexone and 6β-naltrexol to precipitate withdrawal in the mouse may be explained by differential onset of receptor antagonist action.