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The opioid receptor antagonist 3-methoxynaltrexone (3-MeONtx) has previously been shown in rodents to selectively reverse the analgesic actions of heroin and its metabolites 6-monoacetylmorphine (6-MAM), and morphine-6-glucuronide (M6G), but not that of morphine. Based on these and other results, a heroin/6-MAM/M6G μ-opioid receptor binding site or subreceptor mediating their analgesic activity has been proposed. It is however unknown whether this also accounts for the acute psychomotor stimulating properties of these opioids. The aim of the present study was therefore to explore if the acute psychomotor stimulating effects of heroin, 6-MAM, and morphine are mediated by distinct μ-opioid receptor binding sites or subreceptors. To address this aim, we examined how pretreatment with 3-MeONtx or naltrexone (NTX) affected the acute increase in locomotor activity induced by heroin, 6-MAM, or morphine in mice. The pharmacokinetic profiles of 3-MeONtx and NTX were also assessed in mouse brain. We found that 3-MeONtx similarly antagonized the acute increase in locomotor activity induced by equipotent doses of heroin, 6-MAM, or morphine. This antagonistic effect was comparable to the one observed following administration of NTX, and both antagonists gave similar pharmacokinetic profiles in mouse brain. Our findings do not support that different μ-opioid receptor subtypes or a distinct binding site at the μ-opioid receptor is involved in morphine-induced versus heroin/6-MAM-induced psychomotor activation. This might suggest that the opioid-induced psychomotor stimulation is mediated by different μ-opioid subreceptors than those responsible for their analgesic effects., (Copyright © 2014 Elsevier Inc. All rights reserved.)

After intake of heroin or morphine, active metabolites are formed in the body. The two most important morphine metabolites are morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G). M6G and M3G are present for longer time periods and in higher concentrations than the parent drug, but their potential contribution to reward and to development of dependence and addiction is not clear. We tested the effects of morphine and M6G separately (doses of 10, 20, 30 and 50 micromol/kg), administered together, and also in combination with with 200 microm l/kg M3G in male C57BL/6J-Bom mice. M3G in doses of 50, 100, 200, 300 and 400 micromol/kg were also tested alone. We evaluated the rewarding effects in a conditioning place preference (CPP) model and the psychomotor stimulating effects by recording locomotor activity. Mice were subjected to three consecutive conditioning days with drugs or saline before testing. Changes in locomotor activity from conditioning day one to day three were also compared to the expression of CPP on the test day. This study revealed that coadministration of morphine and M6G induced CPP of similar magnitude to the sum of equimolar doses of these compounds alone, and different ratios of the two drugs did not affect the results. M3G did not cause CPP and reduced the CPP induced by both morphine and M6G when coadministered with these drugs. Morphine induced locomotor activity was reduced by coadministration of M3G, but this was not seen when M3G was co-injected with M6G. The changes in locomotor activity during the conditioning periods did not correlated with the expression of CPP. This study revealed that the morphine-glucuronides in different and complex ways can influence the pharmacological effects of psychomotor activation and reward observed after intake of morphine.

A number of studies have investigated the reward potential of morphine, using the Conditioned Place Preference (CPP) procedure. The morphine-metabolite morphine-6-glucuronide (M6G) is known to have analgesic activity comparable to morphine, but its reward properties are unclear. An unbiased two compartment counterbalanced procedure was used to investigate the induction of CPP by morphine or M6G in C57BL/6J-Bom mice using different conditioning schedules. The conditioning sessions took place either immediately after the injections and lasted either 20 or 40 min, or were delayed until 15 min after the injections and lasted for 20 min. Locomotor activity was recorded during the conditioning sessions. Morphine induced CPP when the 20-minute conditioning sessions were conducted directly after the injections, but not when they were delayed. M6G induced CPP when the 20-minute conditioning sessions were delayed, but not when the animals were conditioned directly after the injections. Neither morphine nor M6G induced CPP after 40-minute direct conditioning sessions. M6G had a biphasic effect on locomotor activity, with an initial decrease followed by excitation. This study indicates that M6G has rewarding effects, and might contribute to the development of addiction after heroin or morphine administration. However, in any attempts to explore the reward properties of M6G, the choice of time schedule should be carefully considered.

Morphine-6-glucuronide (M6G), an active metabolite of morphine has been shown to produce analgesia and fewer side effects than morphine, and the introduction of M6G as a new drug for treatment of postoperative pain is planned in 2007. Following morphine intake in humans, the metabolites morphine-3-glucuronide (M3G) and M6G are present in substantial concentrations and for longer periods than the parent drug. The possible reward effects of the morphine glucuronides have previously not been well studied. In the present study, conditioned place preference (CPP) was recorded after conditioning with subcutaneous injections of 5, 10, 20, 30 or 50 micromol/kg morphine or M6G, or 240 or 500 micromol/kg M3G in C57BL/6J-Bom mice, using a biased two compartment ("closed" and "open") counterbalanced paradigm. CPP was induced after treatment with both morphine and M6G with dose dependent increase up to 30 micromol/kg after treatment in the "closed" compartment. No dose response was observed in the "open" compartment, with maximal CPP after 10 micromol/kg morphine or M6G. M3G caused a tendency of condition place aversion (CPA), although not statistically significant. In the present study morphine and M6G demonstrated comparable reward effects, at doses that differed depending on which compartment the mice were conditioned in. M3G showed a tendency to exhibit aversive properties.

The acquisition of two-way shuttle avoidance (40 first trials) was used to test the anxiolytic activity of diazepam (2 and 4 mg/kg) and alprazolam (1.25 mg/kg) vs. vehicle, IP, in rats. These rats had received three different previous treatments: acute, acute with previous handling habituation for 15 days, and handling habituation combined with chronic treatment for 15 days. Results of the acute treatment showed a comparable anxiolytic action of diazepam and alprazolam, reflected by an improvement in avoidance acquisition. After handling habituation, no effect on shuttle box acquisition was obtained in rats acutely treated with diazepam, whereas the alprazolam-treated group showed a significantly impaired avoidance performance. When handling habituation was combined with chronic benzodiazepine treatment, the drugs' anxiolytic action persisted although there was a complete disappearance of their sedative effects. These behavioral results are discussed in relation to the emotional changes induced by the procedures of handling. They are tentatively linked with possible changes in the functionality of GABA neurotransmission, possibly at the level of the GABA-benzodiazepine receptor which some studies have found associated to handling habituation.