Long-term Use of Z-Hypnotics and Co-medication with Benzodiazepines and Opioids.

Benzodiazepine-like drugs (z-hypnotics) are the most commonly used drugs for treatment of insomnia in Norway. Z-hypnotics are recommended for short-term treatment not exceeding 4 weeks. We aimed to study the use of z-hypnotics in the adult population in Norway with focus on recurrent use in new users, treatment intensity and co-medication with benzodiazepines and opioids in long-term users.

Codeine to morphine concentration ratios in samples from living subjects and autopsy cases after incubation.

The codeine to morphine concentration ratio is used in forensic toxicology to assess if codeine has been ingested alone or if morphine and/or heroin have been ingested in addition. In our experience, this interpretation is more difficult in autopsy cases compared with samples from living persons, since high morphine concentrations are observed in cases where only codeine is assumed to have been ingested. We have investigated if codeine and morphine glucuronides are subject to cleavage to the same extent in living and autopsy cases in vitro.

The interference of ethanol with heroin-stimulated psychomotor activation in mice is not related to changed brain concentrations of the active metabolites 6MAM or morphine.

It has been suggested that the potentiating effect observed in human beings when combining alcohol and heroin may be due to an interference of ethanol with the pharmacokinetics of heroin, leading to accumulation of the biologically active metabolites, 6-monoacetylmorphine (6MAM) and morphine. However, experimental evidence for this hypothesis is lacking. In this study, we used mice and examined the effect of ethanol on the metabolism of heroin by combining a locomotor activity test, which is a behaviour model representative of psychomotor stimulation, with pharmacokinetic studies in blood and brain tissue.

Long-term methadone treatment impairs novelty preference in rats both when present and absent in brain tissue.

Behavioral consequences of long-term methadone treatment have received little attention either in humans or experimental animals. In this work, we show that methadone (2.5-10 mg/kg) administered (sc) once daily for three weeks with repeated withdrawal on Saturday and Sunday impairs the novelty preference in rats.

Determination of heroin and its main metabolites in small sample volumes of whole blood and brain tissue by reversed-phase liquid chromatography-tandem mass spectrometry.

A high-performance liquid chromatography-tandem mass spectrometry (LC-MS-MS) method has been developed for the quantitative analysis of heroin and its major metabolites 6-acetylmorphine, morphine, morphine-3-glucuronide and morphine-6-glucuronide in blood and brain tissue, using 0.1-mL samples. We evaluated this method for analysis of heroin and its metabolites in samples from heroin treated mice.

Increased locomotor activity induced by heroin in mice: pharmacokinetic demonstration of heroin acting as a prodrug for the mediator 6-monoacetylmorphine in vivo.

We investigated the relative importance of heroin and its metabolites in eliciting a behavioral response in mice by studying the relationship between concentrations of heroin, 6-monoacetylmorphine (6MAM), and morphine in brain tissue and the effects on locomotor activity. Low doses (subcutaneous) of heroin (< or =5 micromol/kg) or 6MAM (< or =15 micromol/kg) made the mice run significantly more than mice given equimolar doses of morphine. There were no differences in the response between heroin and 6MAM, although we observed a shift to the left of the dose-response curve for the maximal response of heroin.

Interactions between morphine and the morphine-glucuronides measured by conditioned place preference and locomotor activity.

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.

Behavioural sensitization in mice induced by morphine-glucuronide metabolites.

Sensitization is thought to be involved in central aspects of drug addiction. Both morphine-3-glucuronid (M3G) and morphine-6-glucuronid (M6G) are rapidly formed in high concentrations shortly after heroin and morphine consumption. Their role in the development of sensitization has not previously been studied.

Different time schedules affect conditioned place preference after morphine and morphine-6-glucuronide administration.

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.

Morphine-3-glucuronide inhibits morphine induced, but enhances morphine-6-glucuronide induced locomotor activity in mice.

The main metabolite of morphine, morphine-3-glucuronide (M3G) has no opioid effects. Some studies have rather indicated that it antagonizes the antinociceptive and respiratory depressive effects of both morphine and the active metabolite morphine-6-glucuronide (M6G). We studied the possible influence of M3G on the psychostimulant properties of morphine and M6G measured by locomotor activity.

Conditioned place preference induced by morphine and morphine-6-glucuronide in mice.

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.

Pharmacokinetic differences of morphine and morphine-glucuronides are reflected in locomotor activity.

The main metabolites of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), have been considered to participate in some of the effects of morphine. There is limited knowledge of the pharmacokinetics and dynamics of morphine and the main metabolites in mice, but mice are widely used to study both the analgesic effects and the psychomotor effects of morphine. The present study aimed to explore pharmacokinetic differences between morphine and morphine-glucuronides in mice after different routes of administration, and to investigate how possible differences were reflected in locomotor activity, a measure of psychostimulant properties.