Pharmacokinetic modeling of subcutaneous heroin and its metabolites in blood and brain of mice

Boix, Fernando; Andersen, Jannike Mørch; Mørland, Jörg

doi:10.1111/j.1369-1600.2010.00298.x

Cited by 42 publications

(55 citation statements)

References 14 publications

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“…Moreover, the maximal increase in the NAc-Muscle differential was at ~20 min, the time interval when locomotor hypoactivity is inverted into hyperactivity. Interestingly, at this time the levels of the primary heroin metabolite (6-MAM), which has high affinity to μ-opioid receptors (Boix et al, 2013; Gottas et al, 2013), are on descending curve after their peaks at ~5 min but levels of morphine, another heroin’s metabolite, are at their peaks (Gottas et al, 2013). …”

Section: Discussionmentioning

confidence: 99%

Brain temperature effects of intravenous heroin: State dependency, environmental modulation, and the effects of dose

Bola

Kiyatkin

2017

Neuropharmacology

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Here we examined how intravenous heroin at a dose that maintains self-administration (0.1 mg/kg) affects brain temperature homeostasis in freely moving rats under conditions that seek to mimic some aspects of human drug use. When administered under standard laboratory conditions (quiet rest at 22°C ambient temperature), heroin induced moderate temperature increases (1.0–1.5°C) in the nucleus accumbens (NAc), a critical structure of the brain motivation-reinforcement circuit. By simultaneously recording temperatures in the temporal muscle and skin, we demonstrate that the hyperthermic effects of heroin results primarily from inhibition of heat loss due to strong and prolonged skin vasoconstriction. Heroin-induced brain temperature increases were enhanced during behavioral activation (i.e., social interaction) and in a moderately warm environment (29°C). By calculating the “net” effects of the drug in these two conditions, we found that this enhancement results from the summation of the hyperthermic effects of heroin with similar effects induced by either social interaction or a warmer environment. When the dose of heroin was increased (to 0.2, 0.4, 0.8, 1.6, 3.2, and 6.4 mg/kg), brain temperature showed a biphasic down-up response. The initial temperature decrease was dose-dependent and resulted from a transient inhibition of intra-brain heat production coupled with increased heat loss via skin surfaces—the effects typically induced by general anesthetics. These initial inhibitory effects induced by large-dose heroin injections could be related to profound CNS depression—the most serious health complications typical of heroin overdose in humans.

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Section: Discussionmentioning

confidence: 99%

Brain temperature effects of intravenous heroin: State dependency, environmental modulation, and the effects of dose

Bola

Kiyatkin

2017

Neuropharmacology

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“…This decrease in HDAC expression was accompanied by increased acetylation of H4, and altered emotional phenotypes and responsivity to an antidepressant. Other labs have also demonstrated a relationship between ELS and HDAC expression (Tesone-Coelho et al, 2013). Additionally, ELS decreased nucleus accumbens DNMT expression rates, which were associated with hyper-methylation of neuronal plasticity genes (Anier et al, 2013).…”

Section: Els and Epigenetic Effectsmentioning

confidence: 96%

Early-life stress interactions with the epigenome

Lewis

2014

Behavioural Pharmacology

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Throughout the 20th century a body of literature concerning the long lasting effects of early environment was produced. Adverse experiences in early life, or early life stress (ELS), is associated with a higher risk for developing various psychiatric illnesses. The mechanisms driving the complex interplay between ELS and adult phenotype has baffled many investigators for decades. Over the last decade, the new field of neuroepigenetics has emerged as one possible mechanism by which ELS can have far reaching effects on adult phenotype, behavior, and risk for psychiatric illness. Here we review two commonly investigated epigenetic mechanisms, histone modifications and DNA methylation, and the emerging field of neuroepigenetics as they relate to ELS. We discuss the current animal literature demonstrating ELS induced epigenetic modulation of gene expression that results in altered adult phenotypes. We also briefly discuss other areas in which neuroepigenetics has emerged as a potential mechanism underlying environmental and genetic interactions.

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“…There are major differences in the presence of heroin-metabolizing enzymes in human and rodent blood (Berry et al, 2009;Bahar et al, 2012), which may complicate the extrapolation of opioid metabolism data across species. Despite these differences, the in vivo half-lives of heroin in rodents and humans have been shown to be remarkably similar (t 1/2 ∼2.5-4 minutes) (Way et al, 1960;Rook et al, 2006b;Boix et al, 2013;Gottas et al, 2013;Raleigh et al, 2013). Fig.…”

Section: An Antibody Against 6-mam Impairs Heroin Effectsmentioning

confidence: 99%

A Monoclonal Antibody Specific for 6-Monoacetylmorphine Reduces Acute Heroin Effects in Mice

Bogen¹,

Boix²,

Nerem³

et al. 2014

J Pharmacol Exp Ther

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Immunotherapy against drugs of abuse is being studied as an alternative treatment option in addiction medicine and is based on antibodies sequestering the drug in the bloodstream and blocking its entry into the brain. Producing an efficient vaccine against heroin has been considered particularly challenging because of the rapid metabolism of heroin to multiple psychoactive molecules. We have previously reported that heroin's first metabolite, 6-monoacetylmorphine (6-MAM), is the predominant mediator for heroin's acute behavioral effects and that heroin is metabolized to 6-MAM primarily prior to brain entry. On this basis, we hypothesized that antibody sequestration of 6-MAM is sufficient to impair heroin-induced effects and therefore examined the effects of a monoclonal antibody (mAb) specific for 6-MAM. In vitro experiments in human and rat blood revealed that the antibody was able to bind 6-MAM and block the metabolism to morphine almost completely, whereas the conversion of heroin to 6-MAM remained unaffected. Mice pretreated with the mAb toward 6-MAM displayed a reduction in heroin-induced locomotor activity that corresponded closely to the reduction in brain 6-MAM levels. Intraperitoneal and intravenous administration of the anti-6-MAM mAb gave equivalent protection against heroin effects, and the mAb was estimated to have a functional half-life of 8 to 9 days in mice. Our study implies that an antibody against 6-MAM is effective in counteracting heroin effects.

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Pharmacokinetic modeling of subcutaneous heroin and its metabolites in blood and brain of mice

Cited by 42 publications

References 14 publications

Brain temperature effects of intravenous heroin: State dependency, environmental modulation, and the effects of dose

Brain temperature effects of intravenous heroin: State dependency, environmental modulation, and the effects of dose

Early-life stress interactions with the epigenome

A Monoclonal Antibody Specific for 6-Monoacetylmorphine Reduces Acute Heroin Effects in Mice

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