Increased Locomotor Activity Induced by Heroin in Mice: Pharmacokinetic Demonstration of Heroin Acting as a Prodrug for the Mediator 6-Monoacetylmorphine in Vivo

Andersen, Jannike Mørch; Ripel, Åse; Boix, Fernando; Normann, Per T.; Mørland, Jörg

doi:10.1124/jpet.109.152462

Cited by 76 publications

(134 citation statements)

References 31 publications

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“…The acute locomotor activity was measured in chambers using VersaMax optical animal activity monitoring system (AccuScan/Omnitech Electronics, Inc., Columbus, OH) as previously described in detail by Andersen et al (2009). In short, the mice were placed individually in an activity chamber for 60 minutes of habituation.…”

Section: Methodsmentioning

confidence: 99%

Pharmacological Effects of a Monoclonal Antibody against 6-Monoacetylmorphine upon Heroin-Induced Locomotor Activity and Pharmacokinetics in Mice

Kvello¹,

Andersen²,

Øiestad³

et al. 2016

The Journal of Pharmacology and Experimental Therapeutics

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Immunotherapy can provide a supplemental treatment strategy against heroin use on the principle of sequestering the active drug in the bloodstream, thereby reducing its distribution to the brain. Previous studies have shown that heroin's first metabolite, 6-monoacetylmorphine (6-MAM), is the main mediator of acute heroin effects. The objective of the present study was to characterize the pharmacological potential of a monoclonal antibody against 6-MAM (anti-6-MAM mAb) to counteract the heroin response. The individual contributions from heroin and 6-MAM to heroin effects were also examined by pretreating mice with anti-6-MAM mAb (10-100 mg/kg) prior to either heroin or 6-MAM injection (1.25-2.5 mmol/kg). The opioid-induced behavioral response was assessed in a locomotor activity test, followed by opioid and antibody quantification in blood and brain tissue. Pretreatment with mAb caused a profound reduction of heroin-and 6-MAM-induced behavior, accompanied by correspondingly decreased levels of 6-MAM in brain tissue. mAb pretreatment was more efficient against 6-MAM injection than against heroin, leading to an almost complete blockade of 6-MAM-induced effects. mAb pretreatment was unable to block the immediate (5-minute) transport of active metabolites across the blood-brain barrier after heroin injection, indicating that heroin itself appears to enhance the immediate delivery of 6-MAM to the brain. The current study provides additional evidence that 6-MAM sequestration is crucial for counteracting the acute heroin response, and demonstrates the pharmacological potential of immunotherapy against heroin use.

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Section: Methodsmentioning

confidence: 99%

Pharmacological Effects of a Monoclonal Antibody against 6-Monoacetylmorphine upon Heroin-Induced Locomotor Activity and Pharmacokinetics in Mice

Kvello¹,

Andersen²,

Øiestad³

et al. 2016

The Journal of Pharmacology and Experimental Therapeutics

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“…heroin administration has not been well characterized in non-vaccinated rodents. Distribution studies have primarily focused on the s.c. route (Umans and Inturrisi, 1982;Pacifici et al, 2000;Andersen et al, 2009), which may subject heroin to increased peripheral degradation and slower distribution to brain compared to the i.v. route used by humans (Klous et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…1A) as: heroin → 6-monoacetylmorphine (6-MAM) → morphine → morphine-6-glucuronide (M-6-G) (Antonilli et al, 2005), which are all active in humans. Heroin enters brain but is presumed to be a pro-drug because it is rapidly metabolized, has considerably lower affinity for opioid receptors than 6-MAM or morphine (Inturrisi et al, 1983), and is generally found at low concentrations in brain (Andersen et al, 2009). 6-MAM is more likely to be the primary mediator of heroin's early behavioral effects, because it is found at high levels in plasma and brain after heroin administration in mice (Way et al, 1960;Andersen et al, 2009) and administration of equimolar heroin or 6-MAM doses results in similar behavioral effects (Andersen et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

“…Heroin enters brain but is presumed to be a pro-drug because it is rapidly metabolized, has considerably lower affinity for opioid receptors than 6-MAM or morphine (Inturrisi et al, 1983), and is generally found at low concentrations in brain (Andersen et al, 2009). 6-MAM is more likely to be the primary mediator of heroin's early behavioral effects, because it is found at high levels in plasma and brain after heroin administration in mice (Way et al, 1960;Andersen et al, 2009) and administration of equimolar heroin or 6-MAM doses results in similar behavioral effects (Andersen et al, 2009). The contributions of morphine and M-6-G to the early effects of heroin are assumed to be smaller due to their lower levels and slower accumulation in brain (Andersen et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

“…6-MAM is more likely to be the primary mediator of heroin's early behavioral effects, because it is found at high levels in plasma and brain after heroin administration in mice (Way et al, 1960;Andersen et al, 2009) and administration of equimolar heroin or 6-MAM doses results in similar behavioral effects (Andersen et al, 2009). The contributions of morphine and M-6-G to the early effects of heroin are assumed to be smaller due to their lower levels and slower accumulation in brain (Andersen et al, 2009). With regard to the mechanism of action of an opioid vaccine, it is unclear whether the antibodies they generate must bind heroin, its downstream metabolites, or both to prevent opioid distribution from plasma to brain and reduce heroin's behavioral effects.…”

Section: Introductionmentioning

confidence: 99%

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Selective Effects of a Morphine Conjugate Vaccine on Heroin and Metabolite Distribution and Heroin-Induced Behaviors in Rats

Raleigh

Pravetoni

Harris

et al. 2013

The Journal of Pharmacology and Experimental Therapeutics

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Morphine conjugate vaccines have effectively reduced behavioral effects of heroin in rodents and primates. To better understand how these effects are mediated, heroin and metabolite distribution studies were performed in rats in the presence and absence of vaccination. In non-vaccinated rats 6-monoacetylmorphine (6-MAM) was the predominant opioid in plasma and brain as early as 1 minute after i.v. administration of heroin and for up to 14 minutes. Vaccination with morphine conjugated to keyhole limpet hemocyanin (M-KLH) elicited high titers and concentrations of antibodies with high affinity for heroin, 6-MAM, and morphine. Four minutes after heroin administration vaccinated rats showed substantial retention of all three opioids in plasma compared to controls and reduced 6-MAM and morphine, but not heroin, distribution to brain. Administration of 6-MAM rather than heroin in M-KLH vaccinated rats showed a similar drug distribution pattern. Vaccination reduced heroin-induced analgesia and blocked heroin-induced locomotor activity throughout 2 weeks of repeated testing. Higher serum opioid-specific antibody concentrations were associated with higher plasma opioid concentrations, lower brain 6-MAM and morphine concentrations, and lower heroin-induced locomotor activity. Serum antibody concentrations over 0.2 mg/ml were associated with substantial effects on these measures. These data support a critical role for 6-MAM in mediating the early effects of i.v. heroin and suggest that reducing 6-MAM concentration in brain is essential to the efficacy of morphine conjugate vaccines.

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Prenatal heroin exposure alters brain morphology and connectivity in adolescent mice

et al. 2022

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The United States is experiencing a dramatic increase in maternal opioid misuse and, consequently, the number of individuals exposed to opioids in utero. Prenatal opioid exposure has both acute and long-lasting effects on health and wellbeing. Effects on the brain, often identified at school age, manifest as cognitive impairment, attention deficit, and reduced scholastic achievement. The neurobiological basis for these effects is poorly understood. Here, we examine how in utero exposure to heroin affects brain development into early adolescence in a mouse model. Pregnant C57BL/6J mice received escalating doses of heroin twice daily on gestational days 4-18. The brains of offspring were assessed on postnatal day 28 using 9.4 T diffusion MRI of postmortem specimens at 36 μm resolution. Whole-brain volumes and the volumes of 166 bilateral regions were compared between heroin-exposed and control offspring. We identified a reduction in whole-brain volume in heroin-exposed offspring and heroin-associated volume changes in 29 regions after standardizing for whole-brain volume. Regions with bilaterally reduced standardized volumes in heroin-exposed offspring relative to controls include the ectorhinal and insular cortices. Regions with bilaterally increased standardized volumes in heroin-exposed offspring relative to controls include the periaqueductal gray, septal region, striatum, and hypothalamus. Leveraging microscopic resolution diffusion tensor imaging and precise regional parcellation, we generated whole-brain structural MRI diffusion connectomes. Using a dimension reduction approach with multivariate analysis of variance to assess group differences in the connectome, we found that in utero heroin exposure altered structure-based connectivity of the left septal region and the region that acts as a hub for limbic regulatory actions. Consistent with clinical evidence, our findings suggest that prenatal opioid exposure may have effects on brain morphology, connectivity, and, consequently, function that persist into adolescence.

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Increased Locomotor Activity Induced by Heroin in Mice: Pharmacokinetic Demonstration of Heroin Acting as a Prodrug for the Mediator 6-Monoacetylmorphine in Vivo

Cited by 76 publications

References 31 publications

Pharmacological Effects of a Monoclonal Antibody against 6-Monoacetylmorphine upon Heroin-Induced Locomotor Activity and Pharmacokinetics in Mice

Pharmacological Effects of a Monoclonal Antibody against 6-Monoacetylmorphine upon Heroin-Induced Locomotor Activity and Pharmacokinetics in Mice

Selective Effects of a Morphine Conjugate Vaccine on Heroin and Metabolite Distribution and Heroin-Induced Behaviors in Rats

Prenatal heroin exposure alters brain morphology and connectivity in adolescent mice

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