Role of 6-monoacetylmorphine in the acute release of striatal dopamine induced by intravenous heroin

Abstract

After injection, heroin is rapidly metabolized to 6-monoacetylmorphine (6-MAM) and further to morphine. As morphine has been shown to increase striatal dopamine, whereas 6-MAM has not been studied in this respect, we gave i.v. injections of 3 μmol 6-MAM, morphine or heroin to rats. Opioids were measured in blood, and dopamine and opioids in microdialysate from brain striatal extracellular fluid (ECF), by UPLC-MS/MS. After 6-MAM injection, 6-MAM ECF concentrations increased rapidly, and reached Cmax of 4.4 μM after 8 min. After heroin injection, 6-MAM increased rapidly in blood and reached Cmax of 6.4 μM in ECF after 8 min, while ECF Cmax for heroin was 1.2 μM after 2 min. T max for morphine in ECF was 29 and 24 min following 6-MAM and heroin administration, respectively, with corresponding Cmax levels of 1 and 2 μM. Dopamine levels peaked after 8 and 14 min following 6-MAM and heroin administration, respectively. The dopamine responses were equal, indicating no dopamine release by heroin per se. Furthermore, 6-MAM, and not morphine, appeared to mediate the early dopamine response, whereas morphine administration, giving rise to morphine ECF concentrations similar to those observed shortly after 6-MAM injection, did not increase ECF dopamine. 6-MAM appeared accordingly to be the substance responsible for the early increase in dopamine observed after heroin injection. As 6-MAM was formed rapidly from heroin in blood, and was the major substance reaching the brain after heroin administration, this also indicates that factors influencing blood 6-MAM concentrations might change the behavioural effects of heroin.

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

“…Nevertheless, both in the presence and absence of mAb we report a more profound psychomotor effect and higher 6-MAM levels in brain after injection of heroin compared with 6-MAM, as previously indicated after both subcutaneous and intravenous administration Gottås et al, 2014). Heroin itself is highly lipophilic and may rapidly cross the BBB for subsequent deacetylation into 6-MAM (Oldendorf et al, 1972;Umans and Inturrisi, 1981).…”

“…Previous work in our laboratory has shown that 6-MAM is the predominating metabolite in brain and blood after subcutaneous and intravenous heroin administration in mice and rats, respectively, indicating that 6-MAM is the main contributor to acute heroin effects Gottås et al, 2013). In addition, the psychomotor-stimulating effect and dopamine peak levels coincided with the rising concentration of 6-MAM in brain tissue, at a time when heroin was no longer detectable Gottås et al, 2013Gottås et al, , 2014. Furthermore, pharmacokinetic studies have indicated that heroin is mainly metabolized outside the brain .…”

Microdialysis as an Important Technique in Systems Pharmacology—a Historical and Methodological Review

“…A 2-min interval was applied when studying heroin and its metabolites 6-acetylmorphine and morphine in rats, giving a very high time resolution of the pharmacokinetics of brain uptake of the compounds in relation to pharmacological effect (88,89).…”

Transporter-Mediated Disposition of Opioids: Implications for Clinical Drug Interactions

“…One animal study found that in the postnatal development of mice, the BBB penetration of morphine decreased while that of diacetylmorphine did not, indicating a possible greater passive diffusion capacity of diactylemorphine (192). Although morphine is often assumed to be the active metabolite responsible for heroin's pharmacodynamic effects, a number of animal studies have proposed that 6-MAM may in fact be more important (193,194).…”