Heroin and its metabolites: relevance to heroin use disorder

Abstract

Heroin is an opioid agonist commonly abused for its rewarding effects. Since its synthesis at the end of the nineteenth century, its popularity as a recreational drug has ebbed and flowed. In the last three decades, heroin use has increased again, and yet the pharmacology of heroin is still poorly understood. After entering the body, heroin is rapidly deacetylated to 6-monoacetylmorphine (6-MAM), which is then deacetylated to morphine. Thus, drug addiction literature has long settled on the notion that heroin is little more than a pro-drug. In contrast to these former views, we will argue for a more complex interplay among heroin and its active metabolites: 6-MAM, morphine, and morphine-6-glucuronide (M6G). In particular, we propose that the complex temporal pattern of heroin effects results from the sequential, only partially overlapping, actions not only of 6-MAM, morphine, and M6G, but also of heroin per se, which, therefore, should not be seen as a mere brain-delivery system for its active metabolites. We will first review the literature concerning the pharmacokinetics and pharmacodynamics of heroin and its metabolites, then examine their neural and behavioral effects, and finally discuss the possible implications of these data for a better understanding of opioid reward and heroin addiction. By so doing we hope to highlight research topics to be investigated by future clinical and pre-clinical studies.

Fig. 1. Molecular structure of heroin and its metabolites.

Schematic representation of the metabolic pathway of heroin with the sequential breakdown into the main metabolites. The involved enzimatic processes are listed in italics.

Fig. 2. Early pharmacokinetic profile of heroin by i.v. administration and metabolite 6-MAM.

Time course of arterial and venous concentrations of heroin (blue line) and 6-MAM (red line), after an i.v. injection of heroin (≅0.8 mg/kg) in humans. Based on data extrapolated from Rentsch et al. 2001 [22].

Fig. 3. Pharmacokinetic profile of heroin by i.v. administration and its main metabolites.

Time course of venous concentrations of heroin (blue line), 6-MAM (red line), morphine (green line), and M6G (dotted grey line), after an i.v. injection of heroin (≅4 mg/kg) in humans. Based on data extrapolated from Rook et al. 2006 [25].

Fig. 4. Concentration-time profiles of heroin and its metabolites in the rat blood and brain.

Concentrations of heroin (blue), 6-MAM (red), and morphine (green) in the blood and in the striatal extracellular fluid of rats, after an i.v. injection of 1.3 µmol ($\cong$4 mg/kg) of heroin (A), 6-MAM (B), or morphine (C). Based on data extrapolated from Gottås et al. 2014 [20] and supplementary data (same animals of Fig. 3). Notice that in this study M6G was not quantified, as in the rat, under normal conditions, the synthesis of this metabolite is negligible.

Fig. 5. Comparative analysis of total opioid and dopamine concentrations in the rat striatum.

Striatal concentration of opioids and dopamine in rats that had received an i.v. injection of 1.3 µmol (≅4 mg/kg) of heroin (blue line), 6-MAM (red line), or morphine (green line). A The total concentration of the injected opioid and its metabolites. Thus, the blue line represents the sum of heroin, 6-MAM, and morphine; the red line represents the sum of 6-MAM and morphine; the green line represents the sole morphine. B The concentrations of Dopamine in the same animals. C The ratio between the concentration of dopamine (DA) and the cumulative concentration of opioids: blue line = DA/(heroin+6-MAM + morphine), red line = DA/(6-MAM + morphine); green line DA/morphine. Based on data extrapolated from Gottås et al. 2014 [20] (same animals of Fig. 4).