Heroin toxicity and addiction: a consequence of heroin or of its metabolites?

Opiate addiction caused by use of heroin is a major problem that imposes a significant burden on society. The negative social and individual consequences are due both to the cost associated to obtaining the daily doses (criminality, prostitution,...) as w ell as the, oft neglected, intoxicating effects of the drug, like accidents (i.e. drugged driving), disease, overdose and premature death. A central reason for this panorama of effects is the ability of heroin to induce compulsory use, addiction, in a lar ge proportion of those individuals who try the drug a few times. A better knowledge on the mechanisms behind its high narcotic power as well as its extreme addiction potential is of significant interest for the prevention and the development of effective interventions against its use and direct detrimental acute effects. Despite its high potency, heroin disappears very fast from the body and has very low pharmacological activity by itself. We have evidence indicating that heroin metabolites are not only excretion products, but they can have a potent pharmacological action, and can be responsible for the effects of heroin, both its acute detrimental outcome and its potential for chronic abuse. Still, there is a large knowledge gap with respect to how her oin and its metabolites, separately and in combination, mediate the effects observed after heroin intake, both at the acute and chronic behavioural level as well as in respect to the neurobiological adaptations and functional changes related to the develo pment of heroin addiction. Further understanding of these processes could lead to new preventive and treatment strategies for its acute and chronic effects, directed either towards the specific blockade of the pharmacological action of the involved metab olites or towards manipulation of heroin metabolism.