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BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering

Heroin abuse and addiction: Heroin metabolism as a key player and possible basis for new pharmacotherapy

Awarded: NOK 4.0 mill.

Background and aim Heroin abuse is a growing problem worldwide and todays treatment options are characterized by a high relapse rate. The goal of this project was to examine new pharmacotherapeutic principles for the treatment of heroin addiction by attacking the substance rather than its biological targets (receptors). Heroin is converted to 6-monoacetylmorfin (6-MAM) within a few minutes after drug intake, and 6-MAM is further metabolized to morphine. Our research group has previously shown that 6-MAM and morphine exert heroins acute effects. By the use of pharmacokinetic methods such as enzyme modulation and immunotherapy we have tried to reduce the amount of 6-MAM entering the brain after heroin intake. To achieve this, we have studied 1) the enzymes involved in brain and peripheral metabolism of heroin, 2) the effect of enzyme inhibition and/or immune therapy against 6-MAM to reduce brain 6-MAM levels, and 3) the effect of these therapeutic approaches to reduce/block acute heroin intoxication and the development of heroin addiction in an experimental animal model. Results To gather knowledge about the metabolism of heroin, we have studied the metabolic rate in different rat and human organs. We have further characterized the esterase enzymes involved in heroin metabolism in the different rat and human tissues. In short our studies show that heroin is metabolized by different enzymes in rodents and humans. The metabolism is very rapid in human liver tissue, while enzymes in the blood contribute to a larger extent in the rat. The results from these studies are presented in two master theses in biology and two scientific articles are in progress. Enzyme inhibitors reduced the transformation of heroin to 6-MAM in vitro, but did not appear suitable to decrease brain 6-MAM concentration or heroin effects in vivo in mice. In contrast, the use of immunotherapy, by employing a monoclonal antibody directed against 6-MAM (6-MAM mAb), successfully prevented drug transfer to the brain by drug sequestration in the circulation. Studies in mice showed that pretreatment with antibody caused a dose-response reduction both in brain levels of 6-MAM and drug effect after a heroin injection. In a follow-up study, we examined the individual contribution of 6-MAM and heroin for the acute intoxication effect after heroin intake, and found that heroin has an important role in terms of quick transport of active metabolites to the brain. The results of this work are published in two articles in the Journal of Pharmacology and Experimental Therapeutics (Bogen et al., 2014; Kvello et al., 2016). In the last part of the project, we have investigated the efficacy of 6-MAM mAb to block heroin reward, addiction, and relapse. This has been performed by using two different experimental animal models of addiction; conditioned place preference in mice and self-administration in the rat. Our studies in mice show that antibody treatment can prevent heroins rewarding effect. The self-administration studies in the rat show that the mAb treatment prevents relapse, however, this effect can be overcome by increasing the heroin dose. One manuscript on this subject is under review and one is in preparation in collaboration with our partners at the University of Sussex where the self-administration studies were performed. The work is expected to be published in the course of 2018. Summary Our studies show that the effects exerted by heroin are mainly mediated by its metabolites 6-MAM and morphine, while heroin is likely to serve a role in terms of rapid transport of active metabolites to the brain. Immune therapy has a potential to counteract the drug effect, however, the protection provided by a monoclonal antibody against 6-MAM can be overcome if the heroin dose is increased. In a continuation of this project, we have provided the antibody to pregnant mice and show that immunotherapy can protect the mouse fetus against long-term effects induced by prenatal heroin exposure. In addition to publications in international peer-reviewed journals and one post doc fellowships, the project has led to two masters degrees and a PhD degree.

Drug abuse is a major national and worldwide public health problem. With 50 deaths per million, Norway is one of the European countries with the highest incidence of narcotic related deaths, and of these about 80% were caused by heroin. Treatment of heroi n addiction has proven to be challenging. Substitution therapy, such as methadone and buprenorphine, has shown some clinical success, but is hampered by a high incidence of relapse to illicit drug consumption and long-term adverse and toxic effects. New t reatment strategies for heroin addiction are therefore highly requested. It has traditionally been assumed that heroin is particularly addictive because it crosses the blood-brain barrier so rapidly, and that morphine is the metabolite responsible for its acute effects since heroin itself is inactive at the opioid receptors. Recent research in our laboratory has demonstrated that 6-monoacetylmorphine (6-MAM), not morphine, is the most important metabolite mediating the acute behavioural effects of heroin. Further, it is presumably the blood-brain permeability to 6-MAM, not heroin, that accounts for the highly efficient delivery of heroin metabolites to the brain. We therefore suggest that pharmacotherapy aiming to reduce the immediate, powerful increases in 6-MAM levels after heroin exposure may have a potential in prevention of acute heroin effects, as well as of addiction. This could be achieved by passive immunization with specific antibodies that sequester 6-MAM and prevent its access to the brain, or by enzyme modulation either inhibiting the formation of 6-MAM or increasing its degradation. These new pharmacotherapeutic approaches, targeting the drug itself rather than brain opioid receptors, open for a possible combination of conventional and new t reatment strategies, and may have clinical applications in early intervention, relapse prevention and overdose treatment.

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BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering