The prodrug heroin: Studies of heroin´s active metabolites and immunotherapeutic approaches to block heroin effects

Heroin’s first metabolite, 6-acetylmorphine, is essential for the immediate rewarding effects of heroin
Heroin is a prodrug mainly acting through its metabolites. In the body, heroin is rapidly metabolized to 6-acetylmorphine (6-AM) and morphine by esterase enzymes. Morphine is further glucuronidated to morphine-6-glucuronide (active) and morphine-3-glucuronide (inactive). For decades, morphine was considered to be the metabolite responsible for heroin’s pharmacological effects. Studies in our laboratory have demonstrated that the immediate heroin response is mediated by 6-AM and that this metabolite is essential for the rewarding and sensitizing effects of heroin. When comparing the effects after heroin and 6-AM injection, heroin is a more potent inducer of psychomotor stimulation and reward than 6-AM. This may be explained by the higher lipophilicity of heroin, providing more efficient drug transfer to the brain immediately after injection.

An immunotherapeutic approach to prevent heroin effects
Immunotherapy against drugs of abuse is being studied as an alternative treatment option in addiction medicine and is based on antibodies (Ab) sequestering the drug in the bloodstream. The resulting drug-Ab complex is too large to cross the blood-brain barrier, and hence, the drug reward is inhibited. Producing an efficient vaccine against heroin has been considered particularly challenging due to the rapid metabolism of heroin to multiple psychoactive metabolites. We have previously shown that passive immunization with anti-6-AM Ab dose-dependently reduced heroin-induced drug effects and the brain levels of 6-AM and morphine in adult male mice. Furthermore, we have demonstrated that passive immunization of pregnant mice prior to heroin injections provides fetal neuroprotection against heroin metabolites and prevents persistent adverse behavioral effects in mice offspring.

Ongoing studies

  • Metabolism of heroin in human and rodent tissue (Project leaders: Fernando Boix and Inger Lise Bogen)
  • Metabolism of heroin in liver organoids and Organ-on-a-Chip-systems (Project leaders: Steven Ray Wilson, Hanne Røberg-Larsen and Gareth Sullivan, University of Oslo)
  • Brain opioid levels during heroin self-administration in the rat (Project leader: Daniele Caprioli, Sapienza University of Rome, Italy)

Project members
Fernando Boix (Senior Scientist, PhD)
Inger Lise Bogen (Senior Scientist, PhD)
Jannike Mørch Andersen (Senior Scientist, PhD)
Vigdis Vindenes (Senior Scientist/Section Leader, PhD)
Synne Steinsland (Laboratory engineer, MSc)
Elisabeth Nerem (Laboratory engineer, BSc)

Past members
Ida Caroline Sneis Boger (MSc student 2018-2020)
Anne Marte S. Kvello (PhD student 2014-2019)
Guro Søe Eriksen (PhD student 2010-2017)
Ingvild Juul-Hansen (MSc student 2013-2015)
Karine Margrethe Hauan (MSc student 2012-2014)
André Gottås (PhD student 2011-2014)
Karianne Haugen (MSc student 2009-2011)
Jørg Mørland (Prof. em.)

Collaboration
Prof. em. Jørg Mørland, National Institute of Public Health, Oslo, Norway
Prof. Steven Ray Wilson, Department of Chemistry, University of Oslo and Hybrid Technology-Hub, Centre of Excellence, Oslo, Norway
Associate Prof. Hanne Røberg-Larsen, Department of Chemistry, University of Oslo, Oslo, Norway
Researcher Gareth Sullivan, Institute of Basic Medical Sciences, University of Oslo and Hybrid Technology-Hub, Centre of Excellence, Oslo, Norway
Prof. Aldo Badiani, Sussex Addiction Research and Intervention Centre, School of Psychology, University of Sussex, Brighton, UK
Prof. Daniele Caprioli, Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy

Funding
Norwegian Research Council (#170534, #196621, #213751)

Press and Media Reports
LC-MS/MS highlights how heroin preparation procedure affects overdose risk
Immunotherapy inhibits heroin effects in research animals
Immunotherapy may help treat heroin addiction
Immunterapi mot heroinrus

If you have questions about the project or suggestions for research collaboration, please contact: Fernando Boix (fernando.boix@ous-hf.no) or Inger Lise Bogen (inger.lise.bogen@ous-hf.no) at the Department of Forensic Sciences, Section of Drug Abuse Research, Oslo University Hospital, Oslo, Norway.

Publications
Andersen JM, Bogen IL, Karinen R, Brochmann GW, Mørland J, Vindenes V, Boix F (2021)
Does the preparation for intravenous administration affect the composition of heroin injections? A controlled laboratory study
Addiction (in press)
DOI 10.1111/add.1549210.1111/add.15492, PubMed 33739552

Skottvoll FS, Hansen FA, Harrison S, Boger IS, Mrsa A, Restan MS, Stein M, Lundanes E, Pedersen-Bjergaard S, Aizenshtadt A, Krauss S, Sullivan G, Bogen IL, Wilson SR (2021)
Electromembrane Extraction and Mass Spectrometry for Liver Organoid Drug Metabolism Studies
Anal Chem, 93 (7), 3576-3585
DOI 10.1021/acs.analchem.0c05082, PubMed 33534551

Kvello AMS, Andersen JM, Boix F, Mørland J, Bogen IL (2019)
The role of 6-acetylmorphine in heroin-induced reward and locomotor sensitization in mice
Addict Biol, 25 (2), e12727
DOI 10.1111/adb.12727, PubMed 30788879

Avvisati R, Bogen IL, Andersen JM, Vindenes V, Mørland J, Badiani A, Boix F (2018)
The active heroin metabolite 6-acetylmorphine has robust reinforcing effects as assessed by self-administration in the rat
Neuropharmacology, 150, 192-199
DOI 10.1016/j.neuropharm.2018.12.023, PubMed 30578794

Kvello AMS, Andersen JM, Øiestad EL, Steinsland S, Aase A, Mørland J, Bogen IL (2018)
A Monoclonal Antibody against 6-Acetylmorphine Protects Female Mice Offspring from Adverse Behavioral Effects Induced by Prenatal Heroin Exposure
J Pharmacol Exp Ther, 368 (1), 106-115
DOI 10.1124/jpet.118.251504, PubMed 30361238

Thaulow CH, Øiestad ÅML, Rogde S, Andersen JM, Høiseth G, Handal M, Mørland J, Vindenes V (2018)
Can measurements of heroin metabolites in post-mortem matrices other than peripheral blood indicate if death was rapid or delayed?
Forensic Sci Int, 290, 121-128
DOI 10.1016/j.forsciint.2018.06.041, PubMed 30015276

Thaulow CH, Øiestad ÅML, Rogde S, Karinen R, Brochmann GW, Andersen JM, Høiseth G, Handal M, Mørland J, Arnestad M, Øiestad EL, Strand DH, Vindenes V (2018)
Metabolites of Heroin in Several Different Post-mortem Matrices
J Anal Toxicol, 42 (5), 311-320
DOI 10.1093/jat/bky002, PubMed 29409037

Kvello AM, Andersen JM, Øiestad EL, Mørland J, Bogen IL (2016)
Pharmacological Effects of a Monoclonal Antibody against 6-Monoacetylmorphine upon Heroin-Induced Locomotor Activity and Pharmacokinetics in Mice
J Pharmacol Exp Ther, 358 (2), 181-9
DOI 10.1124/jpet.116.233510, PubMed 27217591

Eriksen GS, Andersen JM, Boix F, Bergh MS, Vindenes V, Rice KC, Huestis MA, Mørland J (2016)
Comparison of (+)- and (-)-Naloxone on the Acute Psychomotor-Stimulating Effects of Heroin, 6-Acetylmorphine, and Morphine in Mice
J Pharmacol Exp Ther, 358 (2), 209-15
DOI 10.1124/jpet.116.233544, PubMed 27278234

Bogen IL, Boix F, Nerem E, Mørland J, Andersen JM (2014)
A monoclonal antibody specific for 6-monoacetylmorphine reduces acute heroin effects in mice
J Pharmacol Exp Ther, 349 (3), 568-76
DOI 10.1124/jpet.113.212035, PubMed 24700886

Eriksen GS, Andersen JM, Boix F, Mørland J (2014)
3-Methoxynaltrexone is not a selective antagonist for the acute psychomotor stimulating effects of heroin and 6-monoacetylmorphine in mice
Pharmacol Biochem Behav, 122, 82-8
DOI 10.1016/j.pbb.2014.03.018, PubMed 24699386

Gottås A, Boix F, Øiestad EL, Vindenes V, Mørland J (2014)
Role of 6-monoacetylmorphine in the acute release of striatal dopamine induced by intravenous heroin
Int J Neuropsychopharmacol, 17 (9), 1357-65
DOI 10.1017/S1461145714000169, PubMed 24576415

Gottås A, Øiestad EL, Boix F, Vindenes V, Ripel Å, Thaulow CH, Mørland J (2013)
Levels of heroin and its metabolites in blood and brain extracellular fluid after i.v. heroin administration to freely moving rats
Br J Pharmacol, 170 (3), 546-56
DOI 10.1111/bph.12305, PubMed 23865556

Gottas A, Oiestad EL, Boix F, Ripel A, Thaulow CH, Pettersen BS, Vindenes V, Morland J (2012)
Simultaneous measurement of heroin and its metabolites in brain extracellular fluid by microdialysis and ultra performance liquid chromatography tandem mass spectrometry
J Pharmacol Toxicol Methods, 66 (1), 14-21
DOI 10.1016/j.vascn.2012.04.009, PubMed 22561414

Boix F, Andersen JM, Mørland J (2011)
Pharmacokinetic modeling of subcutaneous heroin and its metabolites in blood and brain of mice
Addict Biol, 18 (1), 1-7
DOI 10.1111/j.1369-1600.2010.00298.x, PubMed 21481103

Andersen JM, Ripel A, Boix F, Normann PT, Mørland J (2009)
Increased locomotor activity induced by heroin in mice: pharmacokinetic demonstration of heroin acting as a prodrug for the mediator 6-monoacetylmorphine in vivo
J Pharmacol Exp Ther, 331 (1), 153-61
DOI 10.1124/jpet.109.152462, PubMed 19541908

 
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