The contribution of 6-acetylmorphine to heroin-induced effects: Studies of pharmacokinetics, behavior and immunotherapeutic intervention using a monoclonal antibody in mice
Appears in the following Collection
- Farmasøytisk institutt 
AbstractHeroin is one of the most addictive drugs of abuse, but heroin itself is considered an inactive prodrug which acts mainly through its metabolites. The work of this doctoral thesis highlights the role of heroin’s first active metabolite, 6-acetylmorphine (6-AM), in heroin-induced effects. This was done by combining animal behavior with pharmacokinetic analyses, and by using an antibody specifically targeting 6-AM in the blood. The pharmacological potential of the 6-AM-specific antibody was also evaluated. First, we show that 6-AM is essential for the immediate heroin effect, and for heroin reward and sensitization, suggesting that 6-AM plays an important role in the development of heroin addiction. We found that heroin induced stronger rewarding effects than injected 6-AM, most likely because it provides faster delivery of 6-AM to the brain. Next, we found that even small amounts of heroin administered during pregnancy can cause long-term effects in the offspring. Female mice exposed to heroin during fetal life were hyperactive and more sensitive to heroin in adolescence compared with non-exposed offspring. Finally, we show that the antibody targeting 6-AM can protect the fetus against heroin exposure. When pregnant animals were treated with antibody before heroin injection, the long-term effects in the offspring were successfully prevented. Antibody treatment also protected against heroin-induced behavior in adult mice. The protection offered by this 6-AM-specific antibody underpins the crucial role of 6-AM in heroin-induced effects, and shows that immunotherapy against heroin is dependent on sequestering 6-AM in the bloodstream. Immunotherapy against heroin may have potential as future treatment of specific patient groups, such as pregnant heroin users or people who are susceptible to relapse. By understanding the individual contribution of the heroin metabolites, we may be one step closer to understand the mechanisms underlying heroin effects, and to develop new strategies to treat heroin addiction.
List of papers
|Paper I: Pharmacological effects of a monoclonal antibody against 6-monoacetylmorphine upon heroin-induced locomotor activity and pharmacokinetics in mice. Kvello A.M.S, Andersen J.M., Øiestad E.L., Mørland J., Bogen I.L. Published in The Journal of Pharmacology and Experimental Therapeutics 358 (2016) 181-189. DOI: 10.1124/jpet.116.233510.The article is not available in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.1124/jpet.116.233510|
|Paper II: The role of 6-acetylmorphine in heroin-induced reward and locomotor sensitization in mice. Kvello A.M.S, Andersen J.M., Boix F., Mørland J., Bogen I.L. Published in Addiction Biology (2019). DOI: 10.1111/adb.12727. The article is included in the thesis. Also available at: https://doi.org/10.1111/adb.12727|
|Paper III: A monoclonal antibody against 6-acetylmorphine protects female mice offspring from adverse behavioral effects induced by prenatal heroin exposure. Kvello A.M.S, Andersen J.M., Øiestad E.L., Mørland J., Bogen I.L. Published in The Journal of Pharmacology and Experimental Therapeutics 368 (2019) 106-115. DOI: 10.1124/jpet.118.251504. The article is not available in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.1124/jpet.118.251504|