title: Pharmacological Effects of a Monoclonal Antibody against 6-Monoacetylmorphine upon Heroin-Induced Locomotor Activity and Pharmacokinetics in Mice.
abstract: Immunotherapy can provide a supplemental treatment strategy against heroin use on the principle of sequestering the active drug in the bloodstream, thereby reducing its distribution to the brain. Previous studies have shown that heroin's first metabolite, 6-monoacetylmorphine (6-MAM), is the main mediator of acute heroin effects. The objective of the present study was to characterize the pharmacological potential of a monoclonal antibody against 6-MAM (anti-6-MAM mAb) to counteract the heroin response. The individual contributions from heroin and 6-MAM to heroin effects were also examined by pretreating mice with anti-6-MAM mAb (10-100 mg/kg) prior to either heroin or 6-MAM injection (1.25-2.5 μmol/kg). The opioid-induced behavioral response was assessed in a locomotor activity test, followed by opioid and antibody quantification in blood and brain tissue. Pretreatment with mAb caused a profound reduction of heroin- and 6-MAM-induced behavior, accompanied by correspondingly decreased levels of 6-MAM in brain tissue. mAb pretreatment was more efficient against 6-MAM injection than against heroin, leading to an almost complete blockade of 6-MAM-induced effects. mAb pretreatment was unable to block the immediate (5-minute) transport of active metabolites across the blood-brain barrier after heroin injection, indicating that heroin itself appears to enhance the immediate delivery of 6-MAM to the brain. The current study provides additional evidence that 6-MAM sequestration is crucial for counteracting the acute heroin response, and demonstrates the pharmacological potential of immunotherapy against heroin use.
authors.affiliation: Department of Drug Abuse Research, Domain for Forensic Sciences, Norwegian Institute of Public Health (A.M.S.K., J.M.A., E.L.Ø., J.M. and I.L.B.) and School of Pharmacy, University of Oslo (E.L.Ø.) Oslo, Norway anne.marte.sjursen.kvello@fhi.no.
authors.forename: Anne Marte Sjursen
authors.initials: AM
authors.lastname: Kvello
authors.affiliation: Department of Drug Abuse Research, Domain for Forensic Sciences, Norwegian Institute of Public Health (A.M.S.K., J.M.A., E.L.Ø., J.M. and I.L.B.) and School of Pharmacy, University of Oslo (E.L.Ø.) Oslo, Norway.
authors.forename: Jannike Mørch
authors.initials: JM
authors.lastname: Andersen
authors.affiliation: Department of Drug Abuse Research, Domain for Forensic Sciences, Norwegian Institute of Public Health (A.M.S.K., J.M.A., E.L.Ø., J.M. and I.L.B.) and School of Pharmacy, University of Oslo (E.L.Ø.) Oslo, Norway.
authors.forename: Elisabeth Leere
authors.initials: EL
authors.lastname: Øiestad
authors.affiliation: Department of Drug Abuse Research, Domain for Forensic Sciences, Norwegian Institute of Public Health (A.M.S.K., J.M.A., E.L.Ø., J.M. and I.L.B.) and School of Pharmacy, University of Oslo (E.L.Ø.) Oslo, Norway.
authors.forename: Jørg
authors.initials: J
authors.lastname: Mørland
authors.affiliation: Department of Drug Abuse Research, Domain for Forensic Sciences, Norwegian Institute of Public Health (A.M.S.K., J.M.A., E.L.Ø., J.M. and I.L.B.) and School of Pharmacy, University of Oslo (E.L.Ø.) Oslo, Norway.
authors.forename: Inger Lise
authors.initials: IL
authors.lastname: Bogen
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D003932:Heroin / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009022:Morphine Derivatives / Q000097:blood / Q000276:immunology* / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D000911:Antibodies, Monoclonal; D009022:Morphine Derivatives; D003932:Heroin; C026979:6-O-monoacetylmorphine