title: A morphine conjugate vaccine attenuates the behavioral effects of morphine in rats.
abstract: Vaccines for opioid dependence may provide a treatment that would reduce or slow the distribution of the drug to brain, thus reducing the drug's reinforcing effects. We tested whether a conjugate vaccine against morphine (keyhole limpet hemocyanin-6-succinylmorphine; KLH-6-SM) administered to rats would produce antibodies and show specificity for morphine or other heroin metabolites. The functional effects of the vaccine were tested with antinociceptive and conditioned place preference (CPP) tests. Rats were either vaccinated with KLH-6-SM and received two boosts 3 and 16 weeks later or served as controls and received KLH alone. Anti-morphine antibodies were produced in vaccinated rats; levels increased and were sustained at moderate levels through 24 weeks. Antibody binding was inhibited by free morphine and other heroin metabolites as demonstrated by competitive inhibition ELISA. Vaccinated rats showed reduced morphine CPP, tested during weeks 4 to 6, and decreased antinociceptive responses to morphine, tested at week 7. Brain morphine levels, assessed using gas-chromatography coupled to mass spectrometry (GC-MS) on samples obtained at 26 weeks, were significantly lower in vaccinated rats. This suggests that morphine entry into the brain was reduced or slowed. These results provide support for KLH-6-SM as a candidate vaccine for opioid dependence.
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, TX 77030, United States. tkosten@bcm.edu
authors.forename: Therese A
authors.initials: TA
authors.lastname: Kosten
authors.forename: Xiaoyun Y
authors.initials: XY
authors.lastname: Shen
authors.forename: Patrick W
authors.initials: PW
authors.lastname: O'Malley
authors.forename: Berma M
authors.initials: BM
authors.lastname: Kinsey
authors.forename: Ernest D
authors.initials: ED
authors.lastname: Lykissa
authors.forename: Frank M
authors.initials: FM
authors.lastname: Orson
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Kosten
mesh_terms: D000700:Analgesics / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000097:blood / Q000276:immunology; D003213:Conditioning, Psychological / Q000187:drug effects*; D006433:Hemocyanins / Q000276:immunology; D003932:Heroin / Q000031:analogs & derivatives*; D009020:Morphine / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D018074:Vaccines, Conjugate / Q000276:immunology
chemical_list: D000700:Analgesics; D000906:Antibodies; D018074:Vaccines, Conjugate; D003932:Heroin; D009020:Morphine; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin
keywords: 3-GM; 50% inhibition of maximum binding; 6-AM; 6-GM; 6-SM; 6-acetyl morphine; 6-succinylmorphine; Antinociception; BSA; CPP; Conditioned place preference; EDC; ELISA; GC–MS; Heroin metabolites; IC50; Immunotherapy; KLH; KLH-6-SM; MPE; N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride; N-hydroxysulfosuccinimide; Opioid dependence; alum; aluminum hydroxide gel; bovine serum albumin; conditioned place preference; enzyme-linked immunosorbent assay; gas-chromatography coupled to mass spectrometry; keyhole limpet hemocyanin; keyhole limpet hemocyanin-6-succinylmorphine; maximal possible effect; morphine-3-glucuronide; morphine-6-glucuronide; sulfo-NHS