Raleigh Michael D, Pentel Paul R, LeSage Mark G
Minneapolis Medical Research Foundation, Minneapolis, Minnesota, United States of America; Hennepin Healthcare System, Minneapolis, Minnesota, United States of America.
Minneapolis Medical Research Foundation, Minneapolis, Minnesota, United States of America; Hennepin Healthcare System, Minneapolis, Minnesota, United States of America; Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America; Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America.
PLoS One. 2014 Dec 23;9(12):e115696. doi: 10.1371/journal.pone.0115696. eCollection 2014.
The purpose of this study was to evaluate the effects of a morphine-conjugate vaccine (M-KLH) on the acquisition, maintenance, and reinstatement of heroin self-administration (HSA) in rats, and on heroin and metabolite distribution during heroin administration that approximated the self-administered dosing rate. Vaccination with M-KLH blocked heroin-primed reinstatement of heroin responding. Vaccination also decreased HSA at low heroin unit doses but produced a compensatory increase in heroin self-administration at high unit doses. Vaccination shifted the heroin dose-response curve to the right, indicating reduced heroin potency, and behavioral economic demand curve analysis further confirmed this effect. In a separate experiment heroin was administered at rates simulating heroin exposure during HSA. Heroin and its active metabolites, 6-acetylmorphine (6-AM) and morphine, were retained in plasma and metabolite concentrations were reduced in brain in vaccinated rats compared to controls. Reductions in 6-AM concentrations in brain after vaccination were consistent with the changes in HSA rates accompanying vaccination. These data provide evidence that 6-AM is the principal mediator of heroin reinforcement, and the principal target of the M-KLH vaccine, in this model. While heroin vaccines may have potential as therapies for heroin addiction, high antibody to drug ratios appear to be important for obtaining maximal efficacy.
本研究的目的是评估吗啡共轭疫苗（M-KLH）对大鼠海洛因自我给药（HSA）的获得、维持和复吸的影响，以及对接近自我给药剂量率的海洛因给药期间海洛因及其代谢物分布的影响。用M-KLH疫苗接种可阻断海洛因引发的海洛因反应复吸。接种疫苗还降低了低海洛因单位剂量下的HSA，但在高单位剂量下导致海洛因自我给药出现代偿性增加。接种疫苗使海洛因剂量反应曲线右移，表明海洛因效力降低，行为经济学需求曲线分析进一步证实了这一效应。在另一个实验中，以模拟HSA期间海洛因暴露的速率给予海洛因。与对照组相比，接种疫苗的大鼠血浆中保留了海洛因及其活性代谢物6-乙酰吗啡（6-AM）和吗啡，且脑中代谢物浓度降低。接种疫苗后脑内6-AM浓度的降低与接种疫苗后HSA速率的变化一致。这些数据提供了证据，表明在该模型中6-AM是海洛因强化作用的主要介质，也是M-KLH疫苗的主要作用靶点。虽然海洛因疫苗可能具有作为海洛因成瘾治疗方法的潜力，但高药物抗体比率似乎对获得最大疗效很重要。
