A novel bivalent morphine/heroin vaccine that prevents relapse to heroin addiction in rodents
Introduction
Heroin addiction is a health problem and successful pharmacotherapies have been developed to treat the detoxification, withdrawal, craving and maintenance of the abstinent state of this addictive disorder [1], [2], [3], [4], [5], [6]. Such treatments use long-acting oral opiate agents such as methadone, levo-α-acetylmethadol (LAAM) and the recently FDA-approved buprenorphine that mimic drug action at the opioid receptor [6], [7], [8]. Although the effectiveness of drug mimicry has been documented clinically, there remains significant concern and skepticism towards such treatments [2]. This relates to the fact that the heroin addict is still being exposed to opiates, and consequently may develop tolerance to and experience withdrawal from the treatment agent [2]. Another problem often seen in most out-patient treatments during the maintenance of heroin abstinence is the high incidence of relapse to addictive drug consumption [1], [2], [3], [4], [5], [6]. An alternative pharmacotherapy for both abstinence and prevention of relapse to heroin addiction is based on blocking heroin from reaching its opioid receptor target by using naltrexone and naloxone [7]. Indeed, despite the fact that these antagonists can be used to treat heroin addiction, their use has limitations as both drugs are not inactive in the absence of exogenous opiates and they block the binding of the body's endogenous opioids (e.g., enkephalins and endorphins) causing negative emotional effects in the long-term treated patient [2].
As for other drugs of abuse such as cocaine, nicotine, methamphetamine and phencyclidine [9], [10], [11], an alternative approach for heroin addiction might be an antibody-based antagonism of heroin's brain entry. The feasibility of using an active vaccination approach for treating heroin addiction was explored 30 years ago by Bonese et al. [12]. They showed that responding maintained by this opiate was selectively abolished after active immunization with a morphine-6-hemisuccinyl-bovine serum albumin (BSA) (M-6-H-BSA) conjugate in a single rhesus monkey trained to self-administer heroin. Surprisingly, no further progress was made in conducting more systematic studies focused on the generation of non BSA-based carrier protein models of opiate vaccines appropriate for human use. Besides, we propose that once validated at the pre-clinical level, a novel structural model of a heroin vaccine designed for clinical use, could be subsequently considered as a candidate medication in clinical trials to test its potential therapeutic effectiveness as a co-adjuvant and synergistic therapy for methadone or buprenorphine in preventing relapse to this opiate addiction. Furthermore, the use of such a vaccine in combination with existing therapies could also be useful to reduce the duration of substituted addiction and development of toxic side-effects [13] often seen with the long-term use of these pharmacological agents, that ultimately contribute to the high incidence of treatment abandon and heroin relapse [13].
Section snippets
Preparation of the morphine-tetanus toxoid (M-TT) vaccine
The synthesis of the hapten for M-TT vaccine used the commercial formulation of morphine-sulfate·5H2O (m.w. 758.8) (Sigma–Aldrich, St. Louis, MO, USA) as initial compound to produce morphine base according to a standard experimental procedure reported by Simon et al. [14]. After synthesis, morphine base was subjected to selective succinylation of its 6-hydroxy group in reflux (6 h at 70–80 °C) according to a standard protocol initially reported by Wainer et al. [15], [16] with an excess of
Vaccine design
We initially designed and synthesized a novel structural formulation of a morphine-tetanus toxoid (M-TT) vaccine able to generate a robust and sustained immunologic humoral response for heroin upon active vaccination. In the M-TT conjugate (patent pending #PCT/MX2005/000049), drug was covalently haptenized to the ɛ-amino free groups of the side chain of lysine residues of the highly immunogenic carrier protein tetanus toxoid (TT) using a long (≈20.15 Å) spacer linker arm (Fig. 1). Overall, the
Acknowledgements
We are grateful to Dr. Ramón de la Fuente Muñiz and Dr. Gerardo Heinze for their encouragement in this study, to Dr. Rodrigo Arreola, Dr. Alberto Salazar and the Ass. Res. Juan Carlos-Calva for their input and help in the preparation of the manuscript. This work was supported by grants from The Fundacion Gonzalo del Rio Arronte and The National Institute of Psychiatry, Project INP-2040.
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