Search

Pain is a common symptom in patients with opioid use disorder (OUD), which increases synthetic and illicit synthetic opioid abuse and even fatalities due to opioid overdose. Many FDA-approved drugs are available for the treatment of OUD, however, the use of these medications is limited, mainly due to the development of various side effects. Active vaccination is a new therapeutic approach but the resulting antibodies may compromise the use and efficiency of opioid and non-opioid drugs. In this study, we evaluated whether the antibodies produced by the morphine/heroin vaccine (M-TT) would alter the antinociceptive effects of opioid and non-opioid drugs. Female Balb-c mice were immunized with the M-TT vaccine. A solid-phase antibody-capture ELISA was used for monitoring antibody titer responses after each booster dose in vaccinated animals, followed by tail-flick testing. This study found that the M-TT vaccine did not affect the antinociception induced by different doses of morphine or the ability of non-opioid and synthetic opioid drugs to decrease thermal pain. Moreover, the combination of vaccination and naloxone increased the time-course of morphine antagonism relative to either vaccination or naloxone alone. These results suggest that the antibody titers generated by the M-TT vaccine 1) are capable of reducing morphine-induced antinociception and 2) are selective enough not to alter antinociception induced by non-opioid or synthetic drugs. These characteristics support its potential as a treatment agent for patients with symptoms of pain comorbid to OUD., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Current pharmacotherapies for treating morphine/heroin dependence are designed to substitute or block addiction by targeting the drug itself rather than the brain. The heroin addict is still being exposed to addictive opiates, and consequently may develop tolerance to and experience withdrawal and drug's toxic effects from the treatment with high incidence of relapse to addictive drug consumption. As for other drugs of abuse, an alternative approach for morphine/heroin addiction is an antibody-based antagonism of heroin's brain entry. This review summarizes the literature examining important aspects of neurobiological and pharmacological processes involved in opiate dependence. Thereafter, classical pharmacological interventions for opiate dependence treatment and its major clinical limitations are reviewed. Finally, relevant preclinical studies are examined for comparisons in the design, use, immunogenic profile and efficacy of several models of morphine/heroin vaccine as immunologic interventions on the pharmacokinetics and behavioral of morphine/heroin in the rat as animal model.

Both pre-clinical and clinical studies make feasible the use of vaccines as novel therapeutic medications to treat drug addiction. No reports to date have shown the development of structural models of opiate candidate vaccines for treating human addiction to such compounds. Here we report on the initial development of a novel structural formulation of a bi-valent vaccine against morphine/heroin. This vaccine was able to trigger and establish a high titer antibody response to haptenized drug with antibodies displaying equivalent specificities for both morphine and heroin. Such antibodies did not cross-recognize structurally dissimilar opiate medications. Furthermore, the evaluation of the potential therapeutic effectiveness of this vaccine was targeted to relapse prevention using a schedule of heroin delivery in the rat self-administration model. Antibodies against heroin blocked its reinforcing effects in rodents. The type of carrier protein used in this vaccine allows further evaluation of its potential therapeutic value for preventing relapse to heroin addiction in humans.

We studied the effect of potentiated antibodies to morphine (10(-100) wt %) on self-stimulation of the lateral hypothalamus and behavioral reactions reflecting the severity of withdrawal syndrome in rats with morphine dependence. Repeated treatment with potentiated antibodies to morphine increased the rate of self-stimulation, suppressed active avoidance response, promoted freezing behavior after acoustic stimulation, and decreased tail-flick latency in rats after morphine withdrawal. Distilled water did not produce these changes.

Antibodies to morphine produced after its chronic administration can contribute to changes in the central nervous system during opiate abuse. Facilitation of long-term posttetanic potentiation in mossy fibers of the hippocampus in rats with chronic morphine dependence can be reproduced in hippocampal slices from normal animals treated with antibodies to morphine. Incubation of hippocampal slices with ultralow doses of antibodies to morphine had no effect on control rats, but reduced facilitation of long-term potentiation in hippocampal slices from animals with chronic morphine dependence. This confirms the possibility of using ultralow doses of antibodies to morphine for therapeutic correction of mechanisms underlying the formation of drug abuse.

Different kinds of single, multiple, acute or chronic administrations of morphinized animal models were established, with which a series of experiments in both in vivo and in vitro systems as well as molecular levels were pharmacologically designed to investigate the psychoneuroimmunological effects of morphine (Mor) and the immunoprotection of Ganoderma polysaccharides peptide (GPP) in Mor-dependent mice. It was first discovered that both c-myb and c-myc mRNA expression in splenocytes of repetitive Mor-treated mice were detected to be significantly decreased, and that GPP could induce restoration of several immunologic parameters depressed by Mor treatment to or even beyond normal levels. This provides the experimental animal evidence that immune response modifiers such as GPP could be of potential application in controlling abuse of opiates-induced immunodeficiency.

The phenomenon of induction of antibodies to morphine in morphine-treated animals and opiate addicts was shown by means of ELISA. The reaction of the immune system to injections of a morphine solution had the characteristics of a primary immune response. Opiate addicts differed from normal controls in the level of antibodies to morphine of IgM class. Elevated levels of such antibodies could be detected in about 70-80% of addicts with regular longterm opiate use when the time since the last drug intake did not exceed 60 days. Antibodies to morphine could serve as indicators of chronic opiate use especially in periods long after the last drug intake.

The paper demonstrates induction of antibodies to morphine and neurotransmitters (dopamine, norepinephrine, serotonin) in rats treated with intraperitoneal injections of morphine hydrochloride during 2 and 4 weeks in increasing doses. A contribution of such antibodies to the mechanisms of morphine tolerance and formation of physical dependence is considered.

The role of the immune system in the development of physical dependence and tolerance to morphine was studied in mice in which the immune response was either stimulated or suppressed. Immunization of mice against morphine increased the blood and brain levels of morphine as compared to controls. However, the development of physical dependence and tolerance was decreased. The chronic responses to morphine were also decreased by nonspecific immunosuppression (vincristine-cyclophosphamide treatment and gamma-irradiation exposure) and specific immunosuppression (antithymocyte and antilymphocyte sera treatment). Immunosuppressive treatments did not alter the rate of morphine absorption from the subcutaneous depot used to induce chronic exposure to the drug. However, the blood and brain levels of morphine were higher than control after 72 hours of morphine pellet implantation. It is apparent that manipulation of the immune system can alter the physical dependence and tolerance development to morphine.