Effects of an Oxycodone Conjugate Vaccine on Oxycodone Self-Administration and Oxycodone-Induced Brain Gene Expression in Rats
et al. (2014) Effects of an Oxycodone Conjugate Vaccine on Oxycodone Self-Administration and
Oxycodone-Induced Brain Gene Expression in Rats. PLoS ONE 9(7): e101807. doi:10.1371/journal.pone.0101807
Effects of an Oxycodone Conjugate Vaccine on Oxycodone Self-Administration and Oxycodone-Induced Brain Gene Expression in Rats
Marco Pravetoni 0
Paul R. Pentel 0
David N. Potter 0
Elena H. Chartoff 0
Laura Tally 0
Mark G. LeSage 0
Michael Taffe, The Scripps Research Institute, United States of America
0 1 Minneapolis Medical Research Foundation, Minneapolis, Minnesota, United States of America, 2 University of Minnesota, School of Medicine, Department of Medicine , Minneapolis , Minnesota, United States of America, 3 University of Minnesota, School of Medicine, Department of Pharmacology , Minneapolis , Minnesota, United States of America, 4 Harvard Medical School, Department of Psychiatry, McLean Hospital , Belmont, Massachusetts , United States of America
Prescription opioid abuse is an increasing public health concern in the USA. A vaccine comprising a hapten (OXY) conjugated to the carrier protein keyhole limpet hemocyanin (OXY-KLH) has been shown to attenuate the antinociceptive effects of oxycodone. Here, the vaccine's ability to prevent acquisition of intravenous (i.v.) oxycodone self-administration was studied in rats. Effects of vaccination on oxycodone-induced changes in the expression of several genes within the mesolimbic system, which are regulated by chronic opiate use, were also examined. Vaccination with OXY-KLH reduced the proportion of rats acquiring i.v. self-administration of oxycodone under a fixed ratio (FR) 3 schedule of reinforcement compared to control rats immunized with the unconjugated KLH carrier protein. Vaccination significantly reduced the mean number of infusions at FR3, total number of infusions, and total oxycodone intake during the entire protocol. Compared to oxycodone self-administering control rats immunized with the carrier alone, rats vaccinated with the OXY-KLH immunogen showed increased levels of adenylate cyclase 5 (Adcy5) and decreased levels of early growth response protein 2 (Egr2) and the early immediate gene c-Fos in the striatum. These data suggest that vaccination with OXY-KLH can attenuate the reinforcing effects of oxycodone at a clinically-relevant exposure level. Analysis of mRNA expression identified some addiction-relevant markers that may be of interest in understanding oxycodone effects or the protection provided by vaccination.
-
Funding: This study was supported by NIH DA026300 (Pentel) and Minneapolis Medical Research Foundation Translational Research Program Award (Pravetoni).
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
Current pharmacotherapies for treatment of opioid addiction
are effective, but show side effects and limitations. New strategies
to meet the therapeutic challenge of treating opioid addiction are
needed [1]. Active immunization with conjugate vaccines has been
studied as a complementary option for the treatment of drug
addiction [2].
Early studies of morphine conjugate vaccines showed that
immunization attenuated heroin self-administration in non-human
primates, decreased morphine brain distribution and attenuated
morphine analgesia in mice and rats [35]. Development of
immunotherapy strategies for treatment of opioid addiction was
abandoned in the 70s, presumably because of Food and Drug
Administration (FDA) approval of methadone replacement
therapy, which quickly became the main form of treatment for opioid
addiction [6]. More recent reports have shown that immunization
with heroin or morphine conjugate vaccines, containing haptens
based on morphine or 6-acetlymorphine, decreases brain
distribution of the primary active heroin metabolite 6-acetylmorphine
and attenuates heroin and morphine self-administration in rats [7
12]. These vaccines have not yet reached clinical trials.
Prescription opioids such as oxycodone and hydrocodone have
high abuse liability, are widely prescribed as analgesics, and are
readily accessible to teens and young adults, all of which are
factors that have led to their increased abuse [13]. To address
prescription opioid abuse, our laboratory developed a vaccine
(OXY-KLH) that elicits the production of high titers of serum
antibodies that bind oxycodone and hydrocodone in serum,
prevents early distribution of clinically-relevant doses of
oxycodone and hydrocodone to brain, and blocks oxycodone and
hydrocodone antinociception in mice and rats [1417]. The
purpose of the present study was to test whether vaccination with
OXY-KLH would prevent the acquisition of oxycodone
selfadministration in rats, an addiction-relevant behavior, in order to
assess its efficacy in a pre-clinical model of prescription opioid
abuse. Oxycodone self-administration (...truncated)