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Autoantibodies against opioid or glutamate receptors are associated with changes in morphine reward and physical dependence in mice

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Abstract

Background

Possible interactions between nervous and immune systems during opioid addiction remain elusive. Recombinant μ–δ opioid receptors (MDOR) and the glutamate receptor 1 (GluR1) subunit of amino-3-hydroxy-5-methyl-4-isoxazole propionic acid glutamate receptors are involved in acute and chronic effects of morphine. Elevated levels of autoantibodies (aAbs) to these receptors were demonstrated in heroin human addicts and in animal models. This study characterized the role of aAbs to these receptors in behavioral modulations recruited during opioid tolerance and sensitization.

Methods and findings

Male CD-1 mice, immunized with either MDOR or GluR1 peptide fragments (80 μg intraperitoneal (i.p.)), were examined for spontaneous behavior and response to morphine (5 mg/kg i.p.). Spontaneous home-cage activity, novelty-induced self-grooming and morphine-induced hyperactivity were higher in GluR1 mice compared to Vehicle subjects, whereas MDOR immunization was associated with an increased morphine-induced conditioned place preference. In response to escalating doses of morphine (from 10 to 60 mg/kg i.p., twice daily) and naloxone-precipitated withdrawal (1 mg/kg subcutaneous), GluR1 mice exhibited a more marked stereotyped sniffing behavior and less body tremors compared to Vehicle subjects, whereas less sniffing and teeth chattering were found in MDOR mice. The expected downregulation of μ receptor binding sites, induced by chronic morphine in vehicle subjects, was completely absent following MDOR immunization.

Conclusions

These findings indicate an altered response to morphine-related reinforcing and aversive effects in MDOR mice and altered coping with the environment in GluR1 mice. Circulating aAbs to specific neuroreceptors may alter the response to opiates and play a role as determinants of vulnerability to opiate addiction.

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Acknowledgements

This paper was supported by the NIH-ISS Collaboration Project, Italy; Research Contract with Sigma-Tau SpA, Pomezia, Italy (to G.L.); Reintegration Grant No. 981199, NATO; ISNI Program “Aid for Neurochemistry” (to O.G.). We wish to thank Sandra Columba-Cabezas for her precious help with the immunization procedures.

Conflict of interest statement

There is no conflict of interest to disclose.

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Authors and Affiliations

  1. Section of Behavioral Neuroscience, Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, viale Regina Elena 299, Rome, Italy

    Francesca Capone, Walter Adriani & Giovanni Laviola

  2. Department of Neurology and Neurosurgery, I.P. Pavlov’s State Medical University, St. Petersburg, Russia

    Maria Shumilina & Oleg Granstrem

  3. GeroPharm Ltd, St. Petersburg, Russia

    Maria Shumilina & Oleg Granstrem

  4. Department of Chemistry, Emory University, Atlanta, GA, USA

    Galina Izykenova & Svetlana Dambinova

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  1. Francesca Capone
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  2. Walter Adriani
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  4. Galina Izykenova
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  7. Giovanni Laviola
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Correspondence to Giovanni Laviola.

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Capone, F., Adriani, W., Shumilina, M. et al. Autoantibodies against opioid or glutamate receptors are associated with changes in morphine reward and physical dependence in mice. Psychopharmacology 197, 535–548 (2008). https://doi.org/10.1007/s00213-007-1062-y

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  • DOI: https://doi.org/10.1007/s00213-007-1062-y

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