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IL-4 mediated by HSV vector suppresses morphine withdrawal response and decreases TNFα, NR2B, and pC/EBPβ in the periaqueductal gray in rats

Gene Therapy volume 24, pages 224–233 (2017)Cite this article

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Abstract

Chronic opiates induce the development of physical dependence. Opioid physical dependence characterized by withdrawal symptoms, may have very long-lasting effects on the motivation for reward, including the incubation of cue-induced drug-seeking behavior. Elucidation of the mechanisms involved in physical dependence is crucial to developing more effective treatment strategies for opioid dependence. Chronic morphine induces production of proinflammatory cytokines in regional-specific sites of the brain. Interleukin-4 (IL-4) is a prototypical anti-inflammatory cytokine that globally suppresses proinflammatory cytokines. Here, we used recombinant herpes simplex virus vector S4IL4 that encode mouse il4 gene to evaluate the therapeutic potential of IL-4 in naloxone-precipitation morphine withdrawal (MW). One week after microinjection of the vector S4IL4 into the PAG LacZ or mouse IL-4 immunoreactivity in the vlPAG was visualized. ELISA assay showed that vector S4IL4 into the PAG induced the expression of IL-4. S4IL4 blunted the morphine withdrawal syndrome. S4IL4 suppressed the upregulated TNFα, NR2B and pC/EBPβ in the PAG induced by MW. These results show that inhibition of proinflammatory factor in the PAG suppressed MW. This study may provide a novel therapeutic approach to morphine physical withdrawal symptoms.

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Acknowledgements

This work was partially supported by grants from the NIH DA020078 (SH), DA026734 (SH), DA025527 (SH), NS066792 (SH), DA34749 (SH) and NS038850 (David Fink, Neurology, University of Michigan, MI, USA). We acknowledge the assistance of Vikram Thakur Singh (Neurology, University of Michigan, MI, USA) in vector propagation. We thank the support from the Department of Anesthesiology, University of Miami, FL, USA.

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  1. Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, USA

    H Yi, T Iida, S Liu, D Ikegami, Q Liu, A Iida, D A Lubarsky & S Hao

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Yi, H., Iida, T., Liu, S. et al. IL-4 mediated by HSV vector suppresses morphine withdrawal response and decreases TNFα, NR2B, and pC/EBPβ in the periaqueductal gray in rats. Gene Ther 24, 224–233 (2017). https://doi.org/10.1038/gt.2017.11

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