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Transgene-mediated expression of tumor necrosis factor soluble receptor attenuates morphine tolerance in rats

Gene Therapy volume 19, pages 101–108 (2012)Cite this article

Abstract

Opiate/narcotic analgesics are the most effective treatments for chronic severe pain, but their clinical utility is often hampered by the development of analgesic tolerance. Recent evidence suggests chronic morphine may activate glial cells to release proinflammatory cytokines. In this study, we used herpes simplex virus (HSV) vector-based gene transfer to dorsal root ganglion to produce a local release of p55 tumor necrosis factor (TNF) soluble receptor in the spinal cord in rats with morphine tolerance. Subcutaneous inoculation of HSV vectors expressing p55 TNF soluble receptor into the plantar surface of the hindpaws enhanced the antinociceptive effect of acute morphine in rats. Subcutaneous inoculation of those vectors into hindpaws also delayed the development of chronic morphine tolerance in rats. TNF soluble receptor expressed by HSV vector reduced gene transcription of spinal TNFα and interleukin-1β (IL-1β) induced by repeated morphine. Furthermore, we found that TNF soluble receptor mediated by HSV reversed the upregulation of protein level of TNFα and IL-1β and phosphorylation of p38 mitogen-activated protein kinase induced by repeated morphine. These results support the concept that proinflammatory cytokines may have an important role in the pathogenesis induced by morphine. This study provides a novel approach to treating morphine tolerance.

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Acknowledgements

This work was supported by grants from the NIH DA020078 (SH), DA026734 (SH), DA025527 (SH) and NS066792 (SH), Department of Veterans Affairs and the NINDS NS038850 and NIDDK DK044935 (DJF and MM). We acknowledge the excellent technical assistance of Vikram Thakur.

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Authors and Affiliations

  1. Department of Neurology, University of Michigan, Ann Arbor, MI, USA

    J Sun, S Liu, M Mata, D J Fink & S Hao

  2. Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL, USA

    S Liu & S Hao

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  1. J Sun
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Correspondence to S Hao.

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Competing interests

David Fink receives compensation for professional services from the University of Michigan and from the Department of Veterans Affairs. He also receives payments from the University of Pittsburgh for patents owned by the University on which he is a co-inventor. All others authors declare no conflict of interest.

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Sun, J., Liu, S., Mata, M. et al. Transgene-mediated expression of tumor necrosis factor soluble receptor attenuates morphine tolerance in rats. Gene Ther 19, 101–108 (2012). https://doi.org/10.1038/gt.2011.76

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