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In-vivo transfection of the proopiomelanocortin gene, precursor of endogenous endorphin, by use of radial shock waves alleviates neuropathic pain

  • Original Article
  • Published:
Journal of Orthopaedic Science

Abstract

Background

Neuropathic pain is difficult to control and patient response to current treatment is often inadequate. Opioids have been widely used to treat a variety of pain states, but have several side effects. Endogenous opioids are clinically safe, but are not used for treatment because of rapid metabolism. However, in-vivo transfection of endogenous opioid genes could have a powerful and safe analgesic effect. The purpose of this study was to investigate the efficacy of proopiomelanocortin (POMC, a precursor of the endogenous opioid peptide β-endorphin) gene transfer by use of radial shock waves (RSWs) in a rat neuropathic pain model.

Methods

As a neuropathic pain model, we used the Bennett chronic constriction injury (CCI) method. Immediately after CCI induction, POMC plasmid was injected into the rats’ gastrocnemius muscle followed by exposure to RSW. Mechanical allodynia was measured for 4 weeks and dorsal root ganglion (DRG) neurons were sectioned and immunostained.

Results

β-Endorphin blood levels and the number of β-endorphin-immunoreactive (IR) muscle fibers increased over 28 days. β-Endorphin overexpression caused a decrease in the number of calcitonin gene-related peptide (CGRP)-IR DRG neurons and suppressed neuropathic pain induced by CCI without causing adverse side effects. The size-distribution pattern of CGRP-IR DRG neurons shifted from small to large cells in the CCI group; however, the number of both small and large CGRP-IR cells decreased in the POMC group.

Conclusion

POMC gene transfection alleviated allodynia and reduced CGRP expression in DRG neurons without adverse effects. CGRP is not produced in large neurons under physiologic conditions; however, in this study CGRP expression was shifted to large neurons after nerve injury. This change in cell-size distribution suggests that CGRP expression in large neurons is related to neuropathic pain. These findings suggest that POMC gene transfection using RSWs is a safe and effective treatment for neuropathic pain.

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Acknowledgments

We did not receive grants or external funding in support of our research or preparation of this manuscript. We did not receive payments or other benefits or a commitment or agreement to provide such benefits from any commercial entity.

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Authors and Affiliations

  1. Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan

    Tetsuhiro Ishikawa, Masayuki Miyagi, Hiroto Kamoda, Gen Arai, Miyako Suzuki, Yoshihiro Sakuma, Yasuhiro Oikawa, Sumihisa Orita, Gen Inoue, Kazuhisa Takahashi & Seiji Ohtori

  2. Department of Orthopaedic Surgery, Social Insurance Funabashi Central Hospital, Funabashi, Japan

    Masaomi Yamashita

  3. Department of Orthopaedic Surgery, Matsudo City Hospital, Matsudo, Japan

    Yawara Eguchi

  4. Department of Orthopaedic Surgery, Teikyo University Chiba Medical Center, Chiba, Japan

    Tomoyuki Ozawa & Tomoaki Toyone

  5. Department of Orthopaedic Surgery, Toho University Sakura Medical Center, Sakura, Japan

    Yasuchika Aoki

  6. Department of Neurobiology, Graduate School of Medicine, Chiba University, Chiba, Japan

    Atsushi Yamaguchi

Authors
  1. Tetsuhiro Ishikawa
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  2. Masayuki Miyagi
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  11. Gen Inoue
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  15. Kazuhisa Takahashi
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  16. Atsushi Yamaguchi
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  17. Seiji Ohtori
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Corresponding author

Correspondence to Tetsuhiro Ishikawa.

Additional information

T. Ishikawa and M. Miyagi contributed equally to this work.

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Ishikawa, T., Miyagi, M., Yamashita, M. et al. In-vivo transfection of the proopiomelanocortin gene, precursor of endogenous endorphin, by use of radial shock waves alleviates neuropathic pain. J Orthop Sci 18, 636–645 (2013). https://doi.org/10.1007/s00776-013-0397-y

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  • DOI: https://doi.org/10.1007/s00776-013-0397-y

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