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Long-term Therapeutic Effects of Extracorporeal Shock Wave-Assisted Melatonin Therapy on Mononeuropathic Pain in Rats

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Abstract

We evaluated the ability of extracorporeal shock wave (ECSW)-assisted melatonin (Mel) therapy to offer an additional benefit for alleviating the neuropathic pain (NP) in rats. Left sciatic nerve was subjected to chronic constriction injury (CCI) to induce NP. Animals (n = 30) were randomized into group 1 (sham-operated control), group 2 (CCI only), group 3 (CCI + ECSW), group 4 (CCI + Mel) and group 5 (CCI + ECSW + Mel). By days 15, 22 and 29 after CCI, the thermal paw withdrawal latency (TPWL) and mechanical paw withdrawal threshold (MPWT) were highest in group 1, lowest in group 2, significantly higher in group 5 than in groups 3 and 4, but they showed no difference between the later two groups (all p < 0.0001). The protein expressions of inflammatory (TNF-α, NF-κB, MMP-9, IL-1ß), oxidative-stress (NOXs-1, -2, -4, oxidized protein), apoptotic (cleaved-caspase3, cleaved-PARP), DNA/mitochondrial-damaged (γ-H2AX/cytosolic-cytochrome C), microglia/astrocyte activation (ox42/GFAP), and MAPKs [phosphorylated (p)-p38, p-JNK, p-ERK] biomarkers in dorsal root ganglia neurons (DRGs) and in spinal dorsal horn were exhibited an opposite pattern of TPWL among the five groups (all p < 0.0001). Additionally, protein expressions of Nav.1.3, Nav.1.8 and Nav.1.9 in sciatic nerve exhibited an identical pattern to inflammation among the five groups (all p < 0.0001). The numbers of cellular expressions of MAPKs (p-ERK1/2+/peripherin + cells, p-ERK1/2+/NF200 + cells and p-JNK+/peripherin + cells, p-JNK+/NF200 + cells) and voltage-gated sodium channels (Nav.1.8+/peripherin + cells, Nav.1.8+/NF200 + cells, Nav.1.9+/peripherin + cells, Nav.1.9+/NF200 + cells) in small and large DRGs displayed an identical pattern to inflammation among the five groups (all p < 0.0001). In conclusion, the synergistic effect of combined ECSW-Mel therapy is superior to either one alone for long-term improvement of mononeuropathic pain-induced by CCI in rats.

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Acknowledgements

This study was supported by a program grant from Chang Gung Memorial Hospital, Chang Gung University (Grant Nos.: CMRPG8E0771, CMRPG8E1361).

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Author notes

  1. Chien-Hui Yang and Hon-Kan Yip have contributed equally and share first authorship.

Authors and Affiliations

  1. Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, No. 123, Dapi Rd., Niaosong Dist, Kaohsiung, 83301, Taiwan

    Chien-Hui Yang, Kun-Chen Lin, Yu-Huan Tsou & Kuan-Hung Chen

  2. Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan

    Hon-Kan Yip, Pei-Hsun Sung, Yi-Ling Chen, Yi-Chen Li, Tien-Hung Huang, Chi-Ruei Huang & Chi-Wen Luo

  3. Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 83301, Taiwan

    Hon-Kan Yip

  4. Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 83301, Taiwan

    Hon-Kan Yip & Kuan-Hung Chen

  5. Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan

    Hon-Kan Yip

  6. Department of Nursing, Asia University, Taichung, 41354, Taiwan

    Hon-Kan Yip

  7. Institute of Technological and Vocational Education, National Pingtung University of Science and Technology, Pingtung, 91201, Taiwan

    Hung-Fei Chen

  8. Department of Orthopaedic Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan

    Tsung-Cheng Yin

  9. Department of Computer Science and Engineering, National Sun Yat-Sen University, Kaohsiung, Taiwan

    John Y. Chiang

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  1. Chien-Hui Yang
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  2. Hon-Kan Yip
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  14. Kuan-Hung Chen
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Contributions

H-KY, C-HY and K-HC conceived of the study, and participated in the design of the study, data acquisition and analysis as well as drafting the manuscript. H-FC edited the manuscript. T-CY, JYC, P-H, K-CL and Y-LC were responsible for the laboratory assay and troubleshooting., Y-C, Ti-H, C-RH and CL participated in data acquisition, analysis, and interpretation. All authors read and approved the final manuscript.

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Correspondence to Kuan-Hung Chen.

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Yang, CH., Yip, HK., Chen, HF. et al. Long-term Therapeutic Effects of Extracorporeal Shock Wave-Assisted Melatonin Therapy on Mononeuropathic Pain in Rats. Neurochem Res 44, 796–810 (2019). https://doi.org/10.1007/s11064-018-02713-0

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  • DOI: https://doi.org/10.1007/s11064-018-02713-0

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