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Contributions of spinal d-amino acid oxidase to bone cancer pain

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Abstract

d-Amino acid oxidase (DAAO), a FAD-dependent peroxisomal flavoenzyme that catalyzes oxidation of d-amino acids to hydrogen peroxide, is distributed in the spinal cord almost exclusively expressed within astrocytes. The present study aims to explore potential contributions of spinal DAAO to the development of bone cancer pain and morphine tolerance to analgesia. Tibia inoculation of carcinoma cells produced mechanical allodynia (but not heat hyperalgesia), in synchronous with induction of DAAO expression and DAAO enzymatic activity, as well as activation of spinal astrocytes marked by GFAP. Subcutaneous and intrathecal injection of the specific DAAO inhibitor CBIO (5-chloro-benzo[d]isoxazol-3-ol) blocked mechanical allodynia in a dose- and time-dependent manner in tumor-bearing rats, with maximum inhibition of 40–50 %. Multi-daily intrathecal injections of the DAAO gene silencer siRNA/DAAO also yielded anti-allodynic effects by approximately 40 % and the analgesia remained for at least 6 days. Subcutaneous injection of CBIO suppressed the production of spinal hydrogen peroxide and GFAP expression. 7-Day multiple bi-daily injections of CBIO produced anti-allodynia without inducing self-tolerance to analgesia or cross-tolerance to morphine, and concurrent injections of CBIO with morphine produced apparent additive anti-allodynia and completely prevented morphine tolerance in behaviors and spinal expression of μ-opioid receptors. Our results provide the first evidence that spinal DAAO contributes to the development of morphine tolerance to analgesia and bone cancer pain accounting for 40–50 % pain status, probably via production of hydrogen peroxide leading to activation of astrocytes. The unique characterizations of DAAO inhibitors make them a potential for the treatment of cancer pain when they are administered alone or in combination with morphine.

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Acknowledgments

The work was supported by grants (No. 30973581 and No. 81072623) from National Natural Science Foundation of China and Shanghai Science and Technology Administration Innovation Project (No.11ZR1416400). The authors thank Dr. Kenji Hashimoto at Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan, Dr. Quan-Hai Liu at Shanghai Institute of Pharmaceutical Industry, Shanghai, China, and Dr. Pei-Zuo Zhang at Shanghai GenePharma Co., Ltd., Shanghai, China for their kind gifts of CBIO and Walker 256 cell line, and synthesis of siRNA/DAAO, respectively.

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All authors report no conflict of interest.

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Authors and Affiliations

  1. King’s Lab, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China

    Jin-Lu Huang, Xiao-Ling Chen, Cheng Guo & Yong-Xiang Wang

  2. Department of Pharmacy, The Sixth Affiliated Hospital of Shanghai Jiao Tong University, Shanghai, 200233, China

    Jin-Lu Huang & Cheng Guo

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  1. Jin-Lu Huang
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Correspondence to Cheng Guo or Yong-Xiang Wang.

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Huang, JL., Chen, XL., Guo, C. et al. Contributions of spinal d-amino acid oxidase to bone cancer pain. Amino Acids 43, 1905–1918 (2012). https://doi.org/10.1007/s00726-012-1390-z

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