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The Role of Spinal GABAB Receptors in Cancer-Induced Bone Pain in Rats

  • Ya-Qun Zhou
    Affiliations
    Anesthesiology Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Shu-Ping Chen
    Affiliations
    Anesthesiology Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Dai-Qiang Liu
    Affiliations
    Anesthesiology Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Anne Manyande
    Affiliations
    School of Human and Social Sciences, University of West London, London, UK
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  • Wen Zhang
    Affiliations
    Anesthesiology Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Shao-Bing Yang
    Affiliations
    Anesthesiology Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Bing-Rui Xiong
    Affiliations
    Anesthesiology Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Qiao-Chu Fu
    Affiliations
    Anesthesiology Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Zhen-peng Song
    Affiliations
    Anesthesiology Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Heike Rittner
    Affiliations
    Department of Anesthesiology, University Hospital of Würzburg, Würzburg, Germany
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  • Da-Wei Ye
    Correspondence
    Address reprint requests to Da-Wei Ye, MD, PhD, Cancer Center, Tongji Hospital, Tongji Medical college, Huazhong University of Science and Technology, Wuhan, China.
    Affiliations
    Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Yu-Ke Tian
    Correspondence
    Yu-Ke Tian, MD, PhD, Anesthesiology Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
    Affiliations
    Anesthesiology Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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      Highlights

      • γ-aminobutyric acid B receptors downregulation led to cancer-induced bone pain.
      • Restore diminished γ-aminobutyric acid B receptors attenuated cancer-induced bone pain.
      • Baclofen suppressed the downstream signaling of cyclic adenosine monophosphate.

      Abstract

      Cancer-induced bone pain (CIBP) remains a major challenge in advanced cancer patients because of our lack of understanding of its mechanisms. Previous studies have shown the vital role of γ-aminobutyric acid B receptors (GABABRs) in regulating nociception and various neuropathic pain models have shown diminished activity of GABABRs. However, the role of spinal GABABRs in CIBP remains largely unknown. In this study, we investigated the specific cellular mechanisms of GABABRs in the development and maintenance of CIBP in rats. Our behavioral results show that acute as well as chronic intrathecal treatment with baclofen, a GABABR agonist, significantly attenuated CIBP-induced mechanical allodynia and ambulatory pain. The expression levels of GABABRs were significantly decreased in a time-dependent manner and colocalized mostly with neurons and a minority with astrocytes and microglia. Chronic treatment with baclofen restored the expression of GABABRs and markedly inhibited the activation of cyclic adenosine monophosphate (cAMP)-dependent protein kinase and the cAMP-response element-binding protein signaling pathway.

      Perspective

      Our findings provide, to our knowledge, the first evidence that downregulation of GABABRs contribute to the development and maintenance of CIBP and restored diminished GABABRs attenuate CIBP-induced pain behaviors at least partially by inhibiting the protein kinase/cAMP-response element-binding protein signaling pathway. Therefore, spinal GABABR may become a potential therapeutic target for the management of CIBP.

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