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Toll-like receptor 4-mediated nuclear factor-κB activation in spinal cord contributes to chronic morphine-induced analgesic tolerance and hyperalgesia in rats

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Abstract

Nuclear factor kappa B (NF-κB) in the spinal cord is involved in pro-inflammatory cytokine-mediated pain facilitation. However, the role of NF-κB activation in chronic morphine-induced analgesic tolerance and the underlying mechanisms remain unclear. In the present study, we found that the level of phosphorylated NF-κB p65 (p-p65) was increased in the dorsal horn of the lumbar 4–6 segments after intrathecal administration of morphine for 7 consecutive days, and the p-p65 was co-localized with neurons and astrocytes. The expression of TNF-α and IL-1β was also increased in the same area. In addition, pretreatment with pyrrolidinedithiocarbamate (PDTC) or SN50, inhibitors of NF-κB, prevented the development of morphine analgesic tolerance and alleviated morphine withdrawal-induced allodynia and hyperalgesia. The increase in TNF-α and IL-1β expression induced by chronic morphine exposure was also partially blocked by PDTC pretreatment. In another experiment, rats receiving PDTC or SN50 beginning on day 7 of morphine injection showed partial recovery of the anti-nociceptive effects of morphine and attenuation of the withdrawal-induced abnormal pain. Meanwhile, intrathecal pretreatment with lipopolysaccharide from Rhodobacter sphaeroides, an antagonist of toll-like receptor 4 (TLR4), blocked the activation of NF-κB, and prevented the development of morphine tolerance and withdrawal-induced abnormal pain. These data indicated that TLR4-mediated NF-κB activation in the spinal cord is involved in the development and maintenance of morphine analgesic tolerance and withdrawal-induced pain hypersensitivity.

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Authors and Affiliations

  1. Department of Anesthesiology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China

    Liying Bai, Zhisong Li, Wei Zhang & Ji-Tian Xu

  2. Department of Physiology, Medical School of Zhengzhou University, Zhengzhou, 450001, China

    Liying Bai, Caihong Zhai, Kun Han, Junliang Qian, Ying Jing & Ji-Tian Xu

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  1. Liying Bai
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  2. Caihong Zhai
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Correspondence to Wei Zhang or Ji-Tian Xu.

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Bai, L., Zhai, C., Han, K. et al. Toll-like receptor 4-mediated nuclear factor-κB activation in spinal cord contributes to chronic morphine-induced analgesic tolerance and hyperalgesia in rats. Neurosci. Bull. 30, 936–948 (2014). https://doi.org/10.1007/s12264-014-1483-7

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  • DOI: https://doi.org/10.1007/s12264-014-1483-7

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