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. 2014 Dec 2;30(6):936–948. doi: 10.1007/s12264-014-1483-7

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

Liying Bai 1,2, Caihong Zhai 2, Kun Han 2, Zhisong Li 1, Junliang Qian 2, Ying Jing 2, Wei Zhang 1,✉, Ji-Tian Xu 1,2,✉
PMCID: PMC5562568  PMID: 25446875

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.

Keywords: nuclear factor-κB, pro-inflammatory cytokines, Toll-like receptor 4, morphine tolerance, hyperalgesia

Contributor Information

Wei Zhang, Email: zhangw571012@126.com.

Ji-Tian Xu, Email: jtxu@zzu.edu.cn.

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