title: Toll-like receptor 4-mediated nuclear factor-κB activation in spinal cord contributes to chronic morphine-induced analgesic tolerance and hyperalgesia in rats.
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.
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China.|Department of Physiology, Medical School of Zhengzhou University, Zhengzhou, 450001, China.
authors.forename: Liying
authors.initials: L
authors.lastname: Bai
authors.affiliation: Department of Physiology, Medical School of Zhengzhou University, Zhengzhou, 450001, China.
authors.forename: Caihong
authors.initials: C
authors.lastname: Zhai
authors.affiliation: Department of Physiology, Medical School of Zhengzhou University, Zhengzhou, 450001, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Han
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China.
authors.forename: Zhisong
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Physiology, Medical School of Zhengzhou University, Zhengzhou, 450001, China.
authors.forename: Junliang
authors.initials: J
authors.lastname: Qian
authors.affiliation: Department of Physiology, Medical School of Zhengzhou University, Zhengzhou, 450001, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Jing
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China. zhangw571012@126.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China. jtxu@zzu.edu.cn.|Department of Physiology, Medical School of Zhengzhou University, Zhengzhou, 450001, China. jtxu@zzu.edu.cn.
authors.forename: Ji-Tian
authors.initials: JT
authors.lastname: Xu
mesh_terms: D000818:Animals; D004361:Drug Tolerance; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D009020:Morphine; D016328:NF-kappa B / Q000378:metabolism*; D009294:Narcotics; D010147:Pain Measurement; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D016328:NF-kappa B; D009294:Narcotics; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D009020:Morphine