Antinociceptive effect of tetrandrine on LPS-induced hyperalgesia via the inhibition of IKKβ phosphorylation and the COX-2/PGE₂ pathway in mice.
Tetrandrine (TET) is a bisbenzylisoquinoline alkaloid that is isolated from the Stephania Tetrandra. It is known to possess anti-inflammatory and immunomodulatory effects. We have shown that TET can effectively suppress the production of bacterial lipopolysaccharide (LPS)-induced inflammatory mediators, including cyclooxygenases (COXs), in macrophages. However, whether TET has an antinociceptive effect on LPS-induced hyperalgesia is unknown. In the present study, we investigated the potential antinociceptive effects of TET and the mechanisms by which it elicits its effects on LPS-induced hyperalgesia. LPS effectively evoked hyperalgesia and induced the production of PGE2 in the sera, brain tissues, and cultured astroglia. TET pretreatment attenuated all of these effects. LPS also activated inhibitor of κB (IκB) kinase β (IKKβ) and its downstream components in the IκB/nuclear factor (NF)-κB signaling pathway, including COX-2; the increase in expression levels of these components was significantly abolished by TET. Furthermore, in primary astroglia, knockdown of IKKβ, but not IKKα, reversed the effects of TET on the LPS-induced increase in IκB phosphorylation, P65 phosphorylation, and COX-2. Our results suggest that TET can effectively exert antinociceptive effects on LPS-induced hyperalgesia in mice by inhibiting IKKβ phosphorylation, which leads to the reduction in the production of important pain mediators, such as PGE2 and COX-2, via the IKKβ/IκB/NF-κB pathway.
Department of Dermatology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Hengguang
H
Zhao
Department of Pharmacy, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Fuling
F
Luo
Molecular oncology and epigenetics laboratory, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Hongzhong
H
Li
Department of Pathophysiology, Chongqing Medical University, Chongqing, China.
Li
L
Zhang
Department of Pathology, Molecular Medicine and Tumor Center, Chongqing Medical University, Chongqing, China.
Yongfen
Y
Yi
Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China.
Jingyuan
J
Wan
D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D044182:Benzylisoquinolines / Q000494:pharmacology / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*
D000700:Analgesics; D044182:Benzylisoquinolines; D008070:Lipopolysaccharides; C009438:tetrandrine; D051546:Cyclooxygenase 2; D051550:I-kappa B Kinase; D015232:Dinoprostone