Antinociceptive Effect of Tetrandrine on LPS-Induced Hyperalgesia via the Inhibition of IKKβ Phosphorylation and the COX-2/PGE2 Pathway in Mice

Abstract

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.

Downregulation of spinal astrocytic connexin43 leads to upregulation of interleukin‐6 and cyclooxygenase‐2 and mechanical hypersensitivity in mice

“…The current study also found that in vivo upregulation of spinal dorsal horn IL‐6 and COX‐2 following knockdown of Cx43 directly mediates mechanical hypersensitivity, as demonstrated by blocking IL‐6 activity with an anti‐IL‐6 antibody and inhibiting COX‐2 activity. Production of IL‐6 and prostaglandins produced by COX‐2 can be induced in spinal dorsal horn astrocytes and these molecules significantly facilitate nociceptive transduction in the neuropathic pain state (Dutra et al, ; Guptarak et al, ; Ko et al, ; Zhao et al, ). In the current study, both molecules could be responsible for mediating mechanical hypersensitivity during the maintenance phase of PSNL (14 days post‐injury).…”

“…A previous study showed that knockdown of spinal Cx43 expression led to downregulation of GLT-1 and subsequent enhancement of synaptic glutamatergic neurotransmission in spinal dorsal horn . A number of molecules produced by spinal astrocytes could be involved in maintenance of the neuropathic pain state (Barbeito et al, 2010;Cao et al, 2014;Grace, Hutchinson, Maier, & Watkins, 2014;Hansen & Malcangio, 2013;Imai et al, 2013;Kwiatkowski et al, 2016;Lundborg, Westerlund, Bj€ orklund, Biber, & Hansson, 2011; Mika, Zychowska, Popiolek-Barczyk, Rojewska, & Przewlocka, 2013; horn astrocytes and these molecules significantly facilitate nociceptive transduction in the neuropathic pain state (Dutra et al, 2013;Guptarak et al, 2013;Ko et al, 2016;Zhao et al, 2014). In the current study, both molecules could be responsible for mediating mechanical hypersensitivity during the maintenance phase of PSNL (14 days post-injury).…”

A critical review: traditional uses, phytochemistry, pharmacology and toxicology of Stephania tetrandra S. Moore (Fen Fang Ji)

“…These effects mediated by inhibition of inhibitor kappa B kinaseb (IKKb) phosphorylation. This has been shown to reduce the production of important pain mediators, such as PGE2 and COX-2 via the IKKb/IjB/NF-jB pathway (Zhao et al 2014). In this study, tetrandrine exhibited stronger antinociceptive effects than the positive control morphine (10 mg/kg).…”

Progress on Active Analgesic Components and Mechanisms of Commonly Used Traditional Chinese Medicines: A Comprehensive Review

“…The various classes of flavonoids differ in the level of oxidation and the pattern of substitution of the C ring, whereas individual compounds within a class differ in the pattern of substitution of the A and B rings (11). Flavonoids (41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55) in TCM play an important role in analgesia, and have high application value and prospect.…”