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.
Highlights
Inflammatory mediators, such as prostaglandins (PGs), PG synthases, and cyclooxygenases (COXs), can cause abnormal neuronal activity, which leads to pain hypersensitivity[1]
COX-2 is regulated by nuclear factor (NF)-kB, which is a well-known transcription factor that is involved in inflammation or injury
This was accompanied by adverse reactions, including cachexia, diarrhea, and sustained tumbling, all of which may potentially influence the evaluation of the algesic effect
Summary
Inflammatory mediators, such as prostaglandins (PGs), PG synthases, and cyclooxygenases (COXs), can cause abnormal neuronal activity, which leads to pain hypersensitivity[1]. Many studies have focused on the roles of these mediators in the regulation of hypersensitivity that is induced by environmental stimuli and pro-inflammatory factors, such as bacterial lipopolysaccharide (LPS)[2]. PGE2 can directly trigger pain-sensitive neurons to induce nociception[5,6]. COX-1 is constitutively expressed to regulate normal physiological conditions, whereas COX-2 is initiated in response to inflammatory signals, such as cytokines and LPS. In inflammatory pain conditions, COX-2 itself can act as a nociceptive stimulator to directly cause pain. NF-kB translocates into the nucleus to regulate the transcription of genes that code for inflammatory cytokines and nociceptive substances [12,13]
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