Spinal NF-kB activation induces COX-2 upregulation and contributes to inflammatory pain hypersensitivity
Spinal NF-kB activation induces COX-2 upregulation and contributes to inflammatory pain hypersensitivity
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DOI：
10.1111/j.0953-816x.2004.03441.x
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发表时间：
2004-06-01
影响因子：
3.4
通讯作者：
Cho, HJ
中科院分区：
文献类型：
--
作者：
Lee, KM;Kang, BS;Cho, HJ
环氧合酶-2(COX-2)是脊髓前列腺素E_2(，)升高的主要贡献者，它增强了外周炎症后伤害性刺激的处理，而强啡肽已被证明在急性和慢性疼痛状态中起重要作用。此外，转录因子核因子-kB(NF-kB)调节COX-2和强啡肽的表达。为了阐明脊髓核因子-kB在炎性疼痛超敏反应诱导中的作用，我们检测了激活的核因子-kB是否影响外周炎症后疼痛行为以及COX-2和前强啡肽的mRNAs的表达。鞘内给予不同的核因子-kB抑制剂，即核因子-kB诱饵或吡咯烷二硫代氨基甲酸酯，可显著减轻完全弗氏佐剂(CFA)诱导的单侧后足炎所致的机械性痛觉过敏和热痛敏。这些核因子-kB抑制剂也能抑制脊髓核因子-kB的活化和随后引起的脊髓COX-2mRNA的显著升高，但不能抑制前强啡肽的mRNA的表达。此外，鞘内注射白介素1β受体拮抗剂或半胱氨酸天冬氨酸氨基转移酶-1抑制剂可抑制脊髓核因子-kB的活化。鉴于IL-1β是CFA注射后脊髓COX-2上调的主要诱导者，我们的结果提示IL-1β诱导的脊髓COX-2上调和外周炎症后的疼痛超敏是通过激活核因子-kB相关通路而介导的。
Cyclooxygenase-2 (COX-2) is a major contributor to the elevation of spinal prostaglandin E2(,) which augments the processing of nociceptive stimuli following peripheral inflammation, and dynorphin has been shown to have an important role in acute and chronic pain states. Moreover, the transcription factor, nuclear factor-kappa B (NF-kB), regulates the expressions of both COX-2 and dynorphin. To elucidate the role of spinal NF-kB in the induction of inflammatory pain hypersensitivity, we examined whether activated NF-kB affects pain behavior and the expressions of the mRNAs of COX-2 and prodynorphin following peripheral inflammation. Intrathecal pretreatment with different NF-kB inhibitors, namely, NF-kB decoy or pyrrolidine dithiocarbamate, significantly reduced mechanical allodynia and thermal hyperalgesia following unilateral hindpaw inflammation evoked by complete Freund's adjuvant (CFA). These NF-kB inhibitors also suppressed the activation of spinal NF-kB and the subsequent remarkable elevation of spinal COX-2 mRNA, but not that of prodynorphin mRNA. In addition, the activation of spinal NF-kB following CFA injection was inhibited by intrathecal pretreatments with interleukin-1beta receptor antagonist or caspase-1 inhibitor. In view of the fact that interleukin-1 beta (IL-1beta) is the major inducer of spinal COX-2 upregulation following CFA injection, our results suggest that IL-1beta-induced spinal COX-2 upregulation and pain hypersensitivity following peripheral inflammation are mediated through the activation of the NF-kB-associated pathways.