Intraplantar-injected ceramide in rats induces hyperalgesia through an NF-κB- and p38 kinase-dependent cyclooxygenase 2/prostaglandin E2 pathway
Intraplantar-injected ceramide in rats induces hyperalgesia through an NF-κB- and p38 kinase-dependent cyclooxygenase 2/prostaglandin E2 pathway
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DOI：
10.1096/fj.10-178095
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发表时间：
2011-08-01
期刊：
影响因子：
4.8
通讯作者：
Salvemini, Daniela
中科院分区：
文献类型：
--
作者：
Doyle, Tim;Chen, Zhoumou;Salvemini, Daniela
炎性疼痛是一种重要的未满足的临床需求，具有重要的社会经济意义。神经酰胺是一种有效的促炎性鞘脂，已被证明可引起机械性痛觉过敏，但其机制在很大程度上仍不清楚。我们现在证明，除了机械性痛觉过敏外，足底注射神经酰胺（10 μ g）导致热痛觉过敏的发展，这依赖于诱导型环氧合酶（考克斯-2）的诱导和随后前列腺素E-2（PGE（2））的增加。选择性考克斯-2抑制剂NS-398（15 - 150 ng）可阻断机械和热痛觉过敏的发展以及PGE（2）产生的增加。足底注射PGE（2）单克隆抗体（4 μ g）可阻断痛觉过敏的发生，这一发现强调了神经酰胺信号传导中考克斯-2至PGE（2）通路的重要性。我们的研究结果进一步表明，由于足底注射SC-514，COX-2的诱导受到NF-κ B和p38激酶激活的调节，（0.1 - 1 μ g）或SB 203580（1 - 10 μ g），分别是NF-κ B和p38激酶活化的充分表征的抑制剂，阻断考克斯-2的诱导，并以剂量依赖的方式增加PGE（2）的形成和热痛觉过敏。此外，NF-κ B的激活依赖于p38 MAPK的上游激活，因为SB 203580（10 μ g）阻断p65磷酸化，而p38激酶磷酸化不受SC-514（1 μ g）抑制NF-κ B的影响。我们的研究结果不仅提供了神经酰胺参与痛觉过敏发展的信号通路的机制，而且还为开发针对神经酰胺代谢至考克斯-2通路的抑制剂作为新型镇痛药提供了潜在的药理学基础。道尔，T.，陈志，Muscoli，C.，奥贝德湖M.，Salvemini，D.大鼠足底注射神经酰胺通过NF-κ B和p38激酶依赖性环氧合酶2/前列腺素E-2途径诱导痛觉过敏。FASEB J.25，2782 - 2791（2011）。www.fasebj.org
Inflammatory pain represents an important unmet clinical need with important socioeconomic implications. Ceramide, a potent proinflammatory sphingolipid, has been shown to elicit mechanical hyperalgesia, but the mechanisms remain largely unknown. We now demonstrate that, in addition to mechanical hyperalgesia, intraplantar injection of ceramide (10 mu g) led to the development of thermal hyperalgesia that was dependent on induction of the inducible cyclooxygenase (COX-2) and subsequent increase of prostaglandin E-2 (PGE(2)). The development of mechanical and thermal hyperalgesia and increased production of PGE(2) was blocked by NS-398 (15-150 ng), a selective COX-2 inhibitor. The importance of the COX-2 to PGE(2) pathway in ceramide signaling was underscored by the findings that intraplantar injection of a monoclonal PGE(2) antibody (4 mu g) blocked the development of hyperalgesia. Our results further revealed that COX-2 induction is regulated by NF-kappa B and p38 kinase activation, since intraplantar injection of SC-514 (0.1-1 mu g) or SB 203580 (1-10 mu g), well-characterized inhibitors of NF-kappa B and p38 kinase activation, respectively, blocked COX-2 induction and increased formation of PGE(2) and thermal hyperalgesia in a dose-dependent manner. Moreover, activation of NF-kappa B was dependent on upstream activation of p38 MAPK, since SB 203580 (10 mu g) blocked p65 phosphorylation, whereas p38 kinase phosphorylation was unaffected by NF-kappa B inhibition by SC-514 (1 mu g). Our findings not only provide mechanistic insight into the signaling pathways engaged by ceramide in the development of hyperalgesia, but also provide a potential pharmacological basis for developing inhibitors targeting the ceramide metabolic-to-COX-2 pathway as novel analgesics.-Doyle, T., Chen, Z., Muscoli, C., Obeid, L. M., Salvemini, D. Intraplantar-injected ceramide in rats induces hyperalgesia through an NF-kappa B- and p38 kinase-dependent cyclooxygenase 2/prostaglandin E-2 pathway. FASEB J. 25, 2782-2791 (2011). www.fasebj.org