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Intraplantar‐injected ceramide in rats induces hyperalgesia through an NF‐κB‐ and p38 kinase‐dependent cyclooxygenase 2/prostaglandin E 2 pathway
Author(s) -
Doyle Tim,
Chen Zhoumou,
Muscoli Carolina,
Obeid Lina M.,
Salvemini Daniela
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.10-178095
Subject(s) - cyclooxygenase , ceramide , p38 mitogen activated protein kinases , chemistry , prostaglandin , nf κb , hyperalgesia , kinase , prostaglandin e2 , pharmacology , lipid signaling , prostaglandin e , microbiology and biotechnology , signal transduction , protein kinase a , medicine , enzyme , biology , biochemistry , apoptosis , nociception , receptor
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 μg) 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 μg) blocked the development of hyperalgesia. Our results further revealed that COX‐2 induction is regulated by NF‐κB and p38 kinase activation, since intraplantar injection of SC‐514 (0.1‐1 μg) or SB 203580 (1‐10 μg), well‐characterized inhibitors of NF‐κB 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‐κB was dependent on upstream activation of p38 MAPK, since SB 203580 (10 μg) blocked p65 phosphorylation, whereas p38 kinase phosphorylation was unaffected by NF‐κB inhibition by SC‐514 (1 μg). 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‐κB‐ and p38 kinase‐dependent cyclooxygenase 2/prostaglandin E 2 pathway. FASEB J. 25, 2782‐2791 (2011). www.fasebj.org