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.