Figure 2. Schematic illustration of ceramide and S1P-induced peripheral sensitization.

The illustration describes some inflammatory pathways triggered by ceramide and its bioactive downstream metabolite, S1P. Both NGF and TNF can induce the production of ceramide through the activation of sphingomyelinase (SMase). Once formed, ceramide promotes caspase-dependent apoptosis and stimulates cyclooxygenase-2 (COX-2) activation and prostaglandin E2 (PGE₂) accumulation through a p38 MAPK-dependent NF-κB pathway. Ceramide-derived S1P acting on S1PR1 induces 1) assembly and activation of NADPH oxidase (NOX) holoenzyme and subsequent formation of superoxide (O₂⁻), and 2) nitric oxide (NO) production from nitric oxide synthase (NOS) activation. Superoxide combines with nitric oxide to form peroxynitrite, leading to development of peripheral sensitization and hyperalgesia.