Fig. 7: A role for NAAA-regulated PPAR-α signaling in hyperalgesic priming.
From: NAAA-regulated lipid signaling in monocytes controls the induction of hyperalgesic priming in mice
Left: non-primed state. In this naïve state, PGE2 produces transient (~2 h) heat and mechanical hypersensitivity by engaging protein kinase A (PKA)-coupled EP2/EP4 receptors in isolectin-B4+ nociceptive neurons. Center: initiation and incubation. Various cytokines (e.g., IL-6) and other noxious stimuli (e.g., growth factors, tissue damage, etc.) evoke a self-resolving nocifensive response that lasts ~24 h and is attenuated by standard analgesics (22,23, present study). In parallel, the stimuli initiate priming through a mechanism that is insensitive to analgesics. This initiation phase is followed by an incubation period, which persists for ~72 h, during, which NAAA activity interrupts PPAR-α signaling and drives monocytes into an active (or’primed’) state, which enables them to migrate to target tissues (including the dorsal root ganglia, DRG), interact with nociceptors – presumably via one or more unknown chemical signals (colored circles) – and effect neuroplastic changes that initiate priming. Right: primed state. In primed animals, EP2/EP4 receptors in isolectin-B4+ nociceptors are coupled to an additional transduction pathway that involves protein kinase C-epsilon (PKCε)17. In this state, PGE2 evokes a PKCε-mediated heat hypersensitivity that can last >2 weeks32. Figure created with BioRender.com.
