PLC-β3 signals upstream of PKCε in acute and chronic inflammatory hyperalgesia

While protein kinase Cε has been shown to contribute to acute and chronic mechanical hyperalgesia, its upstream signaling pathway has received little attention. Since phospholipase C can signal to PKCε and has been implicated in nociceptor sensitization, we tested if it is upstream of PKCε in mechanisms underlying primary mechanical hyperalgesia. In the rat, the PKCε-dependent mechanical hyperalgesia and hyperalgesic priming (i.e., a form of chronic latent enhanced hyperalgesia) induced by carrageenan were attenuated by a non-selective PLC inhibitor U-73122. A lipid mediator of PLC signaling, l-α-lysophosphatidylcholine produced dose-dependent mechanical hyperalgesia and hyperalgesic priming, which was attenuated by EAVSLKPT, a selective PKCε inhibitor. However, U-73122 did not attenuate hyperalgesia induced by ψεRACK, a selective PKCε activator. Antisense to PLC-β3 isoform, which was found in small-diameter dorsal root ganglion neurons, also attenuated carrageenan-induced acute and chronic-latent hyperalgesia. These studies support the suggestion that PLC-β3 is an important upstream signaling molecule for PKCε-mediated acute and chronic inflammatory pain.