While
protein kinase C epsilon 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
PKC epsilon and has been implicated in nociceptor sensitization, we tested if it is upstream of
PKC epsilon in mechanisms underlying primary
mechanical hyperalgesia. In the rat, the
PKC epsilon-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-alpha-
lysophosphatidylcholine produced dose-dependent
mechanical hyperalgesia and hyperalgesic priming, which was attenuated by EAVSLKPT, a selective
PKC epsilon inhibitor. However,
U-73122 did not attenuate
hyperalgesia induced by psi epsilon RACK, a selective
PKC epsilon activator. Antisense to
PLC-beta 3
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-beta 3 is an important upstream signaling molecule for
PKC epsilon-mediated acute and chronic inflammatory
pain.