Transient attenuation of protein kinase Cϵ can terminate a chronic hyperalgesic state in the rat

Abstract

Recently we demonstrated that a single 3-day episode of carrageenan-induced acute cutaneous inflammation can create a chronic state of increased susceptibility to inflammatory hyperalgesia. In this latent “primed” state, although there is no ongoing hyperalgesia, the hyperalgesic response to subsequent challenges with inflammatory agent (prostaglandin E 2; PGE 2) is greatly enhanced. Furthermore, the PGE 2-induced hyperalgesia in primed skin was found to require activity of the ϵ isozyme of protein kinase C (PKCϵ), a second messenger that is not required for PGE 2-induced hyperalgesia in control animals. In the present study we tested the hypothesis that activity of PKCϵ not only plays a critical role in the expression of primed PGE 2-induced hyperalgesia, but also in the development and maintenance of the primed state itself. Antisense oligodeoxynucleotide was employed to produce a decrease in PKCϵ in the nerve, verified by Western blot analysis. PKCϵ was found to be essential both for the development of carrageenan-induced hyperalgesic priming, as well as for the maintenance of the primed state. Furthermore, hyperalgesic priming could be induced by an agonist of PKCϵ (pseudo-receptor octapeptide for activated PKCϵ) at a dose that itself causes no hyperalgesia. The finding that transient inhibition of PKCϵ can not only prevent the development of priming, but can also terminate a fully developed state of priming suggests the possibility that selective targeting PKCϵ might be an effective new strategy in the treatment of chronic inflammatory pain.