Multiple PKCε-dependent mechanisms mediating mechanical hyperalgesia

Abstract

We have recently implicated mitochondrial mechanisms in models of neuropathic and inflammatory pain, in some of which a role of protein kinase Cε (PKCε) has also been implicated. Since mitochondria contain several proteins that are targets of PKCε, we evaluated the role of mitochondrial mechanisms in mechanical hyperalgesia induced by proinflammatory cytokines that induce PKCε-dependent nociceptor sensitization, and by a direct activator of PKCε (ψεRACK), in the rat. Prostaglandin E₂ (PGE₂)-induced hyperalgesia is short lived in naïve rats, while it is prolonged in ψεRACK pre-treated rats, a phenomenon referred to as priming. Inhibitors of two closely related mitochondrial functions, electron transport (complexes I–V) and oxidative stress (reactive oxygen species), attenuated mechanical hyperalgesia induced by intradermal injection of ψεRACK. In marked contrast, in a PKCε-dependent form of mechanical hyperalgesia induced by prostaglandin E₂ (PGE₂), inhibitors of mitochondrial function failed to attenuate hyperalgesia. These studies support the suggestion that at least two downstream signaling pathways can mediate the hyperalgesia induced by activating PKCε.