Multiple PKCe-dependent mechanisms mediating mechanical hyperalgesia

We have recently implicated mitochondrial mechanisms in models of neuropathic and inflammatory pain, in some of which a role of protein kinase C epsilon (PKC epsilon) has also been implicated. Since mitochondria contain several proteins that are targets of PKC epsilon, we evaluated the role of mitochondrial mechanisms in mechanical hyperalgesia induced by proinflammatory cytokines that induce PKC epsilon-dependent nociceptor sensitization, and by a direct activator of PKC epsilon (psi epsilon RACK), in the rat. Prostaglandin E(2) (PGE(2))-induced hyperalgesia is short lived in naive rats, while it is prolonged in psi epsilon RACK 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 psi epsilon RACK. In marked contrast, in a PKC epsilon-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 PKC epsilon. (C) 2010 International Association for the Study of Pain. Published by Elsevier B. V. All rights reserved.