Multiple PKCε-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 Cepsilon (PKCepsilon) has also been implicated. Since mitochondria contain several proteins that are targets of PKCepsilon, we evaluated the role of mitochondrial mechanisms in mechanical hyperalgesia induced by proinflammatory cytokines that induce PKCepsilon-dependent nociceptor sensitization, and by a direct activator of PKCepsilon (psiepsilonRACK), in the rat. Prostaglandin E(2) (PGE(2))-induced hyperalgesia is short lived in naïve rats, while it is prolonged in psiepsilonRACK 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 psiepsilonRACK. In marked contrast, in a PKCepsilon-dependent form of mechanical hyperalgesia induced by prostaglandin E(2) (PGE(2)), 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 PKCepsilon.
Joseph
Elizabeth K
EK
Departments of Medicine and Oral Surgery, and Division of Neuroscience, University of California, San Francisco, USA.
Levine
Jon D
JD
D000704:Analysis of Variance; D000818:Animals; D015232:Dinoprostone / Q000494:pharmacology; D004837:Epinephrine / Q000494:pharmacology; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013997:Time Factors
C477271:His-Asp-Ala-Pro-Ile-Gly-Tyr-Asp; D009842:Oligopeptides; D051744:Protein Kinase C-epsilon; D015232:Dinoprostone; D004837:Epinephrine
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