Transient attenuation of protein kinase Cepsilon can terminate a chronic hyperalgesic state in the rat.
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 E2; PGE2) is greatly enhanced. Furthermore, the PGE2-induced hyperalgesia in primed skin was found to require activity of the epsilon isozyme of protein kinase C (PKCepsilon), a second messenger that is not required for PGE2-induced hyperalgesia in control animals. In the present study we tested the hypothesis that activity of PKCepsilon not only plays a critical role in the expression of primed PGE2-induced hyperalgesia, but also in the development and maintenance of the primed state itself. Antisense oligodeoxynucleotide was employed to produce a decrease in PKCepsilon in the nerve, verified by Western blot analysis. PKCepsilon 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 PKCepsilon (pseudo-receptor octapeptide for activated PKCepsilon) at a dose that itself causes no hyperalgesia. The finding that transient inhibition of PKCepsilon can not only prevent the development of priming, but can also terminate a fully developed state of priming suggests the possibility that selective targeting PKCepsilon might be an effective new strategy in the treatment of chronic inflammatory pain.
Parada
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Department of Oral and Maxillofacial Surgery, 521 Parnassus Avenue, Room C-555, Campus Box 0440, NIH Pain Center, University of California, San Francisco, CA 94143-0440, USA.
Yeh
J J
JJ
Reichling
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DB
Levine
J D
JD
D000818:Animals; D002352:Carrier Proteins / Q000494:pharmacology / Q000627:therapeutic use; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D006930:Hyperalgesia / Q000201:enzymology*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D016376:Oligonucleotides, Antisense / Q000494:pharmacology / Q000627:therapeutic use; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051744:Protein Kinase C-epsilon; D051381:Rats; D017207:Rats, Sprague-Dawley
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016376:Oligonucleotides, Antisense; C015482:protein kinase modulator; C497257:Prkce protein, rat; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon