title: Chronic hyperalgesic priming in the rat involves a novel interaction between cAMP and PKCepsilon second messenger pathways.
abstract: Toward the goal of defining new pharmacological targets for the treatment of chronic pain conditions, in previous studies we established a model, termed 'hyperalgesic priming,' in which an acute inflammatory stimulus causes a long-lasting latent susceptibility to hyperalgesia induced by subsequent exposures to the inflammatory mediator, prostaglandin E2 (PGE2). Those investigations suggested the hypothesis that priming induces a novel linkage between the PGE2-activated second messenger cascade and the epsilon isoform of protein kinase C (PKCepsilon). In the present study, comparison of dose-response relations for hyperalgesia produced by PGE2, forskolin, 8-Br-cAMP, or the protein kinase A (PKA) catalytic subunit, in primed versus normal animals, demonstrated that priming-induced enhancement of the PGE2-activated second messenger cascade occurs downstream to adenylate cyclase and upstream to PKA. Therefore, PGE2-induced hyperalgesia in the primed animal is enhanced by the recruitment of a novel cAMP/PKCepsilon signaling pathway in addition to the usual cAMP/PKA pathway. These observations suggest that pharmacological disruption of the novel interaction between cAMP and PKCepsilon might provide a route toward the development of highly specific methods to reverse cellular processes that underlie chronic pain states.
authors.affiliation: Department of Oral and Maxillofacial Surgery, and Program in Neuroscience, University of California, San Francisco, CA 94143-0440, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Parada
authors.forename: D B
authors.initials: DB
authors.lastname: Reichling
authors.forename: J D
authors.initials: JD
authors.lastname: Levine
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000633:toxicity; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002351:Carrageenan; D005576:Colforsin / Q000633:toxicity; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000633:toxicity; D015232:Dinoprostone / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008954:Models, Biological; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D051744:Protein Kinase C-epsilon; D051381:Rats; D017207:Rats, Sprague-Dawley; D015290:Second Messenger Systems / Q000502:physiology*; D013873:Thionucleotides / Q000633:toxicity
chemical_list: D004791:Enzyme Inhibitors; D013873:Thionucleotides; C083763:8-bromoguanosino-3',5'-cyclic monophosphorothioate; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D002351:Carrageenan; D000242:Cyclic AMP; C497257:Prkce protein, rat; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D006152:Cyclic GMP; D015232:Dinoprostone