Acidosis Mediates the Switching of Gs-PKA and Gi-PKCε Dependence in Prolonged Hyperalgesia Induced by Inflammation.
Chronic inflammatory pain, when not effectively treated, is a costly health problem and has a harmful effect on all aspects of health-related quality of life. Previous studies suggested that in male Sprague Dawley rats, prostaglandin E2 (PGE2)-induced short-term hyperalgesia depends on protein kinase A (PKA) activity, whereas long-lasting hyperalgesia induced by PGE2 with carrageenan pre-injection, requires protein kinase Cε (PKCε). However, the mechanism underlying the kinase switch with short- to long-term hyperalgesia remains unclear. In this study, we used the inflammatory agents carrageenan or complete Freund's adjuvant (CFA) to induce long-term hyperalgesia, and examined PKA and PKCε dependence and switching time. Hyperalgesia induced by both agents depended on PKA/PKCε and Gs/Gi-proteins, and the switching time from PKA to PKCε and from Gs to Gi was about 3 to 4 h after inflammation induction. Among the single inflammatory mediators tested, PGE2 and 5-HT induced transient hyperalgesia, which depended on PKA and PKCε, respectively. Only acidic solution-induced hyperalgesia required Gs-PKA and Gi-PKCε, and the switch time for kinase dependency matched inflammatory hyperalgesia, in approximately 2 to 4 h. Thus, acidosis in inflamed tissues may be a decisive factor to regulate switching of PKA and PKCε dependence via proton-sensing G-protein-coupled receptors.
Department of Life Sciences, National Central University, Jhongli, Taiwan.
Wei-Yu
WY
Huang
Department of Life Sciences, National Central University, Jhongli, Taiwan.
Shih-Ping
SP
Dai
Department of Life Sciences, National Central University, Jhongli, Taiwan.
Yan-Ching
YC
Chang
Department of Life Sciences, National Central University, Jhongli, Taiwan; Institute of Systems Biology & Bioinformatics, National Central University, Jhongli, Taiwan.
Wei-Hsin
WH
Sun
D000138:Acidosis / Q000378:metabolism*; D000818:Animals; D002351:Carrageenan; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D005620:Freund's Adjuvant; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D006930:Hyperalgesia / Q000209:etiology / Q000378:metabolism*; D007249:Inflammation / Q000150:complications / Q000378:metabolism*; D051379:Mice; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
C525539:GPR68 protein, mouse; D047428:Protein Kinase Inhibitors; D043562:Receptors, G-Protein-Coupled; D002351:Carrageenan; D005620:Freund's Adjuvant; D017868:Cyclic AMP-Dependent Protein Kinases; D051744:Protein Kinase C-epsilon; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D019205:GTP-Binding Protein alpha Subunits, Gs