Acidosis mediates the switching of G_s-PKA and G_i-PKC_ε 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 C_ε (PKC_ε). 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 PKC_ε dependence and switching time. Hyperalgesia induced by both agents depended on PKA/PKC_ε and Gs/ Gi-proteins, and the switching time from PKA to PKC_ε and from G_s to G_i 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 PKC_ε, respectively. Only acidic solution-induced hyperalgesia required G_s-PKA and G_i-PKC_ε, 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 PKC_εdependence via proton-sensing G-protein-coupled receptors.