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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 E 2  (PGE 2 )-induced short-term hyperalgesia depends on protein kinase A (PKA) activity, whereas long-lasting hyperalgesia induced by PGE 2  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 G s /G i -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, PGE 2  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 ε  dependence via proton-sensing G-protein–coupled receptors.

Acidosis Mediates the Switching of Gs-PKA and Gi-PKCε Dependence in Prolonged Hyperalgesia Induced by Inflammation