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 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.