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

Wei-Yu Huang,Yan-Ching Chang,Wei-Hsin Sun,Shih-Ping Dai,Xiangming Zha

doi:10.1371/journal.pone.0125022

Abstract

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.

Highlights

Tissue injury, infection or tumor growth induces inflammation, which is often accompanied by persistent and chronic pain
Prolonged hyperalgesia depends on a switch of protein kinase A (PKA) and protein kinase Cε (PKCε) kinase activities Carrageenan and complete Freund’s adjuvant (CFA) are commonly used in models of inflammatory pain
To understand whether the prolonged hyperalgesia induced by these two agents depends on PKA and/or PKCε, mice received intraplantar injection of CFA or carrageenan to induce peripheral inflammation

Summary

Introduction

Infection or tumor growth induces inflammation, which is often accompanied by persistent and chronic pain. More sustained pain effects are achieved only with high concentration (10-5 M) of a PLOS ONE | DOI:10.1371/journal.pone.0125022. Acidosis Mediates the Switching of Gs-PKA and Gi-PKCε in Hyperalgesia combination of inflammatory mediators (including BK, 5-HT, PGE2, and histamine)[7]. High local proton concentrations in inflamed tissues excite and sensitize rat skin nociceptors and cause sustained pain in human skin [5,8,9]. The combination of inflammatory mediators (BK, 5-HT, PGE2, and histamine) in acid solution (pH 6.1) excites and sensitizes rat skin nociceptors [10]. Acidosis in inflamed tissues is the decisive factor for ongoing nociceptor excitation and sustained pain [13]

Methods

Results

Conclusion