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

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2015 May 2

PMID 25933021

Citations 16

Authors

Wei-Yu Huang

Shih-Ping Dai

Yan-Ching Chang

Wei-Hsin Sun

Affiliations

Soon will be listed here.

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.

Citing Articles

Activation of the proton-sensing GPCR, GPR65 on fibroblast-like synoviocytes contributes to inflammatory joint pain.

Pattison L, Rickman R, Hilton H, Dannawi M, Wijesinghe S, Ladds G Proc Natl Acad Sci U S A. 2024; 121(51):e2410653121.

PMID: 39661058 PMC: 11665855. DOI: 10.1073/pnas.2410653121.

T cell death-associated gene 8-mediated distinct signaling pathways modulate the early and late phases of neuropathic pain.

Dai S, Yang C, Chin Y, Sun W iScience. 2024; 27(10):110955.

PMID: 39381739 PMC: 11460492. DOI: 10.1016/j.isci.2024.110955.

Novel Molecular Mechanism of Lenalidomide in Myeloid Malignancies Independent of Deletion of Chromosome 5q.

Park I, Phan T, Fang J Cancers (Basel). 2021; 13(20).

PMID: 34680233 PMC: 8534127. DOI: 10.3390/cancers13205084.

Role of GABAAR in the Transition From Acute to Chronic Pain and the Analgesic Effect of Electroacupuncture on Hyperalgesic Priming Model Rats.

Wang S, Du J, Xi D, Shao F, Qiu M, Shao X Front Neurosci. 2021; 15:691455.

PMID: 34220444 PMC: 8248374. DOI: 10.3389/fnins.2021.691455.

GPR68 Contributes to Persistent Acidosis-Induced Activation of AGC Kinases and Tyrosine Phosphorylation in Organotypic Hippocampal Slices.

Zhou G, Zha X Front Neurosci. 2021; 15:692217.

PMID: 34113235 PMC: 8185064. DOI: 10.3389/fnins.2021.692217.

References

Khasar S, Burkham J, Dina O, Brown A, Bogen O, Alessandri-Haber N . Stress induces a switch of intracellular signaling in sensory neurons in a model of generalized pain. J Neurosci. 2008; 28(22):5721-30. PMC: 2518401. DOI: 10.1523/JNEUROSCI.0256-08.2008. View

Hucho T, Dina O, Levine J . Epac mediates a cAMP-to-PKC signaling in inflammatory pain: an isolectin B4(+) neuron-specific mechanism. J Neurosci. 2005; 25(26):6119-26. PMC: 6725047. DOI: 10.1523/JNEUROSCI.0285-05.2005. View

Dina O, Khasar S, Gear R, Levine J . Activation of Gi induces mechanical hyperalgesia poststress or inflammation. Neuroscience. 2009; 160(2):501-7. PMC: 2673984. DOI: 10.1016/j.neuroscience.2009.03.001. View

Chen Y, Huang C, Lin C, Chang W, Sun W . Expression and function of proton-sensing G-protein-coupled receptors in inflammatory pain. Mol Pain. 2009; 5:39. PMC: 2716309. DOI: 10.1186/1744-8069-5-39. View

Basbaum A, Bautista D, Scherrer G, Julius D . Cellular and molecular mechanisms of pain. Cell. 2009; 139(2):267-84. PMC: 2852643. DOI: 10.1016/j.cell.2009.09.028. View

Gao Y, Xu Z, Liu Y, Wen Y, Decosterd I, Ji R . The c-Jun N-terminal kinase 1 (JNK1) in spinal astrocytes is required for the maintenance of bilateral mechanical allodynia under a persistent inflammatory pain condition. Pain. 2009; 148(2):309-319. PMC: 2814908. DOI: 10.1016/j.pain.2009.11.017. View

Joseph E, Reichling D, Levine J . Shared mechanisms for opioid tolerance and a transition to chronic pain. J Neurosci. 2010; 30(13):4660-6. PMC: 2857996. DOI: 10.1523/JNEUROSCI.5530-09.2010. View

Lin C, Amaya F, Barrett L, Wang H, Takada J, Samad T . Prostaglandin E2 receptor EP4 contributes to inflammatory pain hypersensitivity. J Pharmacol Exp Ther. 2006; 319(3):1096-103. DOI: 10.1124/jpet.106.105569. View

Bolick D, Whetzel A, Skaflen M, Deem T, Lee J, Hedrick C . Absence of the G protein-coupled receptor G2A in mice promotes monocyte/endothelial interactions in aorta. Circ Res. 2007; 100(4):572-80. DOI: 10.1161/01.RES.0000258877.57836.d2. View

10.

Huang C, Tzeng J, Chen Y, Tsai W, Chen C, Sun W . Nociceptors of dorsal root ganglion express proton-sensing G-protein-coupled receptors. Mol Cell Neurosci. 2007; 36(2):195-210. DOI: 10.1016/j.mcn.2007.06.010. View

11.

Joseph E, Bogen O, Alessandri-Haber N, Levine J . PLC-beta 3 signals upstream of PKC epsilon in acute and chronic inflammatory hyperalgesia. Pain. 2007; 132(1-2):67-73. DOI: 10.1016/j.pain.2007.01.027. View

12.

Peter C, Waibel M, Radu C, Yang L, Witte O, Schulze-Osthoff K . Migration to apoptotic "find-me" signals is mediated via the phagocyte receptor G2A. J Biol Chem. 2007; 283(9):5296-305. DOI: 10.1074/jbc.M706586200. View

13.

Di Castro A, Drew L, Wood J, Cesare P . Modulation of sensory neuron mechanotransduction by PKC- and nerve growth factor-dependent pathways. Proc Natl Acad Sci U S A. 2006; 103(12):4699-704. PMC: 1450234. DOI: 10.1073/pnas.0508005103. View

14.

Cui M, Honore P, Zhong C, Gauvin D, Mikusa J, Hernandez G . TRPV1 receptors in the CNS play a key role in broad-spectrum analgesia of TRPV1 antagonists. J Neurosci. 2006; 26(37):9385-93. PMC: 6674601. DOI: 10.1523/JNEUROSCI.1246-06.2006. View

15.

Joseph E, Levine J . Multiple PKCε-dependent mechanisms mediating mechanical hyperalgesia. Pain. 2010; 150(1):17-21. PMC: 2916056. DOI: 10.1016/j.pain.2010.02.011. View

16.

Lin S, Chang W, Lin C, Huang C, Wang H, Sun W . Serotonin receptor 5-HT2B mediates serotonin-induced mechanical hyperalgesia. J Neurosci. 2011; 31(4):1410-8. PMC: 6623624. DOI: 10.1523/JNEUROSCI.4682-10.2011. View

17.

Frasch S, Fernandez-Boyanapalli R, Zemski Berry K, Leslie C, Bonventre J, Murphy R . Signaling via macrophage G2A enhances efferocytosis of dying neutrophils by augmentation of Rac activity. J Biol Chem. 2011; 286(14):12108-22. PMC: 3069415. DOI: 10.1074/jbc.M110.181800. View

18.

Belkouch M, Dansereau M, Reaux-Le Goazigo A, Steenwinckel J, Beaudet N, Chraibi A . The chemokine CCL2 increases Nav1.8 sodium channel activity in primary sensory neurons through a Gβγ-dependent mechanism. J Neurosci. 2011; 31(50):18381-90. PMC: 6623900. DOI: 10.1523/JNEUROSCI.3386-11.2011. View

19.

Onozawa Y, Fujita Y, Kuwabara H, Nagasaki M, Komai T, Oda T . Activation of T cell death-associated gene 8 regulates the cytokine production of T cells and macrophages in vitro. Eur J Pharmacol. 2012; 683(1-3):325-31. DOI: 10.1016/j.ejphar.2012.03.007. View

20.

Kim Y, Back S, Davies A, Jeong H, Jo H, Chung G . TRPV1 in GABAergic interneurons mediates neuropathic mechanical allodynia and disinhibition of the nociceptive circuitry in the spinal cord. Neuron. 2012; 74(4):640-7. DOI: 10.1016/j.neuron.2012.02.039. View