Critical Role of p38α MAPK Subclass in the Development of Pain Hypersensitivity After Hind Paw Incision

Daiki Ishikawa,1 Shunsuke Yamakita,1 Kentaro Oh-Hashi,2– 4 Fumimasa Amaya1 1Department of Anesthesiology, Kyoto Prefectural University of Medicine, Kyoto, Japan; 2United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan; 3Center for One Medicine Innovative Translational Research (COMIT), Gifu University, Gifu, 501-1193, Japan; 4Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Gifu, 501-1193, JapanCorrespondence: Fumimasa Amaya, Department of Anesthesiology, Kyoto Prefectural University of Medicine, Kajii-Cho 465, Kamigyo-Ku, Kyoto, 602-0841, Japan, Tel +81-75-251-5633, Email [email protected]: Deeper understanding of the mechanisms of postoperative pain is critical for developing more effective pain management strategies. The present animal study explored the function of four p38 mitogen-activated protein kinase (MAPK) subclasses (α, β, γ, and δ) in dorsal root ganglion (DRG) in the development of post-incisional pain hypersensitivity.Methods: The amount of p38 MAPK subclass mRNA in the DRG of male Sprague-Dawley rats was quantified using real-time PCR. Localization of p38 MAPK expression was analyzed by immunohistochemistry using subclass-selective antibodies. The effects of a p38α MAPK inhibitor on plantar incision-induced pain hypersensitivity was assessed using behavioral tests to measure mechanical and thermal sensitivity. The impact of the inhibitor on phosphorylated p38 MAPK expression was also analyzed by immunohistochemistry.Results: Four p38 MAPK subclass mRNA were identified in the DRG, with p38α, β, and γ MAPK showing significant expression. p38α and γ MAPK were identified in the DRG neurons, whereas p38β MAPK was distributed in satellite glial cells. Selective inhibition of p38α MAPK reduced both mechanical and thermal hypersensitivity following plantar incision. Treatment with the p38α MAPK inhibitor decreased the expression of phosphorylated p38 MAPK in the DRG.Conclusion: These results demonstrated the distinct roles of p38 MAPK subclasses in the DRG, with p38α MAPK playing a dominant role in the development of pain hypersensitivity after tissue injury. Targeting p38α MAPK might be a promising therapeutic strategy for managing postoperative pain.Keywords: p38 MAPK, tissue injury, hyperalgesia