title: ERK potentiates p38 in central sensitization induced by traumatic occlusion.
abstract: This study was to investigate the role of p38 activation via ERK1/2 phosphorylation in neurons and microglia of the spinal trigeminal subnucleus caudalis (Vc) in the promotion of orofacial hyperalgesia induced by unilateral anterior crossbite (UAC) traumatic occlusion in adult rats. U0126, a p-ERK1/2 inhibitor, was injected intracisternally before UAC implant. The effects of the U0126 injection were compared to those following the injection of SB203580, a p-p38 inhibitor. Mechanical hyperalgesia was evaluated via pressure pain threshold measurements. Brain stem tissues were processed for a Western blot analysis to evaluate the activation of ERK1/2 and p38. Double immunofluorescence was also performed to observe the expression of p-ERK1/2 and p-p38 in neurons (labeled by NeuN) and microglia (labeled by OX42). The data showed that UAC caused orofacial hyperalgia ipsilaterally on d1 to d7, peaking on d3 (P<0.05). An upregulation of p-ERK1/2 was observed in the ipsilateral Vc on d1 to d3, peaking on d1. An upregulation of p-p38 was also observed on d1 to d7, peaking on d3 (P<0.05). p-ERK1/2 primarily co-localized with NeuN and, to a lesser extent, with OX42, while p-p38 co-localized with both NeuN and OX42. Pretreatment with U0126 prevented the upregulation of both p-ERK1/2 and p-p38. Similarly to an intracisternal injection of SB203580, U0126 pretreatment attenuated the UAC-induced orofacial hyperalgesia. These data indicate that UAC caused orofacial hyperalgesia by inducing central sensitization via the activation of ERK1/2 and p38 in both neurons and microglia in the Vc, potentially impacting the effects of p-ERK1/2 during p38 activation.
authors.affiliation: State Key Laboratory of Military Stomatology, Shaanxi International Joint Research Center for Oral Diseases, Department of Oral Anatomy and Physiology and TMD, School of Stomatology, The Fourth Military Medical University, 145 Changlexi Road, Xi'an 710032, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Jing
authors.affiliation: State Key Laboratory of Military Stomatology, Shaanxi International Joint Research Center for Oral Diseases, Department of Oral Anatomy and Physiology and TMD, School of Stomatology, The Fourth Military Medical University, 145 Changlexi Road, Xi'an 710032, China.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Military Stomatology, Shaanxi International Joint Research Center for Oral Diseases, Department of Oral Anatomy and Physiology and TMD, School of Stomatology, The Fourth Military Medical University, 145 Changlexi Road, Xi'an 710032, China.
authors.forename: Hong-Xu
authors.initials: HX
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Military Stomatology, Shaanxi International Joint Research Center for Oral Diseases, Department of Oral Anatomy and Physiology and TMD, School of Stomatology, The Fourth Military Medical University, 145 Changlexi Road, Xi'an 710032, China.
authors.forename: Mian
authors.initials: M
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Military Stomatology, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Periodontal Disease, School of Stomatology, The Fourth Military Medical University, 145 Changlexi Road, Xi'an 710032, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institute of Neurosciences, Fourth Military Medical University, 169 Changlexi Road, Xi'an 710032, China.
authors.forename: Li
authors.initials: L
authors.lastname: Duan
authors.affiliation: State Key Laboratory of Military Stomatology, Shaanxi International Joint Research Center for Oral Diseases, Department of Oral Anatomy and Physiology and TMD, School of Stomatology, The Fourth Military Medical University, 145 Changlexi Road, Xi'an 710032, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Military Stomatology, Shaanxi International Joint Research Center for Oral Diseases, Department of Oral Anatomy and Physiology and TMD, School of Stomatology, The Fourth Military Medical University, 145 Changlexi Road, Xi'an 710032, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Military Stomatology, Shaanxi International Joint Research Center for Oral Diseases, Department of Oral Anatomy and Physiology and TMD, School of Stomatology, The Fourth Military Medical University, 145 Changlexi Road, Xi'an 710032, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Military Stomatology, Shaanxi International Joint Research Center for Oral Diseases, Department of Oral Anatomy and Physiology and TMD, School of Stomatology, The Fourth Military Medical University, 145 Changlexi Road, Xi'an 710032, China.
authors.forename: Dong-Mei
authors.initials: DM
authors.lastname: Wang
authors.affiliation: Institute of Neurosciences, Fourth Military Medical University, 169 Changlexi Road, Xi'an 710032, China. Electronic address: lwchen@fmmu.edu.cn.
authors.forename: Liang-Wei
authors.initials: LW
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Military Stomatology, Shaanxi International Joint Research Center for Oral Diseases, Department of Oral Anatomy and Physiology and TMD, School of Stomatology, The Fourth Military Medical University, 145 Changlexi Road, Xi'an 710032, China. Electronic address: mqwang@fmmu.edu.cn.
authors.forename: Mei-Qing
authors.initials: MQ
authors.lastname: Wang
mesh_terms: D000818:Animals; D059333:Central Nervous System Sensitization / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D005157:Facial Pain / Q000201:enzymology* / Q000473:pathology; D005260:Female; D006930:Hyperalgesia / Q000201:enzymology* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D017628:Microglia / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D014279:Trigeminal Nucleus, Spinal / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D048051:p38 Mitogen-Activated Protein Kinases
keywords: P38 mitogen-activated protein kinase (MAPK); extracellular signal-regulated kinase (ERK); hyperalgesia; microglia; neuron; occlusal trauma