title: Activation of peripheral ephrinBs/EphBs signaling induces hyperalgesia through a MAPKs-mediated mechanism in mice.
abstract: EphBs receptors and ephrinBs ligands are present in the adult brain and peripheral tissue and play a critical role in modulating multiple aspects of physiology and pathophysiology. Ours and other studies have demonstrated that spinal ephrinBs/EphBs signaling was involved in the modulation of nociceptive information and central sensitization. However, the role of ephrinBs/EphBs signaling in peripheral sensitization is poorly understood. This study shows that intraplantar (i.pl.) injection of ephrinB1-Fc produces a dose- and time-dependent thermal and mechanical hyperalgesia and the increase of spinal Fos protein expression in mice, which can be partially prevented by pre-treatment with EphB1-Fc. EphrinB1-Fc-induced hyperalgesia is accompanied with the NMDA receptor-mediated increase of expression in peripheral and spinal phosphorylated mitogen-activated protein kinases (phospho-MAPKs) including p-p38, pERK and pJNK, and also is prevented or reversed by the inhibition of peripheral and spinal MAPKs. Furthermore, in formalin inflammation pain model, pre-inhibition of EphBs receptors by the injection of EphB1-Fc reduces pain behavior, which is accompanied by the decreased expression of peripheral p-p38, pERK and pJNK. These data provide evidence that ephrinBs may act as a prominent contributor to peripheral sensitization, and demonstrate that activation of peripheral ephrinBs/EphBs system induces hyperalgesia through a MAPKs-mediated mechanism.
authors.affiliation: Department of Anesthesiology, Affiliated Hospital of Xuzhou Medical College, 99 Huaihai West Road, Xuzhou Jiangsu 221002, PR China Jiangsu Institute of Anesthesiology, Jiangsu Key Laboratory of Anesthesiology, 99 Huaihai West Road, Xuzhou 221002, PR China.
authors.forename: Jun-Li
authors.initials: JL
authors.lastname: Cao
authors.forename: Jia-Ping
authors.initials: JP
authors.lastname: Ruan
authors.forename: Di-Yang
authors.initials: DY
authors.lastname: Ling
authors.forename: Xue-Hai
authors.initials: XH
authors.lastname: Guan
authors.forename: Qi
authors.initials: Q
authors.lastname: Bao
authors.forename: Yan
authors.initials: Y
authors.lastname: Yuan
authors.forename: Li-Cai
authors.initials: LC
authors.lastname: Zhang
authors.forename: Xue-Jun
authors.initials: XJ
authors.lastname: Song
authors.forename: Yin-Ming
authors.initials: YM
authors.lastname: Zeng
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D036387:Ephrin-B1 / Q000494:pharmacology / Q000502:physiology*; D005528:Foot; D005557:Formaldehyde / Q000633:toxicity; D006358:Hot Temperature / Q000009:adverse effects; D006930:Hyperalgesia / Q000209:etiology / Q000503:physiopathology*; D007278:Injections, Spinal; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D009570:Nitriles / Q000494:pharmacology; D010812:Physical Stimulation / Q000009:adverse effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis; D036081:Receptors, Eph Family / Q000819:agonists / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology; D013116:Spinal Cord / Q000737:chemistry / Q000503:physiopathology; D014110:Touch; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: D000873:Anthracenes; D002070:Butadienes; C092571:Efnb1 protein, mouse; D036387:Ephrin-B1; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D016194:Receptors, N-Methyl-D-Aspartate; C113580:U 0126; D005557:Formaldehyde; C432165:pyrazolanthrone; D016291:Dizocilpine Maleate; D036081:Receptors, Eph Family; D048051:p38 Mitogen-Activated Protein Kinases