title: Phosphatidylinositol 3-kinase mediates pain behaviors induced by activation of peripheral ephrinBs/EphBs signaling in mice.
abstract: EphBs receptors and their ephrinBs ligands are present in the adult brain and peripheral tissue and play a critical role in modulating multiple aspects of physiology and pathophysiology. Our recent evidence has shown that ephrinBs acted as a sensitizer to participate in peripheral sensitization and hyperalgesia induced by activation of peripheral ephrinBs/EphBs signaling. In the present study, we explored the role of phosphatidylinositol 3-kinase (PI3K) in ephrinB1-Fc-induced pain behaviors. Intraplantar injection of ephrinB1-Fc produced a time- and dose-dependent increase of PI3K-p110gamma expression and of phosphorylation of AKT in skin of injection site. Pre-treatment with PI3K inhibitor wortmannin or LY294002 prevented activation of peripheral AKT by ephrinB1-Fc. The activated AKT expressed in peripheral nerve terminals and DRG peptide-containing and small non-peptide-containing neurons. Inhibition of peripheral PI3K signaling dose-dependently prevented and reversed pain behaviors and spinal Fos protein expression induced by intraplantar injection of ephrinB1-Fc. Furthermore, pre-treatment with PI3K inhibitor wortmannin or LY294002 prevented ephrinB1-Fc-induced ERK activation in a dose-dependent manner. These data demonstrated that PI3K and PI3K crosstalk to ERK signaling mediated pain behaviors induced by activation of peripheral ephrinBs/EphBs signaling in mice.
authors.affiliation: Jiangsu Institute of Anesthesiology, Jiangsu Key Laboratory of Anesthesiology, 99 Huaihai West Road, Xuzhou 221002, PR China.
authors.forename: Xue-Hai
authors.initials: XH
authors.lastname: Guan
authors.forename: Xian-Fu
authors.initials: XF
authors.lastname: Lu
authors.forename: Hong-Xing
authors.initials: HX
authors.lastname: Zhang
authors.forename: Jing-Ru
authors.initials: JR
authors.lastname: Wu
authors.forename: Yan
authors.initials: Y
authors.lastname: Yuan
authors.forename: Qi
authors.initials: Q
authors.lastname: Bao
authors.forename: Di-Yang
authors.initials: DY
authors.lastname: Ling
authors.forename: Jun-Li
authors.initials: JL
authors.lastname: Cao
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D036342:Ephrins / Q000378:metabolism* / Q000502:physiology; D008297:Male; D051379:Mice; D010146:Pain / Q000378:metabolism* / Q000523:psychology; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D036081:Receptors, Eph Family / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D036342:Ephrins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D036081:Receptors, Eph Family; D000077191:Wortmannin