title: PKA is required for the modulation of spinal nociceptive information related to ephrinB-EphB signaling in mice.
abstract: EphB receptors and their ephrinB ligands are implicated in modulating of spinal nociceptive information processing. Here, we investigated whether protein kinase A (PKA), acts as a downstream effector, participates in the modulation spinal nociceptive information related to ephrinB-EphB signaling. Intrathecal injection of ephrinB2-Fc caused thermal hyperalgesia and mechanical allodynia, which were accompanied by increased expression of spinal PKA catalytic subunit (PKAca) and phosphorylated cAMP-response element-binding protein (p-CREB). Pre-treatment with H89, a PKA inhibitor, prevented the activation of CREB by ephrinB2-Fc. Inhibition of spinal PKA signaling prevented and reversed pain behaviors induced by the intrathecal injection of ephrinB2-Fc. Furthermore, blockade of the EphB receptors by intrathecal injection of EphB2-Fc reduced formalin-induced inflammatory, chronic constrictive injury (CCI)-induced neuropathic, and tibia bone cavity tumor cell implantation (TCI)-induced bone cancer pain behaviors, which were accompanied by decreased expression of spinal PKAca and p-CREB. Overall, these results confirmed the important involvement of PKA in the modulation of spinal nociceptive information related to ephrinBs-EphBs signaling. This finding may have important implications for exploring the roles and mechanisms of ephrinB-EphB signaling in physiologic and pathologic pain.
authors.affiliation: Department of Anesthesiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, China.
authors.forename: X-L
authors.initials: XL
authors.lastname: Zhou
authors.affiliation: Jiangsu Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou 221000, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, China.
authors.forename: C-J
authors.initials: CJ
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, China.
authors.forename: L-N
authors.initials: LN
authors.lastname: Yu
authors.affiliation: Jiangsu Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou 221000, China.
authors.forename: J-L
authors.initials: JL
authors.lastname: Cao
authors.affiliation: Department of Anesthesiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, China; Jiangsu Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou 221000, China. Electronic address: yanminnina@126.com.
authors.forename: M
authors.initials: M
authors.lastname: Yan
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy / Q000503:physiopathology; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004195:Disease Models, Animal; D036388:Ephrin-B2 / Q000008:administration & dosage / Q000378:metabolism*; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009437:Neuralgia / Q000188:drug therapy / Q000503:physiopathology; D059225:Nociception / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D036081:Receptors, Eph Family / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C000601240:EFNB2 protein, mouse; D036388:Ephrin-B2; D036081:Receptors, Eph Family; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: EphB; central sensitization; ephrinB; hyperalgesia; protein kinase A