title: EphrinB2 induces pelvic-urethra reflex potentiation via Src kinase-dependent tyrosine phosphorylation of NR2B.
abstract: Recently, the role of EphB receptor (EphBR) tyrosine kinase and their ephrinB ligands in pain-related neural plasticity at the spinal cord level have been identified. To test whether Src-family tyrosine kinase-dependent glutamatergic N-methyl-d-aspartate receptor NR2B subunit phosphorylation underlies lumbosacral spinal EphBR activation to mediate pelvic-urethra reflex potentiation, we recorded external urethra sphincter electromyogram reflex activity and analyzed protein expression in the lumbosacral (L(6)-S(2)) dorsal horn in response to intrathecal ephrinB2 injections. When compared with vehicle solution, exogenous ephrinB2 (5 μg/rat it)-induced reflex potentiation, in associated with phosphorylation of EphB1/2, Src-family kinase, NR2B Y1336 and Y1472 tyrosine residues. Both intrathecal EphB1 and EphB2 immunoglobulin fusion protein (both 10 μg/rat it) prevented ephrinB2-dependent reflex potentiation, as well as protein phosphorylation. Pretreatment with PP2 (50 μM, 10 μl it), an Src-family kinase antagonist, reversed the reflex potentiation, as well as Src kinase and NR2B phosphorylation. Together, these results suggest the ephrinB2-dependent EphBR activation, which subsequently provokes Src kinase-mediated N-methyl-d-aspartate receptor NR2B phosphorylation in the lumbosacral dorsal horn, is crucial for the induction of spinal reflex potentiation contributing to the development of visceral pain and/or hyperalgesia in the pelvic area.
authors.affiliation: Department of Urology, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Hsi-Chin
authors.initials: HC
authors.lastname: Wu
authors.forename: Chao-Hsiang
authors.initials: CH
authors.lastname: Chang
authors.forename: Hsien-Yu
authors.initials: HY
authors.lastname: Peng
authors.forename: Gin-Den
authors.initials: GD
authors.lastname: Chen
authors.forename: Cheng-Yuang
authors.initials: CY
authors.lastname: Lai
authors.forename: Ming-Chun
authors.initials: MC
authors.lastname: Hsieh
authors.forename: Tzer-Bin
authors.initials: TB
authors.lastname: Lin
mesh_terms: D000818:Animals; D036388:Ephrin-B2 / Q000494:pharmacology / Q000502:physiology*; D005260:Female; D006930:Hyperalgesia / Q000503:physiopathology*; D010388:Pelvis / Q000294:innervation*; D010766:Phosphorylation; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000378:metabolism*; D012018:Reflex / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000187:drug effects; D014443:Tyrosine / Q000378:metabolism; D014521:Urethra / Q000187:drug effects / Q000294:innervation*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C412373:AG 1879; D036388:Ephrin-B2; C121001:NR2B NMDA receptor; D011743:Pyrimidines; D016194:Receptors, N-Methyl-D-Aspartate; D014443:Tyrosine; D019061:src-Family Kinases