Endogenous ephrinB2 mediates colon-urethra cross-organ sensitization via Src kinase-dependent tyrosine phosphorylation of NR2B.
Recently, the role of EphB receptor (EphBR) tyrosine kinase and their ephrinB ligands in spinal pain-related neural plasticity has been identified. To test whether Src-family non-receptor tyrosine kinase-dependent glutamatergic N-methyl-d-aspartate receptor (NMDAR) NR2B subunit phosphorylation underlies lumbosacral spinal EphBR activation to mediate cross-organ sensitization between the colon and the urethra, external urethra sphincter electromyogram activity evoked by pelvic nerve stimulation and protein expression in the lumbosacral (L6-S2) dorsal horn were studied before and after intracolonic mustard oil (MO) instillation. We found MO instillation produced colon-urethra reflex sensitization along with an upregulation of endogenous ephrinB2 expression as well as phosphorylation of EphB 1/2, Src-family kinase, and NR2B tyrosine residues. Intrathecal immunoglobulin fusion protein of EphB1 and EphB2 as well as PP2 reversed the reflex sensitization and NR2B phosphorylation caused by MO. All these results suggest that EphBR-ephrinB interactions, which provoke Src-family kinase-dependent NMDAR NR2B phosphorylation at the lumbosacral spinal cord level, are involved in cross-organ sensitization, contributing to the development of viscero-visceral referred pain between the bowel and the urethra.
Department of Physiology, College of Medicine, Chung-Shan Medical University Hospital, Chung-Shan Medical University, Taichung, Taiwan.
Hsien-Yu
HY
Peng
Gin-Den
GD
Chen
Cheng-Hung
CH
Lai
Kwong-Chung
KC
Tung
Junn-Liang
JL
Chang
Tzer-Bin
TB
Lin
D000818:Animals; D003106:Colon / Q000294:innervation* / Q000378:metabolism; D004558:Electric Stimulation; D004576:Electromyography; D036388:Ephrin-B2 / Q000378:metabolism*; D005260:Female; D023421:Models, Animal; D009149:Mustard Plant; D010766:Phosphorylation; D010938:Plant Oils / Q000494:pharmacology; D020671:Posterior Horn Cells / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D036225:Receptor, EphB1 / Q000378:metabolism; D036183:Receptor, EphB2 / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism*; D014521:Urethra / Q000294:innervation* / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
D036388:Ephrin-B2; C121001:NR2B NMDA receptor; D010938:Plant Oils; D016194:Receptors, N-Methyl-D-Aspartate; D014443:Tyrosine; D036225:Receptor, EphB1; D036183:Receptor, EphB2; D019061:src-Family Kinases; C027793:mustard oil