title: NR2B phosphorylation at tyrosine 1472 in spinal dorsal horn contributed to N-methyl-D-aspartate-induced pain hypersensitivity in mice.
abstract: Calcium influx via N-methyl-D-aspartate (NMDA)-subtype glutamate receptors (NMDARs) regulates the intracellular trafficking of NMDARs, leading to long-lasting modification of NMDAR-mediated synaptic transmission that is involved in development, learning, and synaptic plasticity. The present study investigated the contribution of such NMDAR-dependent synaptic trafficking in spinal dorsal horn to the induction of pain hypersensitivity. Our data showed that direct activation of NMDARs by intrathecal NMDA application elicited pronounced mechanical allodynia in intact mice, which was concurrent with a specific increase in the abundance of NMDAR subunits NR1 and NR2B at the postsynaptic density (PSD)-enriched fraction. Selective inhibition of NR2B-containing NMDARs (NR2BR) by ifenprodil dose dependently attenuated the mechanical allodynia in NMDA-injected mice, suggesting the importance of NR2BR synaptic accumulation in NMDA-induced pain sensitization. The NR2BR redistribution at synapses after NMDA challenge was associated with a significant increase in NR2B phosphorylation at Tyr1472, a catalytic site by Src family protein tyrosine kinases (SFKs) that has been shown to prevent NR2B endocytosis. Intrathecal injection of a specific SFKs inhibitor, PP2, to block NR2B tyrosine phosphorylation eliminated NMDA-induced NR2BR synaptic expression and also attenuated the mechanical allodynia. These data suggested that activation of spinal NMDARs was able to accumulate NR2BR at synapses via SFK signaling, which might exaggerate NMDAR-dependent nociceptive transmission and contribute to NMDA-induced nociceptive behavioral hyperresponsiveness.
authors.affiliation: Department of Molecular Pharmacology, School of Pharmacy, Lanzhou University, Lanzhou, Gansu, People's Republic of China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Cao
authors.forename: Xian
authors.initials: X
authors.lastname: Yang
authors.forename: Zhan-Wei
authors.initials: ZW
authors.lastname: Suo
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.forename: Yan-Ni
authors.initials: YN
authors.lastname: Liu
authors.forename: Hong-Bin
authors.initials: HB
authors.lastname: Yang
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Hu
mesh_terms: D000818:Animals; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology*; D010147:Pain Measurement; D010766:Phosphorylation / Q000502:physiology; D010880:Piperidines / Q000627:therapeutic use; D020671:Posterior Horn Cells / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism
chemical_list: D018691:Excitatory Amino Acid Antagonists; C121001:NR2B NMDA receptor; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; C010739:ifenprodil