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.

Glutamatergic Projections from the Entorhinal Cortex to Dorsal Dentate Gyrus Mediate Context-Induced Reinstatement of Heroin Seeking

“…The excitability of NMDARs is known to be regulated by serine/threonine and tyrosine phosphorylation (Li et al , 2011; Liu et al , 2008), and tyrosine 1472 residue in GluN2B subunits phosphorylated by Src family kinase promote the surface expression of GluN2B (Zhang et al , 2008). We therefore investigated the phosphorylation level of GluN2B at Y1472 (pY1472 GluN2B) and S1480 (pS1480 GluN2B), the two major sites regulating GluN2B trafficking.…”

Striatal-enriched protein tyrosine phosphatase modulates nociception

“…Noxious stimuli rapidly induce GluN2B phosphorylation (pGluN2B) at Tyr1472 causing its redistribution to the membrane of spinal dorsal horn neurons. 11,28,48,51,55 After the activation of glutamate receptors, influx of extracellular calcium activates multiple intracellular protein kinase cascades, including extracellular signal-regulated kinases 1/2 (ERK1/2). 20,21,44 Like GluN2B, ERK1/2 phosphorylation (pERK1/2) is implicated in central sensitization.…”

NMDA receptor mediates chronic visceral pain induced by neonatal noxious somatic stimulation

“…It has been suggested that up-regulated NR2B is able to form functional NMDA receptors with NR1 that is usually in excess of NR2B, however, this remains speculative (Fan et al, 2009). Overall, multiple studies have proposed NR2B as the major subunit involved in the development and maintenance of hyperalgesia (Abe et al, 2005; Iwata et al, 2007; Geng et al, 2010; Li et al, 2011). Intrathecal injection of NR2B antagonists prior to spinal nerve ligation significantly inhibits the development of mechanical allodynia and can block the activity of wide dynamic range neurons in the spinal cord (Qu et al, 2009).…”

“…NR2 can be classified into NR2A, NR2B, NR2C, and NR2D subunits. The NR2B subunit has been shown to be present in the forebrain and superficial lamina of the spinal cord where it is believed to play an important role in chronic sensitization (Li et al, 2011; Li et al, 2012). Multiple studies have shown that blocking the NMDAR reduces pain transmission to noxious stimuli and chronic pain in humans and in animals (Becerra et al, 2009, Costroman and Ness, 2002; Peles et al, 2004).…”