The pathogenic mechanisms underlying
neuropathic pain still remain largely unknown. In this study, we investigated whether spinal
BDNF contributes to dorsal horn LTP induction and
neuropathic pain development by activation of GluN2B-NMDA receptors via Src homology-2 domain-containing
protein tyrosine phosphatase-2 (SHP2) phosphorylation in rats following spinal nerve
ligation (SNL). We first demonstrated that spinal
BDNF participates in the development of long-lasting hyperexcitability of dorsal horn WDR neurons (i.e. central sensitization) as well as
pain allodynia in both intact and SNL rats. Second, we revealed that
BDNF induces spinal LTP at C-fiber synapses via functional up-regulation of GluN2B-NMDA receptors in the spinal dorsal horn, and this
BDNF-mediated LTP-like state is responsible for the occlusion of spinal LTP elicited by subsequent high-frequency electrical stimulation (HFS) of the sciatic nerve in SNL rats. Finally, we validated that
BDNF-evoked SHP2 phosphorylation is required for subsequent GluN2B-NMDA receptors up-regulation and spinal LTP induction, and also for
pain allodynia development. Blockade of SHP2 phosphorylation in the spinal dorsal horn using a potent SHP2
protein tyrosine phosphatase inhibitor
NSC-87877, or knockdown of spinal SHP2 by intrathecal delivery of SHP2
siRNA, not only prevents
BDNF-mediated GluN2B-NMDA receptors activation as well as spinal LTP induction and
pain allodynia elicitation in intact rats, but also reduces the SNL-evoked GluN2B-NMDA receptors up-regulation and spinal LTP occlusion, and ultimately alleviates
pain allodynia in neuropathic rats. Taken together, these results suggest that the
BDNF/SHP2/GluN2B-
NMDA signaling cascade plays a vital role in the development of central sensitization and
neuropathic pain after
peripheral nerve injury.