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Perturbing PSD-95 interactions with NR2B-subtype receptors attenuates spinal nociceptive plasticity and neuropathic pain.

Abstract
Peripheral inflammation or nerve injury induces a primary afferent barrage into the spinal cord, which can cause N-methyl D-aspartate (NMDA) receptor-dependent alterations in the responses of dorsal horn sensory neurons to subsequent afferent inputs. This plasticity, such as "wind-up" and central sensitization, contributes to the hyperexcitability of dorsal horn neurons and increased pain-related behavior in animal models, as well as clinical signs of chronic pain in humans, hyperalgesia and allodynia. Binding of NMDA receptor subunits by the scaffolding protein postsynaptic density protein-95 (PSD-95) can facilitate downstream intracellular signaling and modulate receptor stability, contributing to synaptic plasticity. Here, we show that spinal delivery of the mimetic peptide Tat-NR2B9c disrupts the interaction between PSD-95 and NR2B subunits in the dorsal horn and selectively reduces NMDA receptor-dependent events including wind-up of spinal sensory neurons, and both persistent formalin-induced neuronal activity and pain-related behaviors, attributed to central sensitization. Furthermore, a single intrathecal injection of Tat-NR2B9c in rats with established nerve injury-induced pain attenuates behavioral signs of mechanical and cold hypersensitivity, with no effect on locomotor performance. Thus, uncoupling of PSD-95 from spinal NR2B-containing NMDA receptors may prevent the neuronal plasticity involved in chronic pain and may be a successful analgesic therapy, reducing side effects associated with receptor blockade.
AuthorsRichard D'Mello, Fabien Marchand, Sophie Pezet, Stephen B McMahon, Anthony H Dickenson
JournalMolecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 19 Issue 10 Pg. 1780-92 (Oct 2011) ISSN: 1525-0024 [Electronic] United States
PMID21427709 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Disks Large Homolog 4 Protein
  • Dlg4 protein, rat
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • NR2B NMDA receptor
  • Receptors, N-Methyl-D-Aspartate
Topics
  • Animals
  • Disks Large Homolog 4 Protein
  • Intracellular Signaling Peptides and Proteins (metabolism)
  • Membrane Proteins (metabolism)
  • Neuralgia (metabolism, physiopathology)
  • Neuronal Plasticity
  • Nociception
  • Rats
  • Receptors, N-Methyl-D-Aspartate (metabolism)
  • Spinal Cord (metabolism, physiopathology)

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