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Perturbing PSD-95 Interactions With NR2B-subtype Receptors Attenuates Spinal Nociceptive Plasticity and Neuropathic Pain

D'Mello, R; Marchand, F; Pezet, S; McMahon, SB; Dickenson, AH; (2011) Perturbing PSD-95 Interactions With NR2B-subtype Receptors Attenuates Spinal Nociceptive Plasticity and Neuropathic Pain. MOL THER , 19 (10) 1780 - 1792. 10.1038/mt.2011.42. Gold open access

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. Received 9 December 2010; accepted 18 February 2011; published online 22 March 2011. doi:10.1038/mt.2011.42

Type: Article
Title: Perturbing PSD-95 Interactions With NR2B-subtype Receptors Attenuates Spinal Nociceptive Plasticity and Neuropathic Pain
Open access status: An open access publication
DOI: 10.1038/mt.2011.42
Publisher version: http://www.ncbi.nlm.nih.gov/pmc/ articles/PMC31887...
Keywords: DENSITY PROTEIN PSD-95, D-ASPARTATE RECEPTOR, DORSAL HORN NEURONS, NMDA RECEPTOR, CENTRAL SENSITIZATION, THERMAL HYPERALGESIA, ANTAGONIST KETAMINE, PERSISTENT PAIN, NR2B SUBUNIT, NITRIC-OXIDE
UCL classification: UCL > School of Life and Medical Sciences
UCL > School of Life and Medical Sciences > Faculty of Life Sciences
URI: http://discovery.ucl.ac.uk/id/eprint/1301555
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