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.