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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.

SUBMITTER: D'Mello R

PROVIDER: S-EPMC3188755 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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

D'Mello Richard R Marchand Fabien F Pezet Sophie S McMahon Stephen B SB Dickenson Anthony H AH

Molecular therapy : the journal of the American Society of Gene Therapy 20110322 10

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 all ...[more]

PMID: 21427709

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Project description:BackgroundDeficient endogenous pain modulation and increased nociceptive excitability are key features of central sensitization and can be assessed in humans by conditioned pain modulation (CPM, anti-nociceptive) and temporal summation of pain (TSP, pro-nociceptive), respectively. This study aimed to investigate these measures as proxies for central sensitization in subjects with chronic neuropathic pain (NP) after spinal cord injury (SCI).MethodsIn paraplegic subjects with NP (SCI-NP; n = 17) and healthy controls (HC; n = 17), parallel and sequential sham-controlled CPM paradigms were performed using pressure pain threshold at the hand, that is, above lesion level, as test stimulus. The conditioning stimulus was a noxious cold (verum) or lukewarm water bath (sham) applied contralaterally. Regarding pro-nociceptive mechanisms, a TSP protocol with individually-adjusted pressure pain stimuli at the thenar eminence was used. CPM and TSP magnitudes were related to intensity and spatial extent of spontaneous NP.ResultsNeither the parallel nor sequential sham-controlled CPM paradigm showed any significant inhibition of above-level pressure pain thresholds for SCI-NP or HC. Accordingly, no group difference in CPM capacity was found, however, subjects with more intense spontaneous NP showed lower inhibitory CPM capacity. TSP was observed for both groups but was not enhanced in SCI-NP.ConclusionsOur results do not support altered above-level anti- or pro-nociceptive mechanisms in SCI-NP compared with HC; however, they also highlight the relevance of spontaneous NP intensity with regards to the capacity of endogenous pain modulation in SCI subjects.SignificanceCentral sensitization encompasses deficient endogenous pain modulation and increased nociceptive excitability. These two mechanisms can be assessed in humans by conditioned pain modulation and temporal summation of pain, respectively. Our data demonstrates a lack of descending pain inhibition only in subjects with severe neuropathic pain which may hint towards central sensitization at spinal and/or supra-spinal levels. Disentangling the mechanisms of endogenous pain modulation and neuronal hyperexcitability might improve mechanism-based treatment of neuropathic pain in subjects with spinal cord injury.

Dataset Information

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

Publications

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

Similar Datasets

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