Cell-permeable peptide Tat-PSD-95 PDZ2 inhibits chronic inflammatory pain behaviors in mice.

Abstract

Inflammatory conditions can lead to persistent debilitating pain, and the activation of N-methyl-D-aspartate receptors (NMDARs) has been shown to play an important role in the processing of inflammatory pain. Postsynaptic density protein-95 (PSD-95), a scaffolding protein, has been identified to interact with NMDARs at neuronal synapses of the central nervous system (CNS). However, the role of these interactions in the central sensitization of nociceptive processing has not been defined. In this study, we investigated the effect of disrupting NMDAR/PSD-95 interactions on chronic inflammatory pain behaviors. We constructed a fusion peptide, Tat-PSD-95 PDZ2, comprising the second PDZ domain of PSD-95, to disrupt specifically NMDARs/PSD-95 protein interactions. Western blot analysis showed that Tat-PSD-95 PDZ2 intraperitoneally injected into mice was delivered intracellularly into neurons in the CNS. By in vitro and in vivo binding assays, we found that the Tat-PSD-95 PDZ2 dose dependently inhibited the interactions between NMDARs and PSD-95. Furthermore, behavioral testing showed that mice given Tat-PSD-95 PDZ2 exhibited significantly reduced complete Freund's adjuvant (CFA)-induced chronic inflammatory pain behaviors compared to the vehicle-treated group. Our results indicate that by disrupting NMDAR/PSD-95 protein interactions, the cell-permeable fusion peptide Tat-PSD-95 PDZ2 provides a new target and approach for chronic inflammatory pain therapy.

• Authors: Feng Tao, Qingning Su, Roger A Johns
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 16 Issue 11 Pg. 1776-82 (Nov 2008) ISSN: 1525-0024 [Electronic] United States
• PMID: 18781143 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Gene Products, tat
• Nerve Tissue Proteins
• Peptides
• Receptors, N-Methyl-D-Aspartate
• Recombinant Fusion Proteins
• postsynaptic density proteins

Topics

• Animals
• Behavior, Animal (drug effects)
• Cell Membrane Permeability
• Cells, Cultured
• Chronic Disease
• Gene Products, tat (genetics)
• Inflammation (drug therapy, metabolism)
• Injections, Intraperitoneal
• Injections, Spinal
• Male
• Mice
• Mice, Inbred C57BL
• Nerve Tissue Proteins (genetics)
• Neurons (metabolism)
• PDZ Domains
• Pain (drug therapy, metabolism)
• Pain Measurement
• Peptides (genetics, metabolism, therapeutic use)
• Receptors, N-Methyl-D-Aspartate (metabolism)
• Recombinant Fusion Proteins (genetics, metabolism, therapeutic use)
• Spinal Cord (metabolism)
• Synapses (metabolism)