title: 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.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ftao1@jhmi.edu
authors.forename: Feng
authors.initials: F
authors.lastname: Tao
authors.forename: Qingning
authors.initials: Q
authors.lastname: Su
authors.forename: Roger A
authors.initials: RA
authors.lastname: Johns
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D002908:Chronic Disease; D015696:Gene Products, tat / Q000235:genetics*; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D054731:PDZ Domains; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D010147:Pain Measurement; D010455:Peptides / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D013116:Spinal Cord / Q000378:metabolism; D013569:Synapses / Q000378:metabolism
chemical_list: D015696:Gene Products, tat; D009419:Nerve Tissue Proteins; D010455:Peptides; D016194:Receptors, N-Methyl-D-Aspartate; D011993:Recombinant Fusion Proteins; C033652:postsynaptic density proteins
references.citation: J Neurosci. 2002 Jul 1;22(13):5423-31
references.pmid: 12097494
references.citation: Annu Rev Cell Dev Biol. 1995;11:417-40
references.pmid: 8689564
references.citation: Methods. 2001 Jul;24(3):247-56
references.pmid: 11403574
references.citation: Nature. 1993 Jan 7;361(6407):31-9
references.pmid: 8421494
references.citation: Cell. 1996 Mar 8;84(5):757-67
references.pmid: 8625413
references.citation: Brain Res. 1992 Dec 11;598(1-2):271-8
references.pmid: 1362520
references.citation: Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7058-61
references.pmid: 11416187
references.citation: Pain. 2003 Dec;106(3):411-417
references.pmid: 14659524
references.citation: Nature. 1995 Nov 23;378(6555):383-6
references.pmid: 7477374
references.citation: Neuroreport. 2001 Oct 29;12(15):3251-5
references.pmid: 11711866
references.citation: Pain. 1992 Sep;50(3):331-344
references.pmid: 1454389
references.citation: J Biol Chem. 2003 Sep 19;278(38):36669-75
references.pmid: 12853458
references.citation: Eur J Pharmacol. 1980 Oct 17;67(2-3):313-6
references.pmid: 6893963
references.citation: Curr Opin Biotechnol. 2002 Feb;13(1):52-6
references.pmid: 11849958
references.citation: J Biol Chem. 1999 Sep 24;274(39):27467-73
references.pmid: 10488080
references.citation: J Neurosci. 1997 Oct 1;17(19):7339-50
references.pmid: 9295380
references.citation: Neuroscience. 2003;120(3):847-54
references.pmid: 12895524
references.citation: Neuroscience. 2004;128(2):421-30
references.pmid: 15350652
references.citation: J Neurosci. 1996 Dec 1;16(23):7407-15
references.pmid: 8922396
references.citation: Nat Neurosci. 2001 Feb;4(2):164-9
references.pmid: 11175877
references.citation: Neuroreport. 2000 Jan 17;11(1):49-55
references.pmid: 10683828
references.citation: Pain. 1983 Jun;16(2):109-110
references.pmid: 6877845
references.citation: Pain. 1994 Dec;59(3):345-352
references.pmid: 7708408
references.citation: Science. 2002 Oct 25;298(5594):846-50
references.pmid: 12399596
references.citation: Trends Pharmacol Sci. 2003 May;24(5):216-8
references.pmid: 12767717
references.citation: J Neurosci. 2007 Sep 12;27(37):9901-15
references.pmid: 17855605
references.citation: Neuroscience. 2003;117(3):731-9
references.pmid: 12617977
references.citation: Neuroscience. 2000;98(2):201-6
references.pmid: 10854750
references.citation: Science. 1995 Sep 22;269(5231):1737-40
references.pmid: 7569905