Cell-permeable peptide Tat-PSD-95 PDZ2 inhibits chronic inflammatory pain behaviors in mice.
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.
Tao
Feng
F
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ftao1@jhmi.edu
Su
Qingning
Q
Johns
Roger A
RA
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
D015696:Gene Products, tat; D009419:Nerve Tissue Proteins; D010455:Peptides; D016194:Receptors, N-Methyl-D-Aspartate; D011993:Recombinant Fusion Proteins; C033652:postsynaptic density proteins
J Neurosci. 2002 Jul 1;22(13):5423-31
12097494
Annu Rev Cell Dev Biol. 1995;11:417-40
8689564
Methods. 2001 Jul;24(3):247-56
11403574
Nature. 1993 Jan 7;361(6407):31-9
8421494
Cell. 1996 Mar 8;84(5):757-67
8625413
Brain Res. 1992 Dec 11;598(1-2):271-8
1362520
Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7058-61
11416187
Pain. 2003 Dec;106(3):411-417
14659524
Nature. 1995 Nov 23;378(6555):383-6
7477374
Neuroreport. 2001 Oct 29;12(15):3251-5
11711866
Pain. 1992 Sep;50(3):331-344
1454389
J Biol Chem. 2003 Sep 19;278(38):36669-75
12853458
Eur J Pharmacol. 1980 Oct 17;67(2-3):313-6
6893963
Curr Opin Biotechnol. 2002 Feb;13(1):52-6
11849958
J Biol Chem. 1999 Sep 24;274(39):27467-73
10488080
J Neurosci. 1997 Oct 1;17(19):7339-50
9295380
Neuroscience. 2003;120(3):847-54
12895524
Neuroscience. 2004;128(2):421-30
15350652
J Neurosci. 1996 Dec 1;16(23):7407-15
8922396
Nat Neurosci. 2001 Feb;4(2):164-9
11175877
Neuroreport. 2000 Jan 17;11(1):49-55
10683828
Pain. 1983 Jun;16(2):109-110
6877845
Pain. 1994 Dec;59(3):345-352
7708408
Science. 2002 Oct 25;298(5594):846-50
12399596
Trends Pharmacol Sci. 2003 May;24(5):216-8
12767717
J Neurosci. 2007 Sep 12;27(37):9901-15
17855605
Neuroscience. 2003;117(3):731-9
12617977
Neuroscience. 2000;98(2):201-6
10854750
Science. 1995 Sep 22;269(5231):1737-40
7569905