US EPA

1313589 

Journal Article 

Treatment of inflammatory and neuropathic pain by uncoupling Src from the NMDA receptor complex 

Liu, XJ; Gingrich, JR; Vargas-Caballero, M; Dong, YN; Sengar, A; Beggs, S; Wang, SH; Ding, HK; Frankland, PW; Salter, MW 

2008 

1 

Nature Medicine
ISSN: 1078-8956
EISSN: 1546-170X 

14 

12 

1325-1332 

English 

19011637 

10.1038/nm.1883 

http://dx.doi.org/10.1038/nm.1883
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Chronic pain hypersensitivity depends on N-methyl-D-aspartate receptors (NMDARs). However, clinical use of NMDAR blockers is limited by side effects resulting from suppression of the physiological functions of these receptors. Here we report a means to suppress pain hypersensitivity without blocking NMDARs, but rather by inhibiting the binding of a key enhancer of NMDAR function, the protein tyrosine kinase Src. We show that a peptide consisting of amino acids 40-49 of Src fused to the protein transduction domain of the HIV Tat protein (Src40-49Tat) prevented pain behaviors induced by intraplantar formalin and reversed pain hypersensitivity produced by intraplantar injection of complete Freund's adjuvant or by peripheral nerve injury. Src40-49Tat had no effect on basal sensory thresholds, acute nociceptive responses or cardiovascular, respiratory, locomotor or cognitive functions. Thus, through targeting of Src-mediated enhancement of NMDARs, inflammatory and neuropathic pain are suppressed without the deleterious consequences of directly blocking NMDARs, an approach that may be of broad relevance to managing chronic pain.