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


ABSTRACT: 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.

SUBMITTER: Liu XJ 

PROVIDER: S-EPMC3616027 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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

Liu Xue Jun XJ   Gingrich Jeffrey R JR   Vargas-Caballero Mariana M   Dong Yi Na YN   Sengar Ameet A   Beggs Simon S   Wang Szu-Han SH   Ding Hoi Ki HK   Frankland Paul W PW   Salter Michael W MW  

Nature medicine 20081116 12


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 t  ...[more]

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