Article abstract
Nature Medicine 14, 1325 - 1332 (2008)
Published online: 16 November 2008 | doi:10.1038/nm.1883
Treatment of inflammatory and neuropathic pain by uncoupling Src from the NMDA receptor complex
Xue Jun Liu1,2,3, Jeffrey R Gingrich1,2, Mariana Vargas-Caballero1,2, Yi Na Dong1,2,3, Ameet Sengar1,2, Simon Beggs1,2,3, Szu-Han Wang1,2, Hoi Ki Ding1,2, Paul W Frankland1,2 & Michael W Salter1,2,3
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.
- Program in Neurosciences & Mental Health, the Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.
- Department of Physiology, University of Toronto, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.
- University of Toronto Centre for the Study of Pain, University of Toronto, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.
Correspondence to: Michael W Salter1,2,3 e-mail: Mike.salter@utoronto.ca
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