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

Nature Medicine volume 14, pages 1325–1332 (2008)Cite this article

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.

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Figure 1: Src40–49Tat suppresses the Src-NMDAR interaction in vitro and in vivo.
Figure 2: Src40–49Tat suppresses formalin-induced behaviors in rats with i.v.
Figure 3: Src40–49Tat disrupts Src association with ND2 and with NMDAR and prevents the formalin-induced increase in tyrosine phosphorylation of NR2B in spinal cord dorsal horn.
Figure 4: Src40–49Tat reverses CFA-induced thermal and mechanical hypersensitivity.
Figure 5: The effect of Src40–49Tat on formalin-induced behavior is occluded in Src−/− mice.
Figure 6: The effect of Src40–49Tat on PNI-induced tactile and cold hypersensitivity.

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Acknowledgements

This work is supported by grants from the Canadian Institutes of Health Research (CIHR; grant number MT-12682), the Neuroscience Canada Brain Repair Program and its partner the Ontario Neurotrauma Foundation through the Brain Repair Program, and the Krembil Foundation (all to M.W.S.). M.W.S. is an International Research Scholar of the Howard Hughes Medical Institute and holds a Canada Research Chair (Tier I) in Neuroplasticity and Pain. X.J.L. is a CIHR & Ronald Melzack Pain Research Award recipient and a fellow of the Canadian Arthritis Network, as well as of the Pain: Molecules to Community Strategic Training Initiative in Health Research of CIHR. M.V.-C. is an International Fellow of the Wellcome Trust UK. Src knockout mice were obtained as gift from B.F. Boyce, University of Rochester Medical Center. We thank S. Singhroy and D. Wong for technical support and T. Trang and J. Hicks for helpful comments on the manuscript.

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Authors and Affiliations

  1. Program in Neurosciences & Mental Health, the Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, M5G 1X8, Ontario, Canada

    Xue Jun Liu, Jeffrey R Gingrich, Mariana Vargas-Caballero, Yi Na Dong, Ameet Sengar, Simon Beggs, Szu-Han Wang, Hoi Ki Ding, Paul W Frankland & Michael W Salter

  2. Department of Physiology, University of Toronto, 555 University Avenue, Toronto, M5G 1X8, Ontario, Canada

    Xue Jun Liu, Jeffrey R Gingrich, Mariana Vargas-Caballero, Yi Na Dong, Ameet Sengar, Simon Beggs, Szu-Han Wang, Hoi Ki Ding, Paul W Frankland & Michael W Salter

  3. University of Toronto Centre for the Study of Pain, University of Toronto, 555 University Avenue, Toronto, M5G 1X8, Ontario, Canada

    Xue Jun Liu, Yi Na Dong, Simon Beggs & Michael W Salter

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Contributions

X.J.L. designed the project, conducted most of the experiments, analyzed the data and wrote the manuscript. J.R.G. and Y.N.D. performed the in vitro binding assays. M.V.-C. performed the electrophysiological recordings. A.S. carried out the Src kinase assay. S.B. conducted the experiments on CFA-induced mechanical sensitization. S.-H.W. and H.K.D. conducted the learning and memory studies. P.W.F. designed and analyzed the learning and memory studies. M.W.S. conceived the study, analyzed data, supervised the overall project and wrote the manuscript.

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Correspondence to Michael W Salter.

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M.W.S. is a shareholder in a company that has been assigned the rights to the intellectual property that has been developed from the work described in this manuscript.

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Liu, X., Gingrich, J., Vargas-Caballero, M. et al. Treatment of inflammatory and neuropathic pain by uncoupling Src from the NMDA receptor complex. Nat Med 14, 1325–1332 (2008). https://doi.org/10.1038/nm.1883

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