Treatment of inflammatory and neuropathic pain by uncoupling Src from the NMDA receptor complex.
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.
Liu
Xue Jun
XJ
Program in Neurosciences & Mental Health, the Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
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
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D005557:Formaldehyde / Q000494:pharmacology; D015696:Gene Products, tat / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D007858:Learning / Q000187:drug effects; D051379:Mice; D009422:Nervous System Diseases / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000627:therapeutic use; D011485:Protein Binding; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
D015696:Gene Products, tat; D010455:Peptides; D016194:Receptors, N-Methyl-D-Aspartate; D005557:Formaldehyde; D019061:src-Family Kinases