期刊
PAIN
卷 153, 期 5, 页码 1042-1053出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1016/j.pain.2012.02.006
关键词
Spinal nerve ligation; SIRP alpha 1; SHP2; PSD-95; NMDA; NR2B; NSC-87877
资金
- National Science Council of Taiwan [NSC 97-2320-B-040-008-MY3, 98-2320-B-040-006-MY3, NSC 99-2320-B-039-036]
- China Medical University [CMU99-S-19, CMU99-lab, DMR-100-160]
The fact that neuropathic pain mechanisms are not well understood is a major impediment in the development of effective clinical treatments. We examined whether the interaction between signal regulatory protein alpha 1 (SIRP alpha 1) and Src homology-2 domain-containing protein tyrosine phosphatase 2 (SHP2), and the downstream spinal SHP2/postsynaptic density 95 (PSD-95)/N-methyl-D-aspartate receptor NR2B subunit signaling cascade play a role in neuropathic pain. Following spinal nerve ligation (L5), we assessed tactile allodynia using the von Frey filament test and analyzed dorsal horn samples (L4-5) by Western blotting, reverse transcription polymerase chain reaction, coimmunoprecipitation, and immunofluorescence. Nerve ligation induced allodynia, SIRP alpha 1, SHP2, phosphorylated SHP2 (pSHP2), and phosphorylated NR2B (pNR2B) expression, and SHP2-PSD-95, pSHP2-PSD-95, PSD-95-NR2B, and PSD-95-pNR2B coimmunoprecipitation in the ipsilateral dorsal horn. In allodynic rats, injury-induced SHP2 immunoreactivity was localized in the ipsilateral dorsal horn neurons and coincident with PSD-95 and NR2B immunoreactivity. SIRP alpha 1 silencing using small interfering RNA (siRNA; 1, 3, or 5 mu g/rat for 7 days) prevented injury-induced allodynia and the associated changes in protein expression, phosphorylation, and coimmunoprecipitation. Intrathecal administration of NSC-87877 (an SHP2 antagonist; 1, 10, or 100 mu M/rat) and SIRP alpha 1-neutralizing antibodies (1, 10, or 30 mu g/rat) suppressed spinal nerve ligation-induced allodynia, spinal SHP2 and NR2B phosphorylation, and SHP2/phosphorylated SHP2-PSD-95 and PSD-95-NR2B/phosphorylated NR2B coprecipitation. SHP2 siRNA led to similar effects as the NSC-87877 and SIRP alpha 1 antibody treatments, except it prevented the allodynia-associated spinal SHP2 expression. In conclusion, our results suggest that a spinal SIRP alpha 1-SHP2 interaction exists that subsequently triggers SHP2/PSD-95/NR2B signaling, thereby playing a role in neuropathic pain development. (C) 2012 International Association for the Study of Pain. Published by Elsevier B. V. All rights reserved.
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